1. Move down the gut sections and review the secretions of ...people.musc.edu/~decristc/Adv Patho/Unit 9 GI... · Adv Pathophysiology Unit 9: GI Page 1 of 29 File: advpatho_unit9_2secrete.pdf

Adv Pathophysiology Unit 9: GI Page 1 of 29

File: advpatho_unit9_2secrete.pdf Source: C. DeCristofaro, MD

Learning objectives for this file: 1. Move down the gut sections and review the secretions of each area and their function 2. Know the different cell types and their secretions 3. Review bile secretion and function 4. Review neurologic and hormonal control of intestinal secretions



SECRETORY FUNCTIONS: Secretory glands line the gut to produce both digestive enzymes and mucus. A. FUNCTIONAL ANATOMY: 1. Specialized structures & cells: specialized structures (e.g. glands, villi, Crypts of Lieberkahn) specialized cells (e.g. goblet, mucus, columnar microvilli, peptic, oxyntic)

2. Accessory Organs of Digestion:

Exocrine pancreas: (NOT the endocrine pancreas) the endocrine pancreas releases its product to the bloodstream (e.g. insulin, glucagon) the exocrine pancreas sends its products locally to gut for digestion (digestive

enzymes). Liver:

processes nutrients from portal vein makes bile emulsifiers other functions (e.g. detoxification, synthesis)

Gallbladder:

Stores and releases bile acids to aid digestion.



3. Release of Secretions:

reflex release o mechanical – presence of food stimulates mechanoreceptors (stretch, distension

of gut) o chemical – presence of food stimulates chemoreceptors

Nervous system o parasympathetic activity increases secretions o sympathetic activity increases secretion but causes vasoconstriction so reduced

blood supply winds up reducing secretions overall Gut hormones

o multiple gastric peptide hormones locally produced in the gut, so there is feedback control from one part of the gut to another.

o Part of this feedback control affects secretions. 4. Gut Mucus:

water, electrolytes, proteoglycans (complex sugar-proteins), and bicarbonate lubricates, coats, causes fecal compaction, & the bicarbonate acts as an acid buffer resistant to digestion & contains bicarbonate to neutralize stomach acid. Total volume = 6,700 ml daily. different pH depending on local gut content (e.g. gastric pH = 2, bile = pH 7.8).



B. SALIVA (SALIVARY GLAND SECRETIONS): Glandular Macroscopic anatomy: Parotid, submandibular, sublingual numerous small buccal glands SUBMANDIBULAR provides the most (70%)



Microscopic anatomy: the acinus cells line a circular space leading to drainage duct (plural = acini) Types of Salivary Secretions: Serous type has ptyalin (starch digestion enzyme) & lingual lipase (starts fat breakdown). Mucus type has mucin (for lubrication). Different mouth glands secrete different types (serous and/or mucus) Chemical composition & functions of saliva: Necessary for taste: necessary to dissolve chemicals in water so taste buds can work. Cleansing:

o Flow of saliva cleans the mouth, 800-1500 ml of saliva produced daily, o Very little production at night (clean your teeth/tongue before sleeping!)

pH is protective: pH 7.0 (neutral) to slightly alkalotic (pH 8.0) (cleanses & destroy bacteria) Mucins:

o lubricate food & protect oral mucosa o help compact food to produce the bolus

Digestive enzymes: o start the digestive process o secretory zymogen granules are released from acinar cells into the ducts

Protection & Immunologic: o contain IgA, lysozyme (attacks bacterial cell walls) o lactoferrin (binds iron & is bacteriostatic o proline-rich proteins (bind toxins & protect tooth enamel) o proteolytic enzymes to destroy bacteria



Stimulation and Reflex Salivation – sensory & motor arms: Afferent stimuli:

o taste & tactile afferent stimuli to appetite area of CNS anterior 2/3 of tongue, Facial Nerve (CN VII) chorda tympani superior

salivatory nucleus in Pons and then reflex outflow (see below) posterior 1/3 of tongue, Hypoglossal Nerve (CN IX) nucleus ambiguus in

