OVERVIEW

Fat-soluble vitamins

• The fat-soluble vitamins are vitamins A, D, E, and K; they are stored in fat.

Water-soluble vitamins

• The water-soluble vitamins are vitamins B and C; being water-soluble, they are NOT stored. The exception is vitamin B12, which is stored in the liver.

Fat malabsorption

• Fat malabsorption is a key cause of vitamin A, D, E, and K deficiency.
  • Fat malabsorption commonly accompanies celiac disease, cystic fibrosis, pancreatic exocrine insufficiency, biliary obstruction, colitis, and can occur iatrogenically (albeit unintentionally) with laxative abuse via excess mineral oil intake, in particular.
  • Vitamins and minerals serve as coenzymes or hormones in key metabolic pathways, thus we can infer that their disorders lead to metabolic dysregulation of these pathways and dysfunctional assembly of key structural components.
• Vitamin A (retinol) deficiency most notably causes night blindness.
• Vitamin D deficiency most notably causes bone anomalies.
• Vitamin E (tocopherol) deficiency most notably causes anemia.
• Vitamin K deficiency most notably causes coagulopathy.

VITAMIN A (RETINOL, RETINAL, RETINOIC ACID)

Source

• Indicate that it’s found in leafy vegetables (eg, carrots) meats, and dairy products.
• It’s found as carotenoids that are metabolized in the body to active vitamin A where its stored in liver cells.

Clinical presentations

• Indicate that night blindness is a key vitamin A deficiency.
  • To remember this, we draw a set of rod and cone photoreceptors because vitamin A is best known for its role in vision where it’s a key pigment in rods and cones.

• It prevents the epithelia from undergoing squamous metaplasia – a further differentiation into keratinized epithelium.
• Indicate that vitamin A deficiency manifests with ocular keratinization: specify the dry eyes (xerophthalmia), which specifically begins with drying of the cornea (xerosis conjunctivae) from keratinization of the lacrimal and mucus-secreting epithelium.
• Show that, later, the keratin debris builds-up as Bitot spots (small opaque spots), which roughen and destroy the cornea.
• Next, indicate that keratinization (squamous metaplasia) occurs in the mucus-secreting epithelium of the lungs and kidneys and, as well.
• Vitamin A also has additional important metabolic effects, especially in fatty acid metabolism.
• It plays a role in infection control, so indicate that immune deficiency is a consequence of vitamin A deficiency.
  • Thus infectious diarrhea in a newborn can be lethal because it can weaken the host’s immune system when it wastes the newborn’s low supply of vitamin A.

Therapeutics

• Now, consider that vitamin A is used to treat AML: acute promyelocytic leukemia; all-trans retionoic acid induces the ultimate apoptosis of acute promyelocyctic cells.
• More commonly, it’s used to treat acne but can have significant teratogenicity.

Side Effects

• Acutely, it causes:
  • GI upset
  • Visual disturbance
• Chronically it causes:
  • Pseudotumor cerebri, which is a syndrome of pathologic increased intracranial pressure that manifests with headaches and a classic intermittent “rushing” sound.
  • Hepatotoxicity (remember it’s stored in the liver).
  • Alopecia.
  • Arthralgias.

VITAMIN D DEFICIENCY & TOXICITY

Source

• Indicate that, for the most part, humans derive vitamin D in the form of vitamin D3 (cholecalciferol).
  • Vitamin D3 is derived from its endogenous synthesis in the skin from its precursor (7-dehydrocholesterol) in a photochemical reaction that involves solar/artificial ultraviolet light.
• Write that vitamin D2 is the plant form, called ergocalciferol or ergosterol.
• Indicate that the liver stores vitamin D as 25-OH-Vit. D (vitamin D undergoes 25-hydroxylation in the liver.)
  • Note that we use vitamin D without a subscript, here, because the source (D2 vs D3) is unidentified.
• Draw a kidney and indicate that it releases 1-alpha hydroxylase, which fully activates vitamin D into 1-25 dihydroxyvitamin D [1,25(OH)2D] (calcitriol): it is the fully biologically activated form.
  • Vitamin D undergoes 1-alpha-hydroxylation in the kidney.

