Gastrointestinal Physiology

Gastrointestinal Physiology
(4) GI SECRETION Salivary Secretion Gastric Secretion Pancreatic Secretion Bile Secretion by the Liver Secretions of the Small Intestine Secretions of the Large Intestine secretory glands subserve two primary functions: First, digestive enzymes are secreted in most areas of the alimentary tract, from the mouth to the distal end of the ileum. Second, mucous glands, from the mouth to the anus, provide mucus for lubrication and protection of all parts of the alimentary tract. 1

SECRETORY GL ANDS IN THE DIGESTIVE TRACT
Goblet cells in digestive epithelium Lubrication of surface • Crypts of Lieberkühn Enzyme secreting cells • Tubular glands Oxyntic or Parietal cells (acid production) Peptic or Chief cells (pepsinogen) •Complex glands Salivary, pancreas, liver

a. Structure of the salivary glands b. Formation of saliva
1. Salivary Secretion a. Structure of the salivary glands b. Formation of saliva c. Regulation of salivary secretion Salivary secretion Typically around 1.0 L per day secreted into the mouth. Functions of saliva include initial digestion of starch by a-amylase, initial digestion of triglycerides by lingual lipase, lubrication of ingested food by mucus and protection of the mouth and esophagus by dilution and buffering of ingested foods.

a. Structure of the salivary glands
serous Three major salivary glands: Parotid glands Submandibular glands Sublingual glands mixed serous + mucous

It initiates and maintains salivation, and produces large amounts of watery saliva containing enzymes.

- The acinar cells secrete the initial saliva.
b. Formation of saliva Step 1 - The acinar cells secrete the initial saliva. - The initial saliva is isotonic. - It has the same electrolyte composition as plasma. Step 2 - The ductal cells modify the initial saliva. - Absorption of Na+, CI- > secretion of K+ and HCO3- - The final saliva is hypotonic.

c. Regulation of salivary secretion
Salivary secretion is exclusively under neural control. Both PSNS and SNS stimulate saliva production. PSNS is primary. Conditioning, food, thought, and nausea etc. also stimulate salivary secretion. Dehydration, fear, and sleep inhibit salivary secretion. Primary controller of salivation, large amount of watery saliva containing enzymes PSNS: SNS: Saliva production is unique in that it is increased by both the parasympathetic and sympathetic activity. Parasympathetic activity is more important. PSNS – CN VII (Facial) and IX (Glossopharyngeal) – pterygopalatine, submandibular and otic ganglia – postganglionic fibers end at muscarinic synapses on target cells (IP3/Ca++ 2nd messenger system). PSNS stimulation increases production of saliva by increasing the transport processes of the acinar and ductal cells and by causing vasodilation. Anticholinergic drugs (e.g., atropine) inhibit the production of saliva and cause dry mouth. SNS – Preganglionic fibers from T1-T3 – Superior Cervical Ganglion = postganglionics end at b- and to a much lesser extent a- receptors. b-receptors are coupled to Gs (increased adenylyl cyclase activity and increaed cAMP). SNS stimulation promotes secretion of a low volume viscous saliva. Saliva production is increased (via activation of the parasympathetic nervous system) by food in the mouth, smells, conditioned reflexes, and nausea. Saliva production is decreased (via inhibition of the parasympathetic nervous system) by sleep, dehydration, fear, and anticholinergic drugs. Small volume of saliva, thick with mucus Because sympathetic stimulation accompanies frightening or stressful situations, the mouth may feel dry at such times.

Summary of Salivary Secretion
Characteristics of saliva secretion: high volume (approx. 1 L/day) high K+ and HCO3- concentrations low Na+ and Cl- concentrations hypotonicity The composition of saliva varies with flow rate(next slide) pH of 6.0 – 7.0 Functions of saliva: First, the flow of saliva itself helps wash away pathogenic bacteria as well as food particles that provide their metabolic support. Second, saliva contains several factors that destroy bacteria. One of these is thorcyanate ions and another is several proteolytic enzymes—most important, lysozyme—that (a) attack the bacteria, (b) aid the thiocyante ions in entering the bacteria where these ions in turn become bactericidal, and (c) digest food particles, thus helping further to remove the bacterial metabolic support. Third, saliva often contains significant amounts of protein antibodies that can destroy oral bacteria, including some that cause dental caries. In the absence of salivation, oral tissues often become ulcerated and otherwise infected, and caries of the teeth can become rampant. lubrication Protection thiocyanate ions, proteolytic enzymes (lysozyme), IgA etc. α-amylase, lingual lipase Kallikrein cleaves kininogen to produce bradykinin (a strong vasodilator, accounts for high salivary blood flow)

The composition of saliva varies with flow rate

THE DIGESTIVE SYSTEM Motility Chewing occurs in the mouth
Swallowing initiates primary peristalsis in the esophagus Stretch of the esophageal wall initiates secondary peristalsis Chewing occurs in the mouth • Chewing is a mechanical digestive process that tears and grinds food into pieces small enough to be swallowed as a bolus • Chewing mixes food with saliva, thereby lubricating the bolus so that it can be swallowed easily • Chewing has both voluntary and involuntary reflex components • The small intestine reflexively slows gastric (stomach) emptying to allow for neutralizing, enzymatic digestion, and absorption of its contents Swallowing initiates primary peristalsis in the esophagus • The only function of the esophagus is to move the bolus from the pharynx (throat) to the stomach • The esophagus moves its contents via peristalsis • Swallowing begins voluntarily but is completed by reflexive (involuntary) primary peristalsis controlled by the swallowing center in the brain stem • The sequence of events in swallowing is as follows: 1. The soft palate rises to close off nasopharynx and prevent bolus from rising into the nasal cavity 2. The tongue retracts to force the bolus into the oropharynx 3. The larynx elevates and the glottis closes 4. The epiglottis covers the glottis 5. The pharyngeal muscles contract and the UES relaxes to allow the bolus to move from the oropharynx into the upper esophagus 6. Primary peristalsis begins and both the LES and stomach relax 7. The bolus moves into stomach and LES closes • The larger the size of the bolus, the more force generated by peristalsis in the esophagus • It takes approximately 9 seconds for a typical bolus to move from the esophagus to the stomach; liquids, like water, take about 1 second to travel down the esophagus Motility in esophagus : Primary and secondary peristalsis. Function of peristalsis is to Propel a bolus of food to stomach.