Medulla o nausea or irritating food (for neutralization) to thalamus & hypothalamus o thinking of food (“cephalic phase” of digestion)

Efferent motor outflow for salivation: o motor outflow to submandibular, sublingual, and parotid glands for saliva secretion o innervated by parasympathetic & sympathetic divisions – oddly enough, BOTH the

sympathetic AND parasympathetic can stimulate salivation (more important is the parasympathetic)

o Parasympathetic: visceral motor outflow to all glands EXCEPT parotid via CN VII via the

submandibular ganglion visceral motor outflow to parotid from CN IX via the otic ganglion

parasympathetic o Sympathetic:

T1-T3 thoracic outflow in the superior cervical ganglion and also to blood vessels of the glands

Facial (CNVII) SENSORY: Superior Salivatory Nucleus (Pons) – TASTE from anterior 2/3 of tongue (Chorda tympani), ear & tympanic membrane sensation

MOTOR: Solitary Nucleus (Pons) – muscles of facial expression & scalp

VISCERAL MOTOR: parasympathetic to all salivatory glands except parotid via submandibular ganglion; lacrimation

Glossopharyngeal (CN IX)

SENSORY: Nucleus ambiguus (Medulla) – TASTE from posterior 1/3 of tongue, internal tympanic membrane sensation

MOTOR: Solitary nucleus (Medulla) – Innervation of pharynx (gag reflex)

VISCERAL MOTOR: Inferior salivatory (Medulla) to parotid gland

REMEMBER excellent websites with CRANIAL NERVE info (hit “next” to see all pages): http://www.meddean.luc.edu/lumen/MedEd/GrossAnatomy/h_n/cn/cn1/table1.htm and http://neuroexam.com/neuroexam/content.php?p=15

http://www.meddean.luc.edu/lumen/MedEd/GrossAnatomy/h_n/cn/cn1/table1.htm

http://neuroexam.com/neuroexam/content.php?p=15



Facial Nerve (CN VII)



Surgical correlate: if a parotidectomy is performed, usually for an impacted stone, sometimes the facial nerve is

removed with it and this can result in postop complications Complications:

o Facial nerve palsy – nerve damage may occur due to bruising (usually the Facial Nerve is held out of the way during surgery); this can occur in 15-20% of cases (in 1% it is permanent)

o Frey’s Syndrome (Gustatory Sweating – after surgery cheek becomes red, flushed and sweaty when eating; nerve supply to the parotid gland re-grows to supply sweat glands of the skin instead of the parotid gland itself



C. ESOPHAGEAL SECRETIONS:

simple mucus glands produce mucoid secretions.

D. GASTRIC (STOMACH) SECRETIONS: 1. GLANDS & CELLS: a variety of specialized glands and cells. Pyloric glands: contain mucus cells & "G" cells mucus cells:

o produce mucus o protect gastric mucosa

G cells: o gastrin produced here

produced in response to vagal activity produced in response to the neuropeptide bombesin

o gastrin goes to bloodstream o Activity:

stimulates peptic cells (pepsinogen production) parietal (oxyntic) cells (HCl production)



Oxyntic (parietal) glands: made up of mucus cells:

o make mucus – function is coating & protecting. peptic (chief) cells:

o make pepsinogen (inactive zymogen) o pepsinogen converted to pepsin in the acid environment of the stomach. o The stimulus for pepsinogen production is both acid in the stomach and the

hormone gastrin (produced by the "G" cells in the pyloric glands of the gastric antrum).

parietal (oxyntic) cells: (NOTE the cells have the SAME name as the GLAND) o Hydrochloric acid production:

HCl acid produced by the proton pump, an H+-Na+ exchange pump. Stimulated by gastrin from the antral "G" cells.