Note that Vitamin D2 is less bioactive than vitamin D3, so you’ll often see vitamin D3 used in reference to biologically active vitamin D.

Causes of vitamin D deficiency

• Inadequate sunlight exposure
• Malabsorption
• Liver failure
• Renal failure (renal osteodystrophy)

Clinical Presentation

• Indicate that in children, vitamin D deficiency presents as rickets, which manifests with bowing of the legs and shortening of bones because of its impact during bone growth.
• In adults it presents as osteomalacia, which manifests with softening of bones.

Vitamin D Toxicity

• Regarding vitamin D excess, draw an osteoblast and show that vitamin D, along with PTH, is a key stimulus for osteoblast release of RANKL, which promotes osteoclast formation.
• Thus, vitamin D excess promotes bone loss and excess calcium in the blood and urine, which manifests with stupor and coma.

VITAMIN E (TOCOPHEROL/TOCOTRIENOL)

• Draw a RBC and indicate that vitamin E is an antioxidant that protects RBCs and membranes from free radical damage.

Clinical Presentations

Hemolytic Anemia

• Indicate that deficiency of vitamin E manifests with hemolytic anemia.
  Spinocerebellar ataxia
• Draw a cross-section of a spinal cord.
• Indicate that vitamin E deficiency may present with spinocerebellar ataxia and most closely resembles Friedreich’s ataxia – so we draw an axial section of Friedreich’s ataxia, now.
• Vitamin E deficiency presents in late childhood or early teens with symptoms of progressive ataxia and clumsiness, with exam findings of:
  • Large fiber sensory loss
  • Arreflexia with positive Babinski signs
  • Spinocerebellar/cerebellar signs of dysdiadochokinesia and dysarthria
• Note that vitamin E deficiency is often mistaken for B12 deficiency because of the combination of motor and sensory findings but, importantly, in B12 deficiency there is a megaloblastic anemia with hypersegmented neutrophils and elevated serum methylmalonic acid levels – which are NOT present in vitamin E deficiency.

VITAMIN K DEFICIENCY

Source

• Indicate that vitamin K is derived from the diet (especially green, leafy vegetables) and from bacterial production in the proximal intestine.
• Draw a liver and small intestine.
• Show that vitamin K is integral for hepatic synthesis of prothrombin (which is factor II) and factors VII, IX, and X, and also protein C and protein S, which all contain 4-6-gamma-carboxyglutamate residues.
  • Vitamin K (hydroquinone) is necessary for the carboxylation of glutamate residues to form these rare amino acids.

Warfarin & Vitamin K Recycling

• Indicate that vitamin K hydroquinone is oxidized to vitamin K epoxide via vitamin K epoxidase.
• Then, show that the epoxide is reduced back to the hydroquinone in two steps vitamin K quinone as an intermediary.
• Show that warfarin blocks each of these steps: the reduction of the vitamin K epoxide back to vitamin K quinone (via vitamin K epoxide reductase) and also the step back to the hydroquinone (via vitamin K quinone reductase).
  • Thus, warfarin promotes bleeding via inhibition of vitamin K epoxide reduction.
• If there’s enough vitamin K in the diet, this recycling can be deemed irrelevant and the creation of coagulation factors will continue.
• On the contrary, if the quantity of vitamin K present in GI tract is insufficient, or it is not properly absorbed and transported to the liver, thrombin production and clot formation will be impaired and bleeding disorders will ensue.

