Gastrointestinal Tract Physiology

Front 1

What are the functions of the gut?
What signals regulate and integrate these functions?

Back 1

Front 2

What are the two types of enteric nerves?

Back 2

Extrinsic and intrinsic
*extrinsic - from vagal or spinal nerves
*intrinsic- part of the digestive tract

Front 3

Where are gut hormones derived from?

Back 3

derived from extra and intra- intestinal endocrine cells

Front 4

What are the two types of major regulatory mediators of the gut?

Back 4

Peptides vs. Non-peptides

Front 5

What are the examples of peptide regulating factors?

Back 5

gastrin, secretin, vasoactive intestinal peptide (VIP)

Front 6

What are the examples of the growth and trophic factor regulating factors (peptides)?

Back 6

Insulin, TGF-alpha, and IGF

Front 7

What are the steroid regulatory factors?

Back 7

Vitamin D, Aldosterone, Hydrocortisone

Front 8

What are the amino acid derivate regulatory factors?

Back 8

NO, NE, Epi, Histamine, and Serotonin

Front 9

What are the phospholipid derived regulatory factors?

Back 9

Arachidonic acid and Platelet activating factor (PAF)

Front 10

What are the major families of gut regulatory peptides?

Back 10

Gastrin and Secretin Families are most important

Front 11

How are gut neurotransmitters grouped?

Back 11

Made/Stored/ Released by enteric neurons

Front 12

What effect does cholera toxin have on G-proteins?

Back 12

Cholera toxin inhibits the exchange of GTP for GDP
*so the Gs is persistently active

Front 13

What are the two types of guanylate cyclases?

Back 13

Front 14

Where is the guanylin receptor located?

Back 14

expressed on the luminal membrane of gut epithelial cells
*activated by either guanylin (gut hormone) or heat stable enterotoxin (STalpha- E.coli)

Front 15

Once the guanylin receptor is activated what action occurs?

Back 15

The guanylate cyclase converts GTP to cGMP
*this leads to net secretion of water and electrolytes and the development of diarrhea (TRAVELER'S DIARRHEA)

Front 16

How does the receptor independent activation of guanylate cyclase occur?

Back 16

NO moves through membrane and acts on the soluble receptor protein
*GTP - cGMP-PKG-Protein phosphorylation = diarrhea

Front 17

Do some intestinal growth factors result in activation of other pathways?

Back 17

YES!
EGF, PDGF, and IGF activate membrane tyrosine kinase receptors

Front 18

What is the important role of Arachidonic Acid?

Back 18

Hormone and neurotransmitter activation of AA metabolism result in the production of prostaglandins and leukotrienes
*which are important intracellular and extracellular signaling molecules

Front 19

What mechanisms are part of the extrinsic regulation pathways?

Back 19

endocrine
paracrine
autocrine
juxtacrine
neurocrine

Front 20

Define endocrine pathway?

Back 20

regulatory hormones are secreted into the blood stream and delivered to distant targets
*multiple tissues and cell types can be regulated simultaneously
*ex: gastrin

Front 21

Define the paracrine pathway?

Back 21

hormones stored in secretory granules at the basal pole are released and stimulate receptors on the cells immediately adjacent
*this is how mucosal endocrine cells that are interspersed between intestinal epithelial cells exert their regulatory effects

Front 22

Define the autocrine pathway?

Back 22

its release stimulates/autoregulates its on behavior and function

Front 23

Describe the juxtacrine pathway?

Back 23

regulatory agents that affect many types of cells that are in close proximity
*histamine secreted by lamina propria - affects mucosal, blood flow, and smooth muscle

Front 24

Explain the neurocrine pathway?

Back 24

utilizes the enteric neurons
synapse directly with the lining cells of the gut to activate specific receptors of target tissues
*specificity

Front 25

Organization of the Enteric nervous system?

Back 25

Enteric nervous system is the gut's own nervous system
*produces a very patterned and predictable response
*sensory neurons will set into the circuitry of events to produce an effect that is integrated with other motor neurons
*this system does receive some signals from the brain

Front 26

Organization of the Enteric nervous system?

Back 26

Enteric nervous system is the gut's own nervous system
*produces a very patterned and predictable response
*sensory neurons will set into the circuitry of events to produce an effect that is integrated with other motor neurons
*this system does receive some signals from the brain

Front 27

What two aspects are integrated for intestinal function?

Back 27

Enteric Neurons and Endocrine cells of the gastrointestinal mucosa

Front 28

Where can endocrine and enterochromaffin cells be found?

Back 28

these cells are found intercalated among epithelial cells
*secretions are paracrine in fashion

Front 29

Is the distribution of most mucosal endocrine cells random?