This effect is blocked when the pH < 3.0. Drug correlate: Almost 100% of acid production is blocked by drugs

called "proton pump inhibitors" (PPIs) Also stimulated by histamine due to the H2 receptors located on the

parietal cells Drug correlate: H2 blocker (H2B) drugs can block 80% of acid

production Prostaglandins (PGs) coat the H2 receptor and prevent the

histamine-induced production of acid Drug correlate: synthetic PG drugs block this acid production; NSAID

drugs prevent PG production and protection against excess acid is lost

o Intrinsic factor production: Intrinsic factor is needed to absorb vitamin B12 in the small

intestine. Lack of production leads to pernicious anemia (neurologic as well as

hematologic complications)



2. OTHER STOMACH SECRETIONS: Protective prostaglandins:

are made by the gastric mucosa using the COX-1 enzyme of the arachidonic acid pathway.

They block histamine-induced acid secretion o by interfering with cAMP second messenger activity o and/or by coating the H2 receptor in the stomach – prevents entry of

stimulating histamine onto the receptor o Thus, have a protective role in preventing acid secretion.

NSAID drugs that prevent PG synthesis can cause ulcers o NSAID gastropathy with ulceration and GI bleeding o Note this GI bleeding usually does NOT have symptoms of pain as a warning!!

REMEMBER – REVIEW THE ARACHIDONIC ACID PATHWAY: Cell Membrane Phospholipid or Dietary EFAs (essential Fatty Acids)

Many Many

enzymes enzymes

lipoxygenase “Inflammatory” “Native” cyclooxygenase cyclooxygenase “COX-2” "COX-1"

Arachidonic Acid

Leukotrienes (LTs) – implicated in asthma & allergic rhinitis

Inflammatory Prostaglandins (PGs) – pain -AND- Protective Beneficial capillary vasodilators (PG-I2)

Protective Prostaglandins (PGs) (gastric mucosa, kidney vasculature) – AND - Thromboxanes (TXs) (platelet aggregation)



3. PHASES OF GASTRIC SECRETIONS:

cephalic phase – thinking about food gastric phase – food enters stomach (main stimulus) intestinal phase – duodenal gastrin + amino acid absorption stomach acid production.

Interdigestive Secretions:

mostly mucoid. Emotional stimuli can increase acid & pepsinogen secretion even without food

o Stress peptic ulcer disease, PUD 4. PARASYMPATHETIC NERVOUS SYSTEM ACTIVITY:

Vagal activity (ACh release) and the neuropeptide bombesin o causes gastrin secretion by "G" cells of pyloric glands in antrum of stomach

Gastrin: o causes stimulation of peptic cells to make pepsinogen o stimulates parietal cells to produce HCl acid

5. INTESTINAL INHIBITION OF STOMACH ACTIVITY:

negative feedback from food in small intestine or breakdown products of fat/protein intestinal hormones of secretin, gastric inhibitory peptide (GIP), vasoactive intestinal

polypeptide (VIP), and somatostatin inhibit both gastric secretions & motility this way – if the intestine is full of food and needs more time to digest it, the stomach is

STOPPED from sending more food to the intestine an example of auto-regulation by the enteric system “the gut talks to itself”



See MORE pictures next page… E. PANCREATIC SECRETIONS:

the exocrine pancreas releases digestive juices into the gut the endocrine pancreas releases hormones into the bloodstream 20 cm long, head tucked into duodenal curve, tail touching spleen, behind stomach.

1. Anatomy & Blood Supply: Anatomy:

o head of pancreas is tucked into the “C” curve of the duodenum o the tail of the pancreas heads out towards the spleen (tucked under the liver)

Microscopic Anatomy: o Acini (produce enzymes) pancreatic duct (of Wirsung) o empty into the duodenum at the ampulla of Vater (where the Sphincter of Oddi

controls entry of secretions) Anatomical variants:

o accessory duct (duct of Santorini) branching off pancreatic duct o drain directly into duodenum at a minor duodenal papilla o Clinical correlate: when blocked may cause recurrent pancreatitis

Blood supply: o celiac & mesenteric arteries o venous blood drains the head via the portal vein; body & tail blood drained by splenic

vein. o SIGNIFICANCE:

from the endocrine pancreas, all hormones, such as insulin, FIRST go to the liver before then going to systemic circulation