Vitamin K deficiency syndromes:

• Neonatal hemorrhages occur secondary to sterile intestine and inadequate vitamin K in the breast milk.
  • Vitamin K is present only in very low concentrations in human milk and very little vitamin K actually crosses the placenta from mother to infant, so to prevent vitamin K deficiency in the newborn, intramuscular or oral vitamin K prophylaxis is necessary
  • Newborns are given an injection of vitamin K at birth to prevent vitamin K deficiency.
• Indicate that prolonged antibiotic-use can also wipe-out intestinal bacteria and cause vitamin K deficiency.
• Then, indicate that liver failure is a common cause of vitamin K deficiency because the coagulation factors, themselves, are synthesized in the liver, which commonly accompanies a prolonged PT/INR with normal fibrinogen concentration and normal platelet count.
  • In fact, a tip-off of liver failure is an elevated INR in a patient not already on warfarin.

STARVATION AND PROTEIN-ENERGY MALNUTRITION

• Denote that in kwashiorkor there is malnutrition with severe protein depletion.
• Denote that marasmus refers to malnutrition from generalized calorie deficiency.

Kwashiorkor

• Indicate that the loss of plasma oncotic pressure leads to peripheral edema, which, to some extent masks the visceral wasting, and is associated with:
  • Protuberant belly
  • Edematous feet
  • Fatty liver from loss of apolipoprotein synthesis
  • “Flaky paint” skin appearance so named because it alternates between hyper- to hypo- pigmentation
  • Shiny skin and alopecia

Marasmus

• We show a classic picture of a purely wasted thorax from starvation.
• There’s pure wasting.
• Growth retardation.
• Anemia.

Summary Distinction

• Marasmus patients have an emaciated appearance rather than a swollen appearance because it is typified by a loss of body fat and muscle whereas kwashiorkor results in a loss in plasma oncotic pressure, which produces signs of swelling from edema.

OVERVIEW

Intrinsic control

• The Enteric Nervous System (ENS):
  • Is intrinsic to the GI wall.
  • Runs the length of the GI tract.
  • Primarily coordinates local activity in the digestive tract via two key nerve plexuses:

1. The submucosal plexus (aka Meissner’s plexus)
2. The myenteric plexus (aka Auerbach’s plexus)

Extrinsic control

• Parasympathetic innervation stimulates digestion: it stimulates GI motility and the secretion of hormones and digestive juices.
  • Remember its tagline is “Rest and Digest”.
• Sympathetic nervous system inhibits digestive activity.
  • Remember its tagline is “fight or flight” – neither of which have anything to do with digestion.

INTRINSIC SYSTEM

Anatomy of the digestive tract.

From inside to outside:

• The GI lumen
• The mucosal layer
  • Epithelial layer
  • Lamina propria
  • Muscularis mucosae
• The submucosal layer
  • The submucosal plexus (Meissner’s plexus) lies within the outer portion of this layer.
• The smooth muscle (muscularis externa) layer.
  • The inner, circular layer.
  • The myenteric plexus (Auerbach’s plexus) lies in between the inner, circular and outer, longitudinal layers.
  • The outer, longitudinal layer.

The different orientations of the inner, circular and outer, longitudinal muscle layers allow us to distinguish them.

• The adventitia/serosa layer; it’s serosa within the abdominal cavity.

EXTRINSIC SYSTEM

Parasympathetic nervous system

• Cranial nerve 10 (the vagus nerve) innervates the gut.
  • It innervates the upper 2/3 of the GI tract (ie, the foregut and midgut).
  • It is this wandering nature of the vagus nerve all the way to the gut that give it its name “vagus,” which is Latin for “wandering.”
• Spinal neurons S2 to S4 of the intermediolateral cell column of the sacral spinal cord innervate pelvic splanchnic nerves, which innervate the gut.
  • They innervate the lower 1/3 of the GI tract (ie, the hindgut).

Sympathetic nervous system

• Originates from the T5 to L2 neurons of the intermediolateral cell column.
• Abdominopelvic splanchnic nerves innervate prevertebral ganglia, which innervate the GI tract.