Back 29

No! the region specific expression is relevant to their primary physiological actions

Front 30

What is this slide showing?

Back 30

How regional specificity is very important
*Gastrin- distal 1/3 of the stomach
*Duod and prox jej - CCk, Secretin, GIP, and Motilin
*Ileum and colon - neurotensin, peptide YY, enteroglucagon
*Colon - Guanylin

Front 31

Describe the digestion of a meal?

Back 31

1. Stomach expands and this activates the baroreceptors - leading to the secretion of gastrin
2.endocrine gastin (luminal nutrients) enter circulation and is carried back to the proximal 2/3 of the stomach which stimulates the secretion of gastric acid (hydrochloric)
- pepsin also now secreted
-increases motility
3) Gastric chyme stimulates the duodenal release of GIP, CCK, and secretin
4)CCK and secretin stimulate the pancreatic and biliary secretions
- which are very important for normal digestion
5) GIP, CCK, and secretin feedback inhibit gastric secretions
*GIP also slows gastric emptying - efficient digestion of all nutrients

Front 32

What does this patient have?

Back 32

rare endocrine tumor
- makes are secretes larges amounts of gut peptides: VIP, motilin, and neurotensin

Front 33

What does this patient have?

Back 33

rare endocrine tumor
- makes are secretes larges amounts of gut peptides: VIP, motilin, and neurotensin

Front 34

Why is facial flushing and hypotension seen with VIPoma?

Back 34

VIP causes vasodilation and one of its manifestations is facial flushing and hypotension

Front 35

What does VIP normally do?

Back 35

it regulates numerous intestinal functions: motility, intestinal water and electrolyte transport, and blood flow

*potent secretagogues - this action is stimulated by adenylate cyclase and increased cAMP

Front 36

What is the mechanism of action for VIP?

Back 36

VIP stimulates VIP receptors
activating adenylate cyclase
*leading to active water secretions
*inhibits absorption
*activate vasodilation

Front 37

Why does hypokalemia occur with VIPoma patients?

Back 37

stool losses and the chronic effects of aldosterone, that is secreted in response to hypovolemia.
*Aldosterone increases renal absorption of Na at the expense of increased K excretion

Front 38

How would you treat VIPoma?

Back 38

with somatostatin analog = Octreotide
*inhibition of hormone release is the major mechanism this drug uses

Front 39

What are the effects of somatostatin on the GI tract?

Back 39

Front 40

What does this patient have?

Back 40

Celiac Sprue

Front 41

What is normally secreted where Celiac sprue has its major effects?

Back 41

affects the duodenum and proximal jejunum
*where secretin and cck is made
* aren't have the release of pancreatic and biliary secretions

Front 42

what are the histological characteristics of celiac disease?

Back 42

*small intestine mucosal inflammation
*villus atrophy (shortening or absence)
* crypt hypertrophy
* lamina propria packed with immune cells

Front 43

What comprises the innervation to the gut?

Back 43

The extrinsic sympathetic and parasympathetic fibers & the enteric nervous system

Front 44

What are the parasympathetic fibers to the gut?

Back 44

vagus and pelvic nerves
*pelvic supply distal colon and rectum
*synapse with post-ganglionic parasympathetics or enteric neurons located in intestinal wall plexus

Front 45

What are the sympathetics to the GI tract?

Back 45

pre-ganglionic efferent fibers from spinal cord synapse at paraveterbral ganglia and post ganglionic project into intestine

Front 46

Where is the enteric nervous system (ENS) found?

Back 46

Intrinsic enteric neurons are found in the gut wall located in two major plexuses ( Auerbach's and Meissner's)

Front 47

Where is Auerbach's plexus is located where?

Back 47

found between the circular and longitudinal muscle layer

Front 48

Where is the Meissner's plexus found?

Back 48

located in the submucosa

Front 49

What does the diversity of ENS neurons reflect?

Back 49

The wide range of the physiological functions of the GI tract

Front 50

Propulsive motor contractions of the intestine require the coordination of?

Back 50

Excitatory and inhibitory enteric neurons

Front 51

What function do the interneurons in the ENS provide?

Back 51

interneuronal connections that permit complex and integrated responses involving many digestive processes

Front 52

Why are the functions of the guy hardwired?

Back 52

Because timing is everything in the gut

Front 53

Describe the events of Peristalsis?

Back 53

1) intestinal contents distend the lumen -stimulating intramural baroreceptors
2) activating excitatroy motor neurons = contraction
*relaxation of longitudinal and contraction of circular muscle
3) at the same time there are inhibitory neurons in the segment immediately distal to the contracting muscle
*prepares the receiving segment for luminal contents
**events NEED to be coordinated

Front 54

Explain the events of Peristalsis?