Clinical correlaton- -Peptic Ulcer.
-Gastroesophageal reflux disease(GERD) -Achalasia- Chagas disease Barium swallow showing bird's beak“ or "rat's tail" appearance in achalasia.

2. Gastric Secretion a. Structure and cell types of the gastric mucosa b. HCL secretion c. Pepsinogen secretion and activation d. Intrinsic factor secretion

Stomach Motility After A Meal
1. Fasting state 2. Meal enters stomach Food bolus receptive relaxation accommodation Vago-vagal reflex MMC * (90 mins) Gastric motility 1. Receptive relaxation to facilitate the entry of food into the stomach, regulated by a vagovagal reflex. Mechanism neither cholinergic or adrenergic 2. Accommodation in response to gastric filling without causing a rise in intragastric pressure. Vagovagal reflex, enteric nervous system mediated. 3. Slow Sustained contractions in proximal stomach designed to press food into distal stomach 4. Contractions of distal stomach serve to grind the food (trituration) and to mix it with gastric juice. Powerful propulsive contractile waves called “antral systole” at the rate of 3-4 per min. propel the luminal contents to the partially closed pylorus. No particle >2m.m leaves the stomach in the immediate postprandial period. 5. Retropulsion - Food is forcefully reflected back from pyloric sphincter into the stomach 4. Antral systole 3. Peristalsis begins ↑ gastric pressure retropulsion * migrating myoelectric complexes

a. Structure and cell types of the gastric mucosa
Oxyntic glands-cardia,fundus and body(80%) surface epithelium mucous neck cells (mostly mucus but also pepsinogen) peptic or chief cells (pepsinogen) parietal or oxyntic cells (HCl and intrinsic factor) paracrine cells (histamine) Pyloric glands(20%) mucous cells (pepsinogen, mucus) G cells (gastrin) The cardia, fundus and body of the stomach comprise the oxyntic gland area (roughly the proximal 80% of the stomach). The major exocrine secretions are all derived from this region. The pyloric gland area is the major source of gastric hormones and comprises the remaining 20% of the stomach. Gastric secretion Gastric mucosal cells secrete GASTRIC JUICE. The four major components in gastric juice are H+ Cl- (HCl), pepsinogen, intrinsic factor and mucus. Intrinsic factor is necessary for absorption of dietary Vitamin B12 in the terminal ileum.

Gastric pit The stomach mucosa consists of pits and glands. The surface mucosa and the pits are lined by mucus cells. The oxyntic glands project downwards and are composed of oxyntic (parietal) cells which secrete HCl and intrinsic factor and peptic (chief) cells secreting pepsinogen. In pyloric glands the cell types are G-cells, secreting gastrin, D-cells secreting somatostatin, and mucus cells. Between the pit and gland is a narrow neck region, consisting of mucus cells. A stem cell is also present in this area. When the stem cell divides, one of the daughter cells remains to become the next stem cell, the other goes on to divide many times, with cells migrating both upwards and downwards to differentiate into the different cell types present. This explains why gastric epithelium is able to rapidly regenerate following injuries that are restricted to the epithelial cell layer – a process called RESTITUTION. [ Enterochromaffin-like (ECL)] histamine

(in gastric venous blood)
b. HCI secretion K+ channel Omeprazole (-) Alkaline tide (in gastric venous blood) Mechanism of gastric H+ secretion Parietal cells secrete HCl into the lumen of the stomach and, concurrently, absorb HCO3- into the bloodstream. In parietal cells, CO2 and H2O are converted to H+ and HCO3-, catalyzed by carbonic anhydrase. The H+ is secreted into the lumen of the stomach by the H+/K+ pump (H+-K+ ATPase). Because Cl- is secreted along with H+, the secretion product of the parietal cells is HCl. The drug omeprazole is useful in the treatment of ulcer disease because it inhibits the H+-K+ ATPase and blocks H+ secretion. The HCO3- produced in the cells is absorbed into the bloodstream in exchange for Cl- (Cl-/HCO3- exchange). As HCO3- is added to the venous blood, the pH rises ("alkaline tide"). Eventually, this HCO3- will be secreted back into the lumen of the GI tract in the pancreatic secretions to neutralize H+ in the small intestine. If vomiting occurs and there is no H+ to neutralize in the small intestine, then arterial blood becomes alkaline (metabolic alkalosis) because of the HCO3- added to it by the parietal cells (relative buffer excess in ECF fluids). Figure 8-7 Mechanism of HCl secretion by gastric parietal cells. ATP, Adenosine triphosphate.

Summary of HCI Secretion
Intracellular fluid: Carbonic anhydrase Apical membrane H+-K+ ATPase, inhibited by omeprazole CI- channel Basolateral membrane Cl-—HCO3- exchanger alkline tide Net secretion of HCl, net absorption of HCO3-

Release of histamine by gastrin is a major pathway via
The oxyntic (parietal) cell has receptors for gastrin, acetylcholine and histamine. Each individual agonist is able to stimulate acid secretion. Gastrin and Ach stimulate secretion via an increase in intracellular Ca2+. Histamine causes an increase in cAMP. Locally produced prostaglandin E2, reduces cAMP production. An important aspect of histamine action is the potentiation of Ach and gastrin. The histamine involved in acid secretion comes from enterochromaffin-like (ECL) cells, which are the main paracrine signalling cells in the oxyntic gland area. Both gastrin and Ach stimulate ECL cells to release histamine. Release of histamine by gastrin is a major pathway via which gastrin stimulates acid production. This explains why histamine receptor antagonists (H2 is the receptor on oxyntic cells) are effective at reducing gastric acid production. In the interdigestive state, gastric secretion continues at about 15% of maximal, producing the characteristic low pH of the stomach contents at rest. Release of histamine by gastrin is a major pathway via which gastrin stimulates acid production.