This immediate effect on the liver has implications for glucose control and lipid metabolism

Clinical correlate – when we give insulin therapy, it isn’t physiologic since the drugs isn’t going to the liver first (as it does in the body)



Note pancreas empties into the Ampulla of Vater



2. Pancreatic Enzymes: Stimulation of enzyme seretion: Acetylcholine (Ach) (parasympathetic vagus) Cholecystokinin (CCK) (duodenum) Proteolytic enzymes: trypsin, chymotrypsin, carboxypolypeptidase, elastases & nucleases. proteolytic enzymes are in the "pro" form (trypsinogen, chymotrypsinogen,

procarboxypolypeptidase). all activated by one main enzyme – trypsin (itself made in "pro" form)

o Trypsinogen is activated by enterokinase (secreted by intestinal mucosa, upon contact with chyme) trypsin.

o Trypsin activates the other proteolytic enzymes. o Trypsin inhibitor is made by the pancreas to prevent activation of trypsinogen in the

pancreas this prevents auto-digestion & pancreatitis

Clinical: o damaged pancreas (alcohol, infection, trauma, blocked duct) can pool large amount of

enzyme and overwhelm the inhibitor o pancreatitis o sequelae of pseudocyst and/or pancreatic insufficiency

Carbohydrate enzymes: pancreatic amylase Fat digestion enzymes: pancreatic lipase, cholesterol esterase, phospholipase Lab: Pancreatitis – elevations of these enzymes (lipase, amylase) 3. Production of Bicarbonate & Water: neutralizes chyme.

Produced by ductal cells. Secretin (from "S" cells, duodenal mucosa)

o stimulates production & secretion of bicarbonate o prolongs the intestinal phase of digestion.



F. SMALL INTESTINE SECRETIONS: 1. Mucus: by Brunner's glands

pH is alkaline production stimulated by both vagal stimulation & tactile stimulation (presence of food).

Duodenal ulcers:

Sympathetic stimulation decreases mucus production factor in etiology of duodenal ulcers 85% OF ALL PEPTIC ULCERS are duodenal.



SEE PICTURES NEXT PAGE …

2. Functional Microanatomy & Specialized Cells: Villi: a villus is a finger-like projection specialized columnar cells with microvilli have increased surface area (SA) better absorption of digested food molecules

bloodstream enzymes are ALSO found on the microvilli Villus cells have lifespan of 5 - 7 days, are sloughed and digested (endogenous protein

source). Cannibals!! Cells of Villus are called Enterocytes:

o columnar cells with microvilli o this area has a brush border with enzymes o this is actually where digestion takes place in the small intestine o these enzymes finish digestion of food into basic building blocks o proteins amino acids, starch/carbohydrate monsaccharide, fats glycerol &

fatty acids o also secrete bicarbonate & water to neutralize the HCl from stomach o Undifferentiated cells move up & replace dying surface cells

Crypts of Lieberkahn: invaginations into the submucosa at the base of the villi, crypt cells migrate upwards and differentiate, to replace lost villus cells.

Goblet cells: secrete mucus



Surface area “trick” in the body and everywhere in nature: ANY time we see that “up and down” winding appearance, it is for more SURFACE AREA

(SA) We’ve seen this in the integument for release of excess heat in the rete pegs of the dermis of

the skin; think of a tree line on a ridge with all that surface area to absorb sunlight Imagine this line pulled out to its full length We can get more surface area compressed into a small area by putting it into this sinusoidal (wavy line) shape.