Back 54

1) the distention of the lumen by intestinal contents stimulates intramural baroreceptors
2) these receptors activate excitatory motor neurons that cause contraction (relaxation of longitudinal and contraction of circular)
3) at the same time, inhibitory neurons in the segment immediately distal to the contracting segment are relaxed
**this prepares the the receiving segment to take on the luminal contents

Front 55

what is this slide showing?

Back 55

Steps of Peristalsis

Front 56

Where is smooth muscle and striated muscle found within the gut?

Back 56

Skeletal muscle is found in the upper third of the esophagus and the external anal sphincter
**everywhere else is smooth muscle

Front 57

How can the smooth muscle of the gut contract as a single unit?

Back 57

* especially in circular smooth muscle cells, as annular contraction requires simultaneous activation of all muscle fibers in that region

Front 58

Describe the longitudinal muscle of the GI tract?

Back 58

oriented with their axis running along the length of the bowel
* in colon, they are organized into a separate thick cords = teniae coli

Front 59

What are the two types of electrical activity seen in the intestinal smooth muscle?

Back 59

1) BER
2) spike potnential

Front 60

What are BER's and where are they found?

Back 60

Basic electrical rhythm = BER
found throughout except in esophagus and proximal stomach

Front 61

Where does the BER arise from?

Back 61

from specialized "pacemaker" cells throughout the GI tract
*BER frequency is different in different parts of the gut

Front 62

What is the relationship between contraction and BER

Back 62

They serve as setting a certain beat and under certain circumstances where contraction is activated then you will see the contraction with BER
* BER =10 so the most contractions you can have is 10 the least is 0 but never more than 10

Front 63

What greatly affects the appearance and frequency of spike potentials?

Back 63

hormonal and neurotransmitter signals
** greater number of spike potentials = greater the degree of muscular contraction

Front 64

What is this slide showing?

Back 64

muscarinic receptor agonist = Ac is added which provides increased spike potentials at the top of the depol phase - increase in muscle contraction

VS. when Epi is associated then see disappearance of spike potentials - decreasing muscle contraction
**Neither agent affects BER frequency

Front 65

Regulation of intestinal motor function
*excitatory agents

Back 65

increase cytosolic calcium

Front 66

Regulation of intestinal motor function *inhibitory

Back 66

-agents increase cyclic nucleotide levels in smooth muscle cells cause relaxation

Front 67

Regulation of intestinal motor function
*inhibitory

Back 67

- agents that increase cyclic nucleotide levels in smooth muscle cells cause relaxation

Front 68

Describe the Motility pattern of segmentation?

Back 68

Non-propulsive, annular contractions of the circular muscle layer, found in small and large intestine
*important for mixing intestinal chyme with digestive juices (squeezing)
- puts food into a state that it can be effectively absorbed

Front 69

Describe the motility pattern of Tonic Contractions?

Back 69

Zones of increased and continuous pressure that function as sphincters
*important for seperating and regulating intestinal flow into various compartments
*relaxation allows gated passage of luminal contents to another compartment

Front 70

Describe the motility pattern of peristalsis?

Back 70

highly integrated, complex motor pattern characterized by sequential annular contraction of gut segments
*producing a sweeping propulsive wave

Front 71

Primary Esophageal Peristalsis

Back 71

Propulsive, sequential, annular contractions that follow a swallow (2-4 cm/sec)
*The LES relaxes to let food enter - the peristaltic wave stops at the LES and doesn't continue into the stomach

Front 72

Explain Secondary Peristalsis

Back 72

Propulsive wavelike contractions that are initiated in the absence of swallowing and by increased luminal pressure
*serves to clear retained food and fluid or remove refluxed gastric contents from the esophagus

Front 73

What are the two important roles of the LES?

Back 73

allowing food to enter the stomach and preventing the reflux of gastric contents

Front 74

What is reflux esophagitis?

Back 74

inflammation and structure formation that results from inadequate sphincter pressure

Front 75

What is achalasia?

Back 75

arises when the LES pressure is abnormally high, preventing entry of food into the stomach and causing dilation of the proximal stomach

Front 76

What are the regulators of LES pressure and function?

Back 76

Front 77

What are the three major functions of the stomach?

Back 77

1) reservoir for food
2) mixes the meal with gastric secretions to initiate digestion
3) gated release of small amounts of gastric chyme into the small intestine for further digestion and absorption

Front 78

Describe the Reservoir function of the stomach?

Back 78

Upper 1/3 of the stomach serves as a reservoir
**Receptive Relaxation - allows it to accommodate large gastric volumes w/o a large increase in pressure

Front 79

Which nerve regulates receptive relaxation of the upper 1/3 of the stomach?