Stimulation Of Acid Production During The Cephalic Phase
Conditioned reflexes sight, smell, taste hypoglycemia etc. Vagus nerve Gastrin + Ach = ECL cell to give histamine release G-cell Ach The cephalic phase is mediated by the vagus nerve. The thought of a meal is sufficient to increase acid production. Chemoreceptors and mechanoreceptors in the tongue, buccal and nasal cavity signal the smell and taste of food during chewing and swallowing. Afferent signals pass up the vagus nerve to the vagal nucleus and down efferent vagal fibers to the stomach. Hypoglycemia is also a stimulus for gastric acid secretion via the CNS-ENS axis. There are two ways in which acid production is stimulated during the cephalic phase. The most important is direct release of Ach by nerve terminals on oxyntic cells. The second mechanism involves release of gastrin. Post-ganglionic vagal efferents ending on G-cells release GASTRIN RELEASING PEPTIDE (GRP) as a neurotransmitter, causing gastrin secretion into the blood. At the same time cholinergic vagal efferents end on antral D cells to inhibit somatostatin secretion. This is necessary because somatostatin normally inhibits the release of gastrin via a paracrine mechanism. Despite these cephalic phase stimuli, gastrin secretion is suppressed when intragastric pH is below 3. Therefore, until food enters the stomach and buffers gastric acid, the pH remains low and not much gastrin secretion occurs until the gastric phase begins. GRP parietal cell gastrin

Stimulation Of Acid Production During The Gastric Phase
ENS ANS Vagus nerve Stimulation Of Acid Production During The Gastric Phase Parietal cell Ach G-cell GRP Stretch Acid secretion resulting from gastric phase stimuli accounts for at least 50% of the response to a meal. Entry of food into the stomach neutralizes acidity and can cause pH to rise as high as 6, which allows gastrin secretion to occur. Distension of the stomach is a key stimulus during the gastric phase. Long loop vago-vagal reflexes operate, where the efferent pathway is very similar to that described for the cephalic phase. Short reflexes within the ENS also support the same activation mechanism, since cutting the vagus does not abolish neurally mediated acid production. Breakdown products of protein digestion stimulate G-cell activity directly, causing gastrin secretion. Amino acids gastrin

Negative Feedback Of Acid Secretion By H+ Has Several Mechanisms.
Lumen H+ - Antrum - PGE2 - P Lumen H+ - SST ECL + D G Feedback Inhibition of Gastric Acid Production The inhibition of gastric acid secretion is important for two reasons. 1. Secretion of acid is only important during the digestion of food. 2. Excess acid causes mucosal damage. About 1 hour after ingestion of a meal, gastric acid secretion is maximal. The buffering capacity of the meal is saturated and gastric pH starts to fall. By now a significant percentage of the meal will have entered the small intestine. Once pH in the stomach falls below 3, the G-cell is directly inhibited by H + . This is one of the most important negative feedback mechanisms operating to control acid production. Falling gastric pH also stimulates D-cells to release somatostatin which inhibits gastrin release. Low pH also directly inhibits oxyntic cells. D - - SST SST Body

Feedback Inhibition From The Small Intestine:
Enterogastrones CCK Secretin GIP Peptide YY Neurotensin SST VIP (via ENS) - In addition to negative feedback through acidic gastric pH, several hormonal mechanisms operate to inhibit both acid production and gastric motility. The presence of acid, fatty acids and hyperosmotic fluids in the small intestine all stimulate release of hormones from small intestinal endocrine cells that inhibit gastric function. These are known collectively as ENTEROGASTRONES. Secretin is released in response to acidity in the duodenum and is the primary enterogastrone. GIP is released in response glucose and to fatty acids and at high levels can inhibit the oxyntic cell. CCK is released in response to protein and fat digestion products. Its major role as an enterogastrone is to reduce motility rather than acid production Enteric reflexes are also triggered by the presence of chyme in the small intestine that reduce gastric acid secretion and motility. Acid, hyperosmolarity, fats, proteins Diagram source unknown

 Vagus nerve innervates parietal cells  Ach is the neurotransmitter
STIMULATION OF GASTRIC H+ SECRETION Vagal stimulation Direct path:  Vagus nerve innervates parietal cells  Ach is the neurotransmitter Indirect path:  Vagus nerve innervates G cells gastrin H+ secretion  GRP is the neurotransmitter Stimulation of gastric H+ secretion PSNS (Vagus) ACh stimulates H+ secretion by activating muscarinic receptors on the parietal cell membrane. The second messenger for ACh is IP3 and increased intracellular [Ca2+]. Atropine, a muscarinic blocking agent, inhibits H+ secretion by blocking the stimulatory effect of ACh. Atropine is most useful in combination with H2 receptor-blocking drugs because of the potentiating effect of ACh on histamine action.

2. Gastrin 3. Histamine STIMULATION OF GASTRIC H+ SECRETION
is released in response to eating a meal. the second messenger for gastrin on the parietal cell is IP3/Ca2+ 3. Histamine is released from enterochromaffin-like (ECL) cells in the gastric mucosa and diffuse to the nearby parietal cells. stimulates H+ secretion by activating H2 receptor on the parietal cell membrane. Histamine Released from mast cells in the gastric mucosa and diffuses to the parietal cells. Histamine stimulates H+ secretion by activating H2 receptors on parietal cell membranes. The second messenger for histamine at H2 receptors is cyclic AMP. H2 receptor-blocking drugs such as cimetidine (famotidine, ranitidine) inhibit H+ secretion by blocking the stimulatory effect of histamine. Gastrin Released in response to eating a meal (small peptides and amino acids, distention of the stomach, vagal stimulation). The receptor for gastrin on the parietal cell has not been identified. The second messenger for gastrin on the parietal cell has not been identified either, but clearly it is different from those for ACh and histamine since their actions are additive with those of gastrin. The three interact in a complex potentiation relationship. H2 receptor-blocking drugs such as cimetidine (famotidine, ranitidine) inhibit H+ secretion by blocking the stimulatory effect of histamine.