INTERACTION OF THE EXTRINSIC AND INTRINSIC SYSTEMS

Extrinsic neuronal input innervates the myenteric plexus

• Show the extrinsic neuronal input converge on a neuron in the myenteric plexus.
• Show it then innervate a neighboring neuron,
• which extends into the submucosa to innervate a neuron of the submucosal plexus,
• which then innervates the muscular layer of the mucosa to activate or inhibit GI motility.

PHARMACOLOGICAL CORRELATIONS

Neurotransmitters

• Acetylcholine INcreases GI motility (it’s the major parasympathetic neurotransmitter – the “D” in the “SLUDS” acronym stands for defecation or diarrhea.
• Norepinephrine DEcreases GI motility (it’s the major postganglionic sympathetic neurotransmitter).
• Opioid peptides DEcrease GI motility.
• Serotonin INcreases GI motility – serotonin syndrome causes diarrhea.

Drugs

• Amitriptyline decreases circulating acetylcholine, so it decreases GI motility.
• Donepezil increases circulating acetylcholine, so it increases GI motility.
• Beta-blockers decrease circulating norepinephrine, so they increase GI motility.
• Venlafaxine increases circulating norepinephrine, so it decreases GI motility.
• Morphine is an opioid agonist, so it decreases GI motility.
• Naltrexone is an opioid antagonist, so it increases GI motility.
• Quetiapine decreases circulating serotonin, so it decreases GI motility.
• Citalopram increases circulating serotonin, so it increases GI motility.

PROTECTION

Digestive tract utilizes various mechanisms to protect the body (internal environment) from the external environment.
It specifically protects against:

• Chemical damage
• Exposure to toxins
• Microorganism entry

KEY PROTECTIVE FEATURES

(found throughout the entire GI tract)

1. Tight junctions

• Dense network of claudins and other proteins just below the apical surface of the GI epithelium.
• Intrinsic barrier of the digestive tract. They form a nearly impermeable barrier that prevents GI tract luminal contents from freely leaking through the mucosal layer.

Tight junctions prevent entry of microorganisms and other potentially harmful substances or toxins (such as HCl produced in the stomach) into the digestive tract wall.

2. Mucus lining

• Feature of all mucous membranes (mucosa).
• Mucus = alkaline (bicarbonate) secretion that protects against shear stress and chemical damage throughout the digestive tract.
  Secreted by:

1. Mucous cells in oral cavity

• Forms mucus lining
• Secreted as a component of saliva to primarily aid food bolus formation.
• Minor protective role in the oral cavity (protects the mouth from acidic food and pathogens)

2. Mucous neck cell in stomach.

• Mucus lining provides a chemical barrier between the stomach lumen and its epithelium
  Specifically…
• Neutralizes acidic secretions during a meal (with its bicarbonate component), and
• Prevents autodigestion of the mucosa by proteases.

3. Goblet cells in small intestine.

• Mucus lining continues as a chemical barrier between the acidic chyme present in the intestines and the intestinal mucosa.

Unique protective features in these three GI organs.

ORAL CAVITY

Secretes saliva, which contains:

• Lysozymes, which lyse bacteria.
• IgA antibodies, which maintain mucosal immunity, and
• Defensins, which are host defense antimicrobial peptides of innate immunity.

STOMACH

Parietal cells

(in the epithelium of the mucosal layer, which lines the lumen of the stomach)

• Secrete HCl, which primarily digests protein; however,
• HCl creates a harsh environment, which kills many microorganisms. The gastric mucosa is largely protected from this harsh environment by the alkaline mucus lining.

Clinical Correlate: Gastric Ulcers

• Breaks in the mucosal barrier exposes the GI wall to corrosive HCl and proteases
• Causes gastric wall erosion and inflammation
• Common cause: H. pylori (bacteria) is a common cause of gastric ulcers, which erodes the epithelial barrier.
• Ulcers can also occur in lower esophagus and in the small intestine (specifically, the duodenum).