3. Stimulation of intestinal secretions: Chyme Secretin CCK

4. Hormones secreted by the small intestine: CCK, secretin, gastrin Cholecystokinin (CCK) from "I" cells in duodenal mucosa: (1) slow gastric emptying (2) cause contraction of gallbladder (3) cause receptive relaxation of sphincter of Oddi (4) enhances small intestine motility (5) stimulates pancreatic enzyme secretion (6) dysregulation implicated in eating disorders (satiety dysregulation) Secretin from "S" cells in duodenal mucosa: (1) enhances pancreatic fluid & bile flow by increasing bicarbonate & water secretion of pancreas

& bile ducts (2) This will neutralize the chyme acid of duodenal contents & provides fluid for enzymes & bile

salts to work (3) feedback to stomach to slow gastric emptying, giving small intestine time to work Gastrin from "G" cells in stomach antrum & duodenal mucosa: (1) causes stimulation of peptic cells to make pepsinogen (2) stimulates parietal cells to produce HCl acid



G. LIVER & BILIARY TREE SECRETIONS: liver can regenerate, cells are hepatocytes. Note that the liver has MANY functions!! Multiple Synthetic function: the synthetic function of the liver to MAKE de novo lipoproteins proteins (e.g. coagulation pathway, albumin), cholesterol (basis for all sterol hormones, cell membranes). makes bile Detoxification (first-pass effect) function: Rids the body of old hormones, drugs (nothing lasts forever in the body!) degrade substances that need excretion, converting them to forms that are more easily

excreted.



1. Liver Anatomy: Attachment to body: the remnant of our umbilical vein is called the round ligament, & extends along the falciform

ligament the coronary ligament attaches it to underside of diaphragm. Fibrous cover: called by Glisson's capsule Perihepatitis is inflammation of Glisson’s capsule together with monoarticular arthritis, suggests systemic gonococcal infection



Lobes: divided into LOBES by the falciform ligament, which attaches liver to anterior abdominal wall. The lobes are the left & right lobes (right lobe further divided into caudate & quadrate lobes). Liver lobes divided into lobules, which are cords (plates) of hepatocytes lined with MPS cells (Kupffer cells)



2. Blood supply: Receives lots of blood (25% of cardiac output). Input: Hepatic artery for systemic oxygenated blood Hepatic portal vein (from splanchnic circulation) containing deoxygenated blood with nutrients

from digestive tract. Goes to the liver sinusoids (capillary system) between plates of cells. Output: hepatic vein to IVC back to right heart circulation. Other input: deoxygenated blood carrying products of digestion from gut via the portal vein.

Hepatic portal vein draining intestines



4. Bile: alkaline fluid composed of

salts of bile acids water electrolytes steroid hormones bilirubin cholesterol lecithin (phosphatidyl choline) drugs needing excretion (hepatic biotransformation).

Bile functions: digestive & excretory Emulsifies & transports:

emulsify large fat particles so lipase can attack them also aids in transport & absorption of digested fats & fat soluble vitamins. (More below)

Excretion of bilirubin:

bilirubin from hemoglobin destruction is excreted by liver into bile and lost in feces along with porphyrins, drugs, hormones.



Bile secretion & storage: secreted by hepatocytes to hepatic duct. stored via the cystic duct in the gallbladder. Bile finally sent to small intestine by the common bile duct (fused hepatic & cystic ducts). Enters the small intestine via the ampulla of Vater (same place as pancreatic duct) which is

controlled by a smooth muscle sphincter called the Sphincter of Oddi. Note that this sphincter must relax to receive both the secretions of the exocrine pancreas

and the liver & gallbladder.



Bilirubin excretion: allows body to get rid of breakdown of heme via water-soluble routes of excretion First you have water-insoluble bilirubin (not water soluble):

o Insoluble bilirubin is bound to albumin and sent to the liver via the bloodstream o Lab test for this is indirect bilirubin (on lab tests) o this is also referred to as unconjugated bilirubin since it has NOT been acted upon by

liver enzymes to attach to any organic substance (conjugation reaction) o In order to excrete it via the kidney, it must be made water soluble by the liver

Then the liver creates water-soluble bilirubin: o Hepatocytes separate unconjugated bilirubin from albumin o liver cells conjugate it – uses enzymes to combine it with an organic molecule, called

glucuronate o the bilirubin is now conjugated bilirubin and is water soluble o name of lab test is direct bilirubin

Final excretion since it is now water soluble: o Urinary excretion: Bloodstream kidney urine o Biliary excretion: Bile feces (intestinal excretion)

Secretin (from small intestine) stimulates bile secretion via water/bicarbonate fluid production.