4. Potentiating effects of Ach, histamine, and gastrin on H+ secretion
STIMULATION OF GASTRIC H+ SECRETION 4. Potentiating effects of Ach, histamine, and gastrin on H+ secretion Potentiation occurs when the response to stimultaneous administration of two stimulants is greater than the sum of response to either agent given alone. Histamine potentiates the actions of Ach and gastrin; Ach potentiates the actions of histamine and gastrin. Potentiating effects of ACh, histamine, and gastrin on H + secretion Potentiation occurs when the response to simultaneous administration of two stimulants is greater than the sum of responses to either agent given alone. Thus, low concentrations of stimulants given together can produce maximal effects (drugs which block one of the three may also produce more inhibition than predicted by the absence of the one factor blocked alone). The potentiation of gastric H + secretion is explained, in part, by each agent having a different mechanism of action on the parietal cell, which are inter-related at the final pathway of acid release. Histamine potentiates the actions of ACh and gastrin in stimulating H+ secretion. Thus, H2 receptor blockers (e.g., cimetidine) are effective because they block not only the action of histamine but also histamine's potentiating effects on ACh and gastrin. ACh potentiates the actions of histamine and gastrin in stimulating H+ secretion. Thus, muscarinic receptor blockers such as atropine not only block the action of ACh, but they also block the potentiating effects of ACh on histamine and gastrin.

Low pH (< 3) in the stomach
INHIBITION OF GASTRIC H+ SECRETION Low pH (< 3) in the stomach inhibits gastrin secretion by negative feedback, thus inhibits further H+ secretion. 2. Somatostatin direct pathway: indirect pathway: 3. Prostaglandins via Gi protein  cAMP  Inhibition of gastric H+ secretion Negative feedback mechanisms inhibit the secretion of H+ by the parietal cells when the pH of the stomach is low. Low pH (< 3.0) in the stomach inhibits gastrin secretion and thereby inhibits H+ secretion. Acidity directly inhibits G-cell gastrin release and also stimulates the release of somatostatin and GIP, both of which inhibit gastrin release. After a meal is ingested, H+ secretion is turned on by the mechanisms discussed previously. Once the stomach is emptied, further H + secretion lowers the pH of the stomach contents (the presence of food previously buffered the secreted acid). inhibit histamine release from ECL cells inhibit gastrin release from G cells

c. Pepsinogen secretion and activation
This inactive precursor to pepsin is secreted by chief cells and mucous cells. Low pH converts pepsinogen to pepsin and begins the process of protein digestion. Vagal stimulation and H+ secretion are stimuli for pepsinogen release. H+ pepsinogen pepsin

Gastric Mucosal Protection
At the stomach mucosal surface, the presence of a layer of mucus is one barrier mechanism, preventing erosion of the mucosa. It is effective at neutralizing acid due to the HCO 3 - secreted into it by surface mucus cells. HCO becomes trapped in the mucus gel. Placement of a pH-sensitive electrode into the mucus layer shows how effective it normally is, since pH at the apical cell surface is 7.0, when the luminal pH is 1.5. Since the oxyntic glands themselves do not have an appreciable mucus barrier, other mechanisms must operate to protect the stomach. The TIGHT JUNCTIONS between cells is probably the most important factor, preventing back diffusion of H + .

Agents disrupting the gastric mucosal barrier may be ingested (ethanol), refluxed (bile salts) or given as drugs (aspirin/indomethacin). Disruption of the barrier is associated with gastritis and if prolonged with ulcers. The mechanism of disruption is not clear, but in the case of alcohols, weak acids and detergents is probably related to their physical chemistry (e.g. detergents dissolve lipid membranes). Non-steroidal anti-inflammatory drugs inhibit prostaglandin production. PGE’s are important physiological antagonists to histamine in the stomach. PGE’s also normally promote bicarbonate secretion into the mucus barrier and increase gastric blood flow. Thus PGE’s are generally protective and their inhibition promotes gastric damage. HELICOBACTER PYLORI infection is a major risk factor for gastritis, peptic ulcer disease and gastric carcinoma. Unlike most GI pathogens, which are short-lived, it remains in the tract for years/decades, causing chronic inflammation. H. Pylori is able to survive in the stomach due to UREASE activity. This enzyme converts urea into ammonia. The NH 3 is able to buffer H + , producing NH 4 , allowing the bacterium to survive. The large amounts of ammonium released damage the gastric mucosal barrier. H.Pylori is also motile, allowing it to “hang on” during antral systole. When the gastric barrier is damaged H leaks into the mucosa in exchange for Na . H overcomes the buffering capacity and pH defense of cells, causing cell death. As deeper layers of the GI wall are involved, mast cells release histamine, causing a localized fall in capillary blood flow due to interstitial edema. This leads to local ischemia, which promotes ulceration. If damage is severe, bleeding also occurs into the lumen of the stomach. Erosions in the gastric mucosa which do not breach the muscularis mucosa are re-epithelialized very rapidly by restitution. Erosions extending beyond the muscularis mucosa lead to the events above becoming established and require a more complex healing process.

Antral gastritis with erosions
Normal Gastric Antrum o

GASTRIC AND PEPTIC ULCERS
Erosions of the gastric and duodenal mucosa produced by action of HCl Results from Excessive acid secretion (i.e., Zollinger-Ellison syndrome - ↑ secretion of gastrin) ↓ protective properties of the mucosal barrier (i.e., Helicobacter pylori -bacterium that resides in GI tract that liquefy and penetrate the barrier) Treatment: Antibiotics, proton pump inhibitors, inhibitors of gastric secretion, selective vagotomy Gastritis Bacterial infection of gastric mucosa Histamine released by tissue damage and inflammation stimulate further acid secretion Ingested irritant substances (i.e., alcohol, NSAID), smoking

d. Intrinsic factor secretion
Intrinsic factor (IF): a mucoprotein, secreted by parietal cells along with HCl. Vitamin B12 requires IF to be absorbed. IF combines with vitamin B12 to form a complex that is absorbed in the terminal ileum. Vitamin B12 is essential for maturation of red blood cells. The absence of IF prevent absorption of B12 and leads to abnormal production of RBCs, which causes pernicioius anemia. . IF-B12 Intrinsic Factor secretion This mucoprotein necessary for absorption of B12 is secreted by parietal cells. Absence of intrinsic factor causes pernicious anemia. B12 must be injected to bypass the absorption deficiency. The Schilling test is a clinical test for the presence of intrinsic factor.