High Cellular Turnover Rate

• GI epithelium sheds frequently as it becomes damaged from continued exposure to its lumen’s harsh chemical environment and continuous shear stress gastric motility.
• Regeneration: epithelial stem cells replenish damaged or dead epithelial cells.
• The GI epithelium divides, or turns over, almost constantly to replace damaged cells with new, mature ones – unlike the heart, which almost never replaces its cardiac cells.

Stem cells

• Located at the top of gastric glands
• Replenish gastric secretory and mucous cells that protect the stomach surface.

SMALL INTESTINE.

Paneth cells

• Found in its villi crypts
• Contain secretory granules filled antimicrobial peptides, which are secreted into the GI lumen.
• Provide another layer of host defense in the small intestine.

Stem cells

• Replenish damaged, or dead, absorptive and goblet cells that are shed from villi; they reside adjacent to paneth cells in villi crypts.

Paneth cells = “protectors of stem cells”

• Secrete factors to maintain these stem cells to promote cellular renewal.

Note: Although the digestive tract relies on high rates of cellular division to replace old, damaged cells – this also corresponds to higher rates of mutations and, thus, increased incidence of cancer in GI epithelium (carcinoma).

LIVER

Digestive function

• Bile synthesis and secretion

Other functions

• Nutrient metabolism
• Synthesis of plasma proteins
• Secretion and modification of hormones
• Storage of essential molecules
• Removal of aged blood cells
• Detoxification

GALLBLADDER

• Muscular sac
• Stores and concentrates bile (which is synthesized in the liver)

BILE

• Cholesterol-derived and alkaline
• Secreted by the liver
• Stored in the gallbladder.
• Released into the digestive tract postprandially (following ingestion of a meal) upon sphincter of Oddi opening.

Bile Secretion

Regulated by secretin and CCK

Secretin

• Secreted from the duodenum in response to acidic chime in the duodenum
• Acts on the liver to stimulates bile secretion.
• Bile (which contains bicarbonate) neutralizes the acidic chyme.

CCK

• Secreted from duodenum in response to fatty acids present in the chyme
• Acts on the gallbladder – produces gallbladder contraction
• Acts on sphincter of Oddi to promote its relaxation
• Thus, stimulates bile flow into the duodenum – the bile salts (another major component of bile) can emulsify fats (like a detergent) for their digestion and subsequent absorption in the small intestine.

Note: bile also contains cholesterol, lecithin (phospholipids), bile pigments, and trace metals.

Bile Salt Recycling in Enterohepatic Circulation

• Bile salts pass down the length of the small intestine to the ileum
• Reabsorbed into circulation at the ileum (they the enter recycling pathway: enterohepatic circulation).
• Travel through the hepatic portal vein back to the liver where they are recycled and re-secreted into newly formed bile.

Note: The hepatic portal vein drains nutrient-rich blood from the small intestine to the liver for metabolic processing.

• Small amount of bile salts continues through the rest of the digestive tract; approximately 5% of bile salts are eliminated in feces (along with other bile components).

Note: The liver synthesizes more bile salt from cholesterol to account for its loss.

Bile Salt Structure

Bile Salts = Amphipathic molecules, meaning they have hydrophobic and hydrophilic sides.

1. Cholesterol precursor = hydrophobic portion, the cholesterol precursor,

• Composed mainly of non-polar hydrocarbons, which interact with the lipid droplets.

2. Polar hydroxyl and carboxyl groups = hydrophilic portion, polar hydroxyl and carboxyl groups

• Exposed to the surrounded aqueous solution.

Fat Emulsification

Bile salt’s amphipathic nature aids in fat digestion.

• Bile salts and phospholipids (another amphipathic molecule and emulsifying agent) increase the surface area of large fat globules
• Aid in their breakdown into smaller emulsification droplets and prevent their reaggregation.
  Lipid droplets comprise triglycerides.
  Lipase, with the help of colipase, digest triglycerides into their simpler components:

Monoglyceride (glycerol), and

[Two] fatty acids.

which are absorbed by the small intestine.