Bile salts (salts of bile acids): MADE FROM CHOLESTEROL

Synthesis: Precursor is cholesterol converted to cholic acid or chenodeoxycholic acid combine with glycine & taurine to form conjugated bile acids combine with electrolyte (Na) to form bile salts. Function: Bile salts are emulsifiers (detergents) & break up large fat globules into smaller fat

globules that our digestive enzymes can now better digest They can also form micelles for better fat & cholesterol absorption into the body

o micelles of bile salts & lecithin make cholesterol soluble to permit absorption from intestinal lumen.

o helps to absorb fat (lipid) nutrients o the micelles allow for better absorption via the intestinal cells (enterocytes)

Enterohepatic circulation:

Bile salts are reabsorbed and resecreted recirculation of bile salts is called the enterohepatic circulation.

Cholesterol absorption due to bile salts in intestine: insoluble in water micelles of bile salts & lecithin make cholesterol soluble to permit absorption from intestinal

lumen.



2. Gallbladder: stores up to 12 hours of bile secretion reabsorbs water + electrolytes to produce a concentrated bile. Gallbladder bile: contains bile salts, lecithin, cholesterol, bilirubin.

Function: Stimulation of smooth muscle of gallbladder & relaxation of sphincter of Oddi CCK from duodenum and/or vagal stimulation causes GB contraction & receptive relaxation of

sphincter of Oddi (which also relaxes when duodenum relaxes) bile empties into duodenum for digestive function. Gallstones and cholecystitis: precipitation of cholesterol into stones is result of abnormal absorption of water & bile salts by

an inflamed gallbladder. may precipitate calcium as well (radio-opaque stones 15% of the time). Mechanism:

o Inflamed gallbladder can precipitate cholesterol into stones as a result of abnormal absorption of water & bile salts by an inflamed gallbladder.

o There is an abnormal balance of bile salts and cholesterol o Pharmacologic treatment: chenodeoxycholic acid bile salts increase, cholesterol

stones are dissolved; less de novo synthesis of cholesterol in the liver occurs, since bile salt balance is restored.

More in case study file Also read: http://www.merckmanuals.com/professional/SearchResults?query=Cholecystitis&icd9=574.3%3b574.4%3b575.0%3b575.11%3b575.12 (cholecystitis)

http://www.merckmanuals.com/professional/SearchResults?query=Cholecystitis&icd9=574.3%3b



H. LARGE INTESTINE (COLON) SECRETIONS:

many crypts of Lieberkahn for mucus production but no villi or enzyme production.

Parasympathetic activity: Via pelvic nerves to distal ½ of large intestine stimulates mucus production, along with

increased motility Mucus is protective (viscid + alkaline), plus an adherent for fecal matter. Irritations (infectious enteritis) cause copious secretions, diarrhea, washing out the irritant. Enteric nervous system: embedded neurons in myenteric plexus release of serotonin (5HT) onto 5HT receptors cause secondary release of other

neurotransmitters responsible for increased motility, secretions, and proper coordination of peristalsis

Serotonin (5-HT) Normalizes Gut Function –Peristalsis & Receptive Relaxation

Enterochromaffin cells release 5-HT

5-HT

Oradmotor neurons(contraction)Ach / SP

5-HT4

Receptors

CaudadMotor neurons(relaxation)VIP / NO

Interneuronsin the

myentericplexus

Sensoryneuron

CGRP

Proximal Segment Distal Segment

Adapted from Grider et al, Gastroenterology1998; 115:370.

Movement ofGut Contents

Coordination of peristalsis with proximal contraction and distal relaxation accomplished by gut neural plexi and endogenous gut hormones

Documents

1. Move down the gut sections and review the secretions of ...people.musc.edu/~decristc/Adv Patho/Unit 9 GI... · Adv Pathophysiology Unit 9: GI Page 1 of 29 File: advpatho_unit9_2secrete.pdf