A Summary of Gastric Secretion
Gastric mucosal epithelium is made entirely of secretary cells including exocrine, endocrine, and paracrine cells. Gastric juice: Thick alkaline mucus by surface epithelium Thin watery mucus by neck cells HCl by parietal cells Pepsinogen by chief cells Intrinsic factor by parietal cells ~ 1.5 L is secreted per day, pH: 0.8 – 3.5

3. Pancreatic Secretion a. Structure of the pancreatic exocrine glands
b. Formation of pancreatic secretion c. Regulation of pancreatic secretion Most chemical digestion and absorption occur in the small intestine- • The secretions that initiate chemical digestion in the small intestine come from the exocrine (acinar) pancreas Pancreatic secretions The exocrine pancreas secretes approximately 1 L of fluid into the duodenum per day. The 2 main components are an aqueous fluid containing HCO3- to neutralize the contents of the duodenum (gastric H+) and an enzymatic component containing enzymes essential for digestion of proteins, carbohydrates and fats.

Structure of the pancreatic exocrine glands
The exocrine pancreas is organized much like the salivary glands with acini (lined with acinar epithelial cells) leading to ducts (lined with ductal epithelial cells). Special ductal epithelial cells extend back into the acini (centroacinar cells). PSNS stimulates secretion, while SNS inhibits secretion.

b. Formation of pancreatic secretion
amylase lipases proteases Acinar cells enzymes trypsinogen chymotrypsinogen procarboxypeptidase proelastase Exocrine pancreas aqueous alkaline secretion (HCO3-) Ductal cells The exocrine pancreas produces two types of pancreatic juice: o enzyme-rich pancreatic juice (stimulated by CCK) o bicarbonate-rich pancreatic juice (stimulated by secretin) • Exocrine pancreas secretions are delivered through the hepatopancreatic sphincter (a.k.a. sphincter of Oddi) into the duodenum via the pancreatic duct • Exocrine pancreatic secretions include the following enzymes: o Proteases (a.k.a. proteolytic enzymes) o Amylase o Lipase • Pancreatic proteases (in zymogenic or inactive form) include trypsinogen, chymotrypsinogen, procarboxypeptidase • Enterokinase in the intestinal cell membranes, converts (activates) trypsinogen into trypsin • Once produced, trypsin activates more trypsinogen in a positive feedback mechanism • Duct cells secrete bicarbonate into the duodenum to neutralize acid from the stomach; this produces an optimal pH environment for pancreatic digestive enzymes to function in • The endocrine pancreas secretes two antagonistic hormones: o Insulin – regulates the absorptive state o Glucagon – regulates the post-absorptive state Trypsin inhibitor is secreted by acini to prevent activation of trypsin. If the pancreas is damaged, large quantities of pancreatic secretion pools in the damaged areas, and trypsin inhibitor is overwhelmed. Pancreatic secretions can digest the pancreas, which is known as acute pancreatitis.

Enzymes often secreted in an inactive form, and activated near the wall of gastrointestinal tract - so food is broken down where it can be transported into the blood stream.

Formation of pancreatic secretion
The acinus and centroacinar cells Acinar cells secrete enzymes, while centroacinar cells produce a small volume of initial pancreatic juice, which is mostly Na+ and Cl-. Pancreatic amylase and lipase are secreted in the active forms, while the rest of pancreatic enzymes (proteases) are secreted as inactive pro-enzymes. Enzymes or proenzymes are produced on RER and stored in zymogen granules until a stimulus (CCK or PSNS) triggers release. Ductal cells Ductal cells modify the initial pancreatic juice by secreting HCO3- and absorbing Cl- via a Cl-/HCO3- exchange carrier in the luminal membrane of the ductal cells. Final pancreatic secretion has Na+ and K+ concentrations similar to plasma, but HCO3- and Cl- concentrations vary with flow rates. At lowest flow rates, HCO3- and Cl- concentrations are also similar to plasma, but as flow rate increases, the HCO3-/Cl- exchanger is stimulated and HCO3- rises as Cl- falls. Because the pancreatic ducts are permeable to water, H2O moves into the lumen to make the pancreatic juice isosmotic to plasma (increasing the volume). Figure Mechanism of pancreatic secretion. The enzymatic component is produced by acinar cells, and the aqueous component is produced by centroacinar and ductal cells. ATP, Adenosine triphosphate.

c. Regulation of pancreatic secretion
Because pancreatic secretion has two distinct components, an aqueous HCO3- rich component needed for neutralization of duodenal contents, and an enzyme component needed for digestion of carbohydrates, fats and proteins, it seems logical that the two components are regulated separately. The aqueous/HCO3- component is stimulated primarily by the presence of H+ in the duodenum, while the enzyme component is stimulated primarily by the presence of peptides/amino acids, carbohydrates and fatty acids. Acinar cells have receptors for ACh (muscarinic) and CCK, and enzyme secretion is therefore stimulated by PSNS and rising CCK concentrations (CCK release from I-cells is promoted by amino acids, peptides and fatty acids – the most potent CCK secretagogues are phenylalanine, tryptophan and methionine). Vagovagal reflexes based on stomach stretch reception and chemoreception increase PSNS to the pancreas. CCK, secreted by I cells of the duodenum in response to small peptides, amino acids, and fatty acids in the lumen, acts on the pancreatic acinar cells to increase enzyme secretion (amylase, lipase, protease). The second messenger for CCK is IP3 and increased intracellular [Ca2+]. ACh (via vagovagal reflexes), released in response to H+, small peptides, amino acids, and fatty acids in the duodenal lumen, stimulates enzyme secretion by the acinar cells, and, like CCK, potentiates the effect of secretin on HCO3- secretion. Ductal cells have receptors for ACh, CCK and secretin (secretin is the most important regulator of ductal cells). Secretin, secreted by S cells of the duodenum in response to H+ in the lumen, acts on the pancreatic ductal cells to increase HCO3-/Cl- exchange. Thus, when H+ is delivered from the stomach to the duodenum, secretin is released, which causes secretion of HCO3- into the duodenal lumen to neutralize the H+. The second messenger for secretin is cyclic AMP and the effects of secretin are potentiated by CCK and ACh. Figure Regulation of pancreatic secretion. ACh, Acetylcholine; cAMP, cyclic adenosine monophosphate; CCK, cholecystokinin; IP3, inositol 1,4,5-triphosphate.