• Bile salts arrange the monoglyceride, fatty acids, and phospholipids to form spherically-arranged micelles.
• Promoted by amphipathic nature of fatty acids and phospholipids promotes this spherical formation
• Micelles continuously form and breakdown.

Micelles = Holding stations for digested fats

• Continuously exchange lipids with the surrounding solution.
• Form to keep otherwise insoluble fats in small, soluble aggregates.
• Break down to replenish digested fat products that are absorbed.

Secrete saliva which:

• Lubricates ingested food
• Protects the mouth from acidic food and pathogens
• Initiates carbohydrate digestion

Sites of Salivary Secretion

Major (Extrinsic) Salivary Glands

1. Parotid gland
2. Sublingual gland
3. Submandibular gland

Minor (Intrinsic) Salivary Glands in the:

1. Tongue
2. Pharynx

Saliva Composition

• Mostly water: hypotonic relative to plasma
• High bicarbonate and K+ concentrations: (relative to plasma), which neutralize acidic foods in the mouth.
• Low Na+ and Cl- concentrations: (relative to plasma).
• The digestive enzymes:
  Salivary amylase, which initiates carbohydrate digestion, and
  Lingual lipase, which initiates fat digestion.
• Mucin, which forms thick mucus to moisten and lubricate food as well as aid bolus formation.
• Lysozyme and IgA antibodies, which lyse bacteria and protect the mouth against microorganisms.

Saliva Formation

Acinar region = “secretory region”

• Secretes the initial saliva
• Water, bicarbonate, K+, Na+, and Cl- are secreted into the acinar region.

Initial salivary secretion is a plasma-like solution (isotonic relative to plasma.

Ductal region = “modifying region”

• Transport saliva to the oral cavity.
• Modify the ionic composition of the initial saliva by selectively absorbing and/or secreting water and electrolytes.
  Specifically…
• Na+ and Cl- are reabsorbed, which makes their concentration in saliva lower relative to their plasma concentrations.
• Bicarbonate and K+ are secreted into the duct, which makes their concentration in saliva higher relative to their plasma concentration.

Final saliva that enters the oral cavity is hypotonic.

Note: Salivary ducts are nearly impermeable to water. Tight junctions between ductal cells prevent any additional water leakage into or out of salivary ducts, which makes final salivary secretion more dilute than the initial secretory product.

FLOW RATE

Flow rate of saliva through salivary ducts effects it final ionic composition because it affects the time the saliva is in contact with the surface of the ductal epithelium and, thus, the degree of absorption and secretion that occurs along the length of the duct.

Note: bicarbonate secretion is not effected by changes in flow rate; saliva is almost always rich in bicarbonate.

High Flow Rate

• Higher concentration of ions relative to water.
• Final saliva is isotonic to plasma (it’s most similar to the initial saliva secretion) because there is less time for reabsorption and secretion.

Final saliva has higher Na+ and Cl- concentrations and lower K+ concentrations than at average flow rates.

Low Flow Rate

• Water concentration is high and the ionic concentration is low.
• Final saliva is hypotonic to plasma (and the least like the initial saliva secretion); this allows more time for Na+ and Cl- reabsorption as well as K+ secretion into the ducts.

Final saliva is much more dilute than at a normal flow rate.

Although we only discussed water and electrolyte secretion from salivary acinar cells, bear in mind, they also secrete the digestive enzymes (salivary amylase and lingual lipase), mucin, lysozyme, and IgA antibodies, which are present in the final saliva.

REGULATION OF SALIVARY SECRETION

Note: Unlike other GI accessory glands, salivary secretion is not under hormonal regulation and only involves neural regulation.

Parasympathetic branches of the autonomic nervous system stimulate the majority of salivary secretion but that the sympathetic nervous system also plays a minor role in secretion, as well.