The Cl channel is encoded by the cystic fibrosis gene product CFTR
The Cl channel is encoded by the cystic fibrosis gene product CFTR. Thus patients with cystic fibrosis, who lack a functional Cl channel have defective duct transport. The ducts get clogged with precipitated enzymes and mucus and the pancreas undergoes a fibrosis (hence the name of the disease). The physiological significance of this model is twofold, first the HCO3 delivered to the duodenal lumen neutralizes gastric acid and allows the digestive enzymes to operate at their pH optimum, close to neutral. Second, H+ which are produced in the duct cells when HCO is generated for secretion leave via Na-H exchange into the blood. The net effect is to neutralize the alkaline tide in the blood that was generated by gastric acid secretion.

A Summary of Pancreatic Secretion
HCO3- : neutralize the contents from the stomach Enzymes: digestion of protein, carbohydrate, and fats Pancreatic juice is characterized by: - high volume (1 L/day) - virtually the same Na+ and K+ concentrations as plasma - much higher HCO3- concentration than plasma - much lower Cl- concentration than plasma - isotonicity - pancreatic lipase, amylase, and proteases - pH of 8.0 – 8.3

a. Overview of the biliary system b. Composition and functions of bile
4. Bile Secretion a. Overview of the biliary system b. Composition and functions of bile c. Formation of bile and function of the gallbladder d. Regulation of bile excretion from the gallbladder e. Enterohepatic circulation of bile salts f. Clinical correlation One of the many functions of the liver is to secrete bile, normally between 600 and 1000 ml/day. Bile serves two important functions: First, bile plays an important role in fat digestion and absorption, not because of any enzymes in the bile that cause fat digestion, but because bile acids in the bile do two things: (1) they help to emulsify the large fat particles of the food into many minute particles, the surface of which can then be attacked by lipase enzymes secreted in pancreatic juice, and (2) they aid in absorption of the digested fat end products through the intestinal mucosal membrane. Second, bile serves as a means for excretion of several important waste products from the blood. These include especially bilirubin, an end product of hemoglobin destruction, and excesses of cholesterol

Hepatocytes secrete bile into the bile canaliculi and bile ductules.

a. Overview of the biliary system
Physiologic Anatomy of Biliary SecretionThe hepatocytes, bile canaliculi, intrahepatic bile ducts, extrahepatic bile ducts, gall bladder and common bile ducts make up the biliary system. Bile is secreted by hepatocytes into bile canaliculi, passes through intrahepatic bile ducts to the right and left bile ducts, to the common hepatic duct, which joins the cystic duct to form the common bile duct. The CBD joins the main pancreatic duct (forming the hepatopancreatic duct) and empties into the 2nd part of the duodenum at the hepatopancreatic ampulla / sphincter (of Oddi). Bile is secreted in two stages by the liver: (1) The initial portion is secreted by the principal functional cells of the liver, the hepatocytes; this initial secretion contains large amounts of bile acids, cholesterol, and other organic constituents. It is secreted into minute bile canaliculi that originate between the hepatic cells (2) Next, the bile flows in the canaliculi toward the interlobular septa, where the canaliculi empty into terminal bile ducts and then into progressively larger ducts, finally reaching the hepatic duct and common bile duct. From these the bile either empties directly into the duodenum or is diverted for minutes up to several hours through the cystic duct into the gallbladder, second portion of liver secretion is added to the initial bile.This additional secretion is a watery solution of sodium and bicarbonate ions secreted by secretory epithelial cells that line the ductules and ducts. Figure Secretion and enterohepatic circulation of bile salts. Light blue arrows show the path of bile flow; yellow arrows show the movement of ions and water. CCK, Cholecystokinin.

b. Composition and functions of bile
Composition Functions Bile salts including bile acids (50%) Phospholipids (Lecithin, 40%) Bile pigments (2%): bilirubin Cholesterol (4%) Electrolytes (Na+, K+, Ca++, Cl-, HCO3-) Water aids in fat digestion aids in fat absorption emulsifying fat eliminating metabolic wastes Composition of bile Bile contains bile acids (50%), phospholipids (40%), cholesterol (4%), and bile pigments such as bilirubin(2%) in an aqueous solution containing electrolytes. Bile acids/salts are amphipathic molecules, having both hydrophilic and hydrophobic portions. In aqueous solution, bile salts orient themselves around droplets of lipid and keep the lipid dispersed in solution (emulsified), and aid in the intestinal digestion and absorption of lipids by emulsifying and solubilizing them in micelles. Bilirubin is the yellow pigment in bile. Bilirubin is the product of RES degradation of hemoglobin (RBC turnover). Bilirubin is extracted from blood by hepatocytes and conjugated with glucuronide. The conjugated bilirubin is then secreted into bile. Bilirubin in the intestines has three fates: 1) reabsorption into blood (there is a normal circulating amount of conjugated bilirubin), 2) excretion in feces and 3) conversion by intestinal flora to urobilinogen Ions and water in bile are secreted by epithelial cells lining the bile ducts. amphipathic molecules

c. Formation of bile and functions of the gallbladder
Hepatocytes secrete: Bile ducts secrete: watery solution, Na+, HCO3- organic components (bile acids, cholesterol, bilirubin) Bile Gallbladder stores bile, concentrates bile, empties bile. Watery components are reabsorbed by the gallbladder mucosa. Organic constituents are highly concentrated (5 – 20 fold). Formation of bile Bile is produced continuously by hepatocytes, drains into the hepatic ducts and is stored in the gallbladder for release in response to a meal. Choleretic agents increase the formation of bile. The rate-limiting enzyme in bile acid synthesis is cholesterol 7-a-hydroxylase, which is inhibited by high levels of bile acids. Bile is formed by the following process: Primary bile acids (cholic acid and chenodeoxycholic acid) are synthesized by hepatocytes. In the intestine, bacteria convert a portion of each of the primary bile acids to secondary bile acids (deoxycholic acid and lithocholic acid).

is released in response to small peptides and fatty acids in
d. Regulation of bile excretion from the gallbladder CCK is released in response to small peptides and fatty acids in the duodenum. tells the gallbladder that fats need to be emulsified and absorbed – in other words, bile is needed. causes contraction of the gallbladder smooth muscle. causes relaxation of the sphincter of Oddi. ACh also causes contraction of the gallbladder.

e. Enterohepatic circulation of bile salts
diffuse 94% Synthesis of bile acids occurs, as needed, to replace bile acids that are excreted in the feces rather than recirculated back to the liver. The total bile acid pool returning to the liver determines the need for synthesis. If bile acids are not absorbed in the distal ileum (drugs such as cholestyramine or other “anion exchange resins” which promote bile salt excretion with feces, or ileal resection, then bile acid synthesis must occur. Bile secretion and gallbladder The hepatocytes, bile canaliculi, intrahepatic bile ducts, extrahepatic bile ducts, gall bladder and common bile ducts make up the biliary system. Bile is secreted by hepatocytes into bile canaliculi, passes through intrahepatic bile ducts to the right and left bile ducts, to the common hepatic duct, which joins the cystic duct to form the common bile duct. The CBD joins the main pancreatic duct (forming the hepatopancreatic duct) and empties into the 2nd part of the duodenum at the hepatopancreatic ampulla / sphincter (of Oddi). When chyme reaches the small intestine, CCK is released, and gall bladder smooth muscle contracts as the sphinter relaxes, ejecting gall bladder bile into the duodenum. CCK is released in response to small peptides and fatty acids in the duodenum. CCK “tells” the gallbladder that fats need to be emulsified and absorbed –in other words, bile is needed. CCK causes contraction of the gallbladder smooth muscle and relaxation of the sphincter of the hepatopancreatic ampulla (Oddi). ACh also causes contraction of the gallbladder. In the interdigestive period, the hepatopancreatic sphincter is closed and bile flows into the gall bladder, where water and electrolytes are removed (bile organic components are concentrated). The gallbladder concentrates the bile by reabsorbing Na+, Cl- and HCO3-. H2O is reabsorbed isosmotically. Bile mixes with chyme emulsifying fats and forming micelles (solubilizing fat and increasing surface area for digestion and absorption). When chyme reaches the terminal ileum, most bile acids are reabsorbed into the portal circulation and returned to the liver for resecretion into bile. The terminal ileum contains a mechanism for secondary active transport of conjugated bile acids with Na + , which recirculates bile acids to the liver. Therefore, most of the bile acids are not recirculated to the liver until they reach the terminal ileum. This ensures that bile acids will be present for maximal absorption of fats throughout the upper small intestine. Ileal resection causes steatorrhea: Bile acids lost in feces are not recirculated to the liver, and the bile acid pool becomes depleted. active transport Na+-bile salt cotransporter Figure Secretion and enterohepatic circulation of bile salts.

Gallstone formation: precipitated cholesterol
f. Clinical correlation Gallstone formation: precipitated cholesterol high-fat diet, prone to the development of gallstones too much absorption of water from bile inflammation of epithelium Ileal resection IF-Vitamin B12 complex cannot be absorbed. Steatorrhea: recirculation of bile via enterohepatic circulation is reduced. Most secreted bile acids are lost in feces. Oil droplets in the stool. Diarrhea: bile acids  cAMP-dependent Cl- secretion in colonic epithelium, Na+ and water follow Cl- into the lumen

GALLSTONES Mechanisms of stones formation
 absorption of water in the gallbladder  absorption of bile acids ( solubility of cholesterol)  cholesterol concentration (fatty diet) Inflammation of the epithelium Mechanisms  the risk of stones formation Secretion of H+ by the mucosa (acidification of bile)   Ca 2+ precipitation Absorption of large amounts (about 50%) of Ca 2+ Release of the inhibitors of Ca2+ and cholesterol precipitation Secretion of water and electrolytes during digestion which intermittently dilute the gallbladder content Combination of cholesterol with lecithin and bile salts (micelles)   water solubility of cholesterol Contractions prevent accumulation of microcrystal 2 types of stones: Cholesterol stones Calcium bicarbonate stones

5. Secretions of the Small Intestine
Brunner’s glands An extensive array of compound mucus glands Located in the wall of duodenum. Secrete mucus and HCO3- Crypts of Lieberkühn Located over the entire surface of the small intestine. The small intestine secretes fluid, mucus, and hormones • The small intestine secretes watery mucus and hormones • Mucus, secreted by abundant epithelial goblet cells, protects the intestinal mucosa from auto-digestion by proteases and acid • Intestinal glands or crypts (of Lieberkuhn) secrete water and electrolytes to combine with mucus to form intestinal juice • Intestinal epithelial cells contain brush border enzymes in their microvilli cell membranes; these enzymes complete the chemical digestion of foodstuffs Goblet cell: secrete mucus Enterocytes: secrete and absorb water and electrolytes