• Parasympathetic nervous system stimulates secretion of watery (serous), enzyme-rich saliva via cranial nerves IX, X and VII.
• Sight, smell, and taste of food stimulate saliva secretion via parasympathetic activation. Conditioned reflexes and nausea do, as well.

Also:

• Sympathetic activation inhibits salivary secretion.
• Sympathetic nervous system also does stimulate a viscous, mucin-rich saliva

FOUR MAJOR DIGESTIVE HORMONES

Gastrin

• Stimuli: stomach expansion, protein and caffeine in the stomach, alkaline chyme in the stomach
  – Secretion Site: enteroendocrine cells of the stomach mucosa
• Major Actions:
  – Stimulates gastric juice (HCl, mucus, pepsinogen) secretion
  – Stimulates gastric motility
  – Pyloric sphincter relaxation

Secretin

• Stimuli: acidic chyme in the duodenum
  – Secretion Site: enteroendocrine cells of the duodenal mucosa
• Major Actions:
  – Stimulates pancreatic enzyme secretions into duodenum via the sphincter of Oddi (Pancreatic secretions = bicarbonate-rich, neutralize acidic chyme.)

Cholecystokinin (CCK)

• Stimulus: triglycerides, fatty acids, and amino acids (part of chyme) in the duodenum
  – Secretion Site: enteroendocrine cells of the duodenal mucosa
• Major Actions:
  – Stimulates bile secretion from gallbladder
  – Stimulates pancreatic enzyme secretion
  – Promotes sphincter of Oddi relaxation.

CCK and secretin potentiation: together stimulate a much greater release of pancreatic enzymes than if either hormone acts alone.

Glucose-dependent insulinotropic peptide (GIP)

• Stimulus: glucose (also: fatty acids and amino acids; all present in chyme) in the duodenum
  – Secretion Site: enteroendocrine cells of the duodenal mucosa
• Major Action:
  – Stimulates pancreas insulin secretion
  – Inhibits gastric acid secretion.

FOUR CRITERIA OF GASTROINTESTINAL HORMONE

A substance must meet four different criteria to be considered a gastrointestinal hormone.

• The substance is secreted into the bloodstream in response to a physiologic stimulus (in this case, ingestion of a meal) to a target site, resulting in a physiologic action (to regulate digestive actions).
• The function of the substance acts independently of neural activity.
• The substance can be isolated and purified for chemical identification as well as synthesized again.
• The isolated substance, upon intravenous injection, can induce the same physiologic response as when it receives the appropriate stimulus.

The four major digestive tract hormones meet all of these criteria.

CANDIDATE HORMONES

Candidate Hormone Description

• Regulate digestion but fail to meet all four of the aforementioned criteria.
  – Considered to have putative roles in GI regulation.

Key Candidate Hormones

• Motilin – increases GI motility and specifically mediates the migrating myoelectric complex.
• Pancreatic polypeptide – inhibits pancreatic bicarbonate and enzyme secretions.
• Enteroglucagon – responds to low blood glucose concentration and stimulates glycogenolysis and glucagonogenesis by the liver.
• Glucagon-like peptide-1 (GLP-1) – stimulates insulin secretion by the pancreas.

Additional Note:

• There are many unique types of enteroendocrine cells, each of which secrete a specific hormone.
  – For example, G cells are enteroendocrine cells that specifically secrete gastrin.

Process of defecation (a bowel movement), in which undigested fecal waste material exits the body.

Muscular sphincters:

Regulate elimination → under both voluntary and involuntary control.

Internal anal sphincter:

Smooth muscle, involuntary control

External anal sphincter:

Skeletal muscle, voluntary control

Anatomical structures involved in defecation:

• Sigmoid colon → Rectum → Anal Canal → Anus
• Internal anal sphincter and external anal sphincter

Steps of Elimination:

1. Mass movements push feces into the sigmoid colon and rectum.
2. Rectal distension activates stretch receptors, which trigger the defecation reflex.
3. Defecation reflex:

• Rectal smooth muscle contraction → further pushes feces from the rectum to the anal canal
• Internal anal sphincter relaxation and opening → allow feces to pass through the anal canal and exit via the anus.