6. Secretions of the Large Intestine
The large intestine has many crypts of Lieberkühn and secrets an alkline mucus solution containing bicarbonate and K+. The sole function of mucus is protection. It protects the large intestine wall from damage by acids formed in feces from attacking the intestinal wall. Acid and mechanical stimulation, mediated by both long and short reflexes, increase the secretion of mucus. the wall of the large intestine Acid passage of feces Neural reflexes (long and short)  Mucus secretion a mucus layer lining the wall

Case: Zollinger-Ellison Syndrome
Description of Case: A 52-year-old man visits his physician complaining of abdominal pain, nausea, loss of appetite, frequent belching, and diarrhea. The man reports that his pain is worse at night and is sometimes relieved by eating food or taking antacids containing HCO3-. GI endoscopy reveals an ulcer in the duodenal bulb. Stool samples are positive for blood and fat. His serum gastrin level is measured and found to be markedly elevated. A CT scan reveals a 1.5 cm mass in the head of the pancreas. The man is referred to a surgeon. While awaiting surgery, the man is treated with the drug omeprazole, which inhibits H+ secretion by gastric parietal cells. During a laparotomy, a pancreatic tumor is located and excised. After surgery, the man’s symptoms diminish, and subsequent endoscopy shows that the duodenal ulcer has healed. Explanation of Case: All of the man’s symptoms and clinical manifestations are caused, directly or indirectly, by a gastrin-secreting tumor of the pancreas. In Zollinger-Ellison syndrome, the tumor secretes large amounts of gastrin into the circulation. The target cell for gastrin is the gastric parietal cell, where it stimulates H+ secretion. The physiologic source of gastrin, the gastric G cells, are under negative feedback control. Thus, normally, gastrin secretion and H+ secretion are inhibited when the gastric contents are acidified (i.e., when no more H+ is needed). In Zollinger-Ellison syndrome, however, this negative feedback control mechanism does not operate: gastrin secretion by the tumor is not inhibited when the gastric contents are acidified. Therefore, gastrin secretion continues unabated, as does H+ secretion by the parietal cells.

Case: Zollinger-Ellison Syndrome, explanation (cont.)
The man’s diarrhea is caused by the large volume of fluid delivered from the stomach (stimulated by gastrin) to the small intestine; the volume is so great that it overwhelms the capacity of the intestine to absorb it. The presence of fat in the stool (steatorrhea) is abnormal, since mechanisms in the small intestine normally ensure that dietary fat is completely absorbed. Steatorrhea is present in Zollinger-Ellison syndrome for two reasons. 1) The first reason is that excess H+ is delivered from the stomach to the small intestine and overwhelms the buffering ability of HCO3--containing pancreatic juices. The duodenal contents remain at acidic pH rather than being neutralized, and the acidic pH inactivates pancreatic lipase. When pancreatic lipase is inactivated, it cannot digest dietary triglycerides to monoglycerides and fatty acids. Undigested triglycerides are not absorbed by intestinal epithelial cells, and thus, they are excreted in the stool. 2) The second reason for steatorrhea is that the acidity of the duodenal contents damages the intestinal mucosa (evidenced by the duodenal ulcer) and reduces the microvillar surface area for absorption. Treatment: While the man is awaiting surgery to remove the gastrin-secreting tumor, he is treated with omeprazole, which directly blocks the H+-K+-ATPase in the apical membrane of gastric parietal cells. This ATPase is responsible for gastric H+ secretion. The drug is expected to reduce H+ secretion and decrease the H+ load to the duodenum. Later, the gastrin-secreting tumor is surgically removed.

Case: Resection of the Ileum
Description of Case: A 36-year-old woman has 75% of her ileum resected following a perforation caused by severe Crohn’s disease (chronic inflammatory disease of the intestine). Her postsurgical management included monthly injections of vitamin B12. After surgery, she experienced diarrhea and noted oil droplets in her stool. Her physician prescribed the drug cholestyramine to control her diarrhea, but she continues to have steatorrhea. Explanation of Case: The woman’s severe Crohn’s disease caused an intestinal perforation, which necessitated a subtotal ileectomy, removal of the terminal portion of the small intestine. Consequences of removing the ileum include decreased recirculation of bile acids to the liver and decreased reabsorption of the intrinsic factor-vitamin B12 complex. In normal persons with an intact ileum, 95% of the bile acids secreted in bile are returned to the liver, via the enterohepatic circulation, rather than being excreted in feces. This recirculation decreases the demand on the liver for the synthesis of new bile acids. In a patient who has had an ileectomy, most of the secreted bile acids are lost in feces, increasing the demand for synthesis of new bile acids. The liver is unable to keep pace with the demand, causing a decrease in the total bile acid pool. Because the pool is decreased, inadequate quantities of bile acids are secreted into the small intestine, and both emulsification of dietary lipids for digestion and micelle formation for absorption of lipids are compromised. As a result, dietary lipids are excreted in feces, seen as oil droplets in the stool (steatorrhea). This patient has lost another important function of the ileum, the absorption of vitamin B12. Normally, the ileum is the site of absorption of the intrinsic factor-vitamin B12 complex. Intrinsic factor is secreted by gastric parietal cells, forms a stable complex with dietary vitamin B12, and the complex then is absorbed in the ileum. The patient cannot absorb vitamin B12 and must receive monthly injections, bypassing the intestinal absorptive pathway. The woman’s diarrhea is caused, in part, by high concentrations of bile acids in the lumen of the colon (because they are not recirculated). Bile acids stimulate cAMP-dependent Cl- secretion in colonic epithelial cells. When Cl- secretion is stimulated, Na+ and water follow Cl- into the lumen, producing a secretory diarrhea (sometimes called bile acid diarrhea). Treatment: The drug cholestyramine, used to treat bile acid diarrhea, binds bile acids in the colon. In bound form, the bile acids do not stimulate Cl- secretion or cause secretory diarrhea. However, the woman will continue to have steatorrhea.

Contraction of the gallbladder is correctly described by which of the following statements?
a. It is inhibited by a fat-rich meal b. It is inhibited by the presence of amino acids in the duodenum c. It is stimulated by atropine d. It occurs in response to cholecystokinin e. It occurs simultaneously with the contraction of the sphincter of Oddi D.

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