4. Defecation: both the external and internal anal sphincters relax.

Abdominal contraction also aids defecation → increases intra-abdominal pressure and pushes feces through the distal GI tract.

Voluntary external anal sphincter contraction prevents defecation.

The distended rectal wall relaxes and the urge to eliminate dissipates.
Subsequent mass movements reactivate rectal stretch receptors and defecation reflex initiation.

Clinical Correlation: Diverticular Disease

• Lower portion of the large intestine.
• Pouches (diverticula) form at weak areas of colon wall → form outpockets of the mucosa and submucosa → bulge through, disrupt the smooth muscle layer.
• Diverticula form following straining during a bowel movement (i.e. during constipation) → causes high pressures in the colon, weakening the colon wall.

• Smooth muscle layer thickens over time at areas of diverticula formation. The muscle contracts more strongly to eliminate feces.

Other contributors to diverticular disease are:

• Age, more common in elderly.
• Diets low in fiber, which cause hardened feces.
• Defects in GI motility.
• Defects in wall strength.

Diverticular disease = asymptomatic

Diverticulitis: diverticula become infected and progress to an inflammatory state, which causes severe pain.

HAUSTRAL CONTRACTIONS

(Definition): Slow, segmenting movements that further mix chyme.

• About every 30 minutes.
• Occur in haustra: small pouches caused by the teniae coli (longitudinal smooth muscle ribbons that run along outside the entire length of the colon). Because they are shorter than the large intestine, the large intestine tucks between the teniae and form sacs
• Primarily occur in ascending and transverse colons.
• Produced by contractions of smooth muscle layer

Steps

1. Chyme fills a haustrum
2. Distension in the haustrum.
3. Smooth muscle layer contracts
4. Contractions move chyme into the next haustrum and subsequent haustra, where the sequence begins again.
   #Note that haustral contractions play a relatively minor role in propelling fecal waste through the large intestine; their main function to further mix waste.

Contractions also bring chyme in close contact with the large intestine mucosal layer to maximize water and electrolyte absorption

• Hasutral contractions also occur in the descending and sigmoid colon to further concentrate stored fecal waste prior to elimination.

MASS MOVEMENTS

(Definition): slow, but powerful contractions of the large intestine that move undigested waste to the rectum for defecation via the anus.

• Much like stronger and sustained peristaltic contractions.
• 3-4 times a day.
• Mainly in the transverse, descending, and sigmoid colons.
• Produced by circular layer (smooth muscle) contractions

Steps

1. Undigested waste in the transverse colon.
2. Triggered by the gastrocolic reflex (initiated following ingestion of a meal when food enters the stomach causes its distension)
3. Circular layer contracts in the transverse colon
4. Contractions move waste towards the rectum.

Note: Unlike peristalsis, the circular remains contracted for some time following its initial trigger mass movement.

5. Fecal waste moves down the descending colon and into the sigmoid colon toward the rectum
   #Prepares for elimination (defecation)

PERISTALSIS.

(Definition) uni-directional propulsion of digested food forward through the digestive tract.

• Peristaltic contractions continue from the upper GI and the small intestine to gradually move undigested waste through the remainder of the GI tract.
• Rhythmic, alternating contractions of the circular and longitudinal smooth muscle layers causes peristalsis.

Steps

1. Circular layer contracts behinds the chyme, decreases the diameter of the large intestine to propel chyme forward.
   Longitudinal layer relaxes.
2. Longitudinal layer contracts, which shortens the small intestine and decreases the distance the chyme must travel.
   Circular layer relaxes.
3. Circular layer contracts and pinches the large intestine further distally, which propels chyme forward through the large intestine towards the rectum.
   Longitudinal layer relaxes.