Back 79

Vagal nerve
-vagotomy - reduces distensibiltiy and you feel full quicker

Front 80

Describe the mixing function of the stomach?

Back 80

distal 2/3 of the stomach
- mixes gastric contents with digestive juices (through peristalsis)
**regulated by primary pacemaker

Front 81

What and where is the primary pacemaker of the stomach?

Back 81

located in the mid-portion of the greater curvature of the stomach
- phase lag in distal segments of BER in the stomach
- this allows waves to being in upper regions and propagate down

Front 82

Describe the grinding and gated release of gastric contents within the stomach?

Back 82

Gastric peristalsis through the antrum coupled with increased pyloric sphincter tone
- large food particles reflex back into gastric lumen to undergo additional breakdown
- so only small amount enter intestine at one time

Front 83

What is dumping syndrome?

Back 83

When gastric emptying is rapid and inappropriate
*characterized by nausea, sweating, abdominal cramps, and weakness

Front 84

What is Gastroparesis?

Back 84

condition associated with severe diabetic patients who have autonomic neuropathy
* caused by impaired or absent gastric motility and delayed emptying of the stomach
* will experience post-prandial (after meal) bloating, nausea, and early satiety

Front 85

What is the second step?

Back 85

2) Receptive relaxation or the upper 1.3 of the stomach allows food to stored wtihout significant increase in intra-gastric pressure

Front 86

Explain the 3rd step

Back 86

Boluses of food are mixed with gastric juices and moved towards the antrum

Front 87

Explain step 4

Back 87

As peristalsis sweeps through the antrum (antral systole) the pyloric sphincter is maintained in a partially open state, only allowing liquefied contents to enter the small intestine. Larger food particles reflux for further grinding and mixing

Front 88

What is the purpose to small intestinal motility?

Back 88

major site of digestion and absorption of nutrients
* motility patterns found here are primarily for mixing and propulsion of luminal contents

Front 89

what is this slide showing?

Back 89

Decreasing gradient of BER frequencies promotes distal movement of intestinal contents

Front 90

What determines the max rate of segmentation of that region?

Back 90

BER

Front 91

What are agents will increase spike potentials = increasing likelihood of contraction?

Back 91

Ach
Bombesin
CCK

Front 92

What are the inhibitory agents of spike potential and therefore contractions?

Back 92

Alpha-adrenergics
NO
VIP
glucagons

Front 93

What are Migrating Motor Complexes(MMC)?

Back 93

A motor pattern only seen during fasting or inter-digestive periods that producing a wavelike contraction running the entire length of the bowel

Front 94

Why are MMC thought to be important?

Back 94

sweeping the lumen free of content and preparing the small intestine for receipt of the next meal

Front 95

Back 95

Good Job

Front 96

Back 96

Has 3 different phases
In fasting state- phase 3
*MMC disappears during meal and reappears after a meal

Front 97

What is this showing?

Back 97

Gastrin or CCK initiate the initially phases of MMC
*hormones from the early phase of digestion
*this is showing the possibly that gastrin and CCK are the main reason MMC's stop with meals

Front 98

Back 98

Motilin will reset the MMC
- 90 min phase is shortened and then reset
- Initiation may be hormone-dependent

Front 99

How much does the colon receive per day?
Consisting of what?

Back 99

0.5-2.5 L /day
* undigested and porrly absorbed food residue, water, electrolytes

Front 100

What does the colon need to reduce the load to so diarrhea doesn't result?

Back 100

200 gm/day

Front 101

Back 101

THe movements of the colon are slow and irregular and aimed at increasing contact time between luminal fluid and the absorptive mucosal surface

Front 102

What are teniae coli?

Back 102

are the longitudinal muscles that are organized into three seperate bands
*change the length of the colon

Front 103

What are haustrations?

Back 103

Segmentation of the colon
*segmentation is the major motor activity of the colon

Front 104

Are rectal motility and anal sphincter function distinct from colonic motility?

Back 104

Yes

Front 105

How does the rectum function as a storage site

Back 105

Receptive relaxation
- allows accommodation of large stools

Front 106

Back 106

when rectal contraction pressure increases (intraluminal baroreceptors)
- the internal sphincter relaxes and the external sphincter contracts

Front 107

What is Valsalva maneuver?

Back 107

individual initiates defecation by voluntarily decreasing the tone of the external anal sphincter and increasing intraabdominal pressure by forcing air against the closed glottis

Front 108

Back 108

-compromised LES function
- autonomic neuropathy can also affect gastric emptying b/c the stomach becomes flaccid and antral peristalsis is lost

Front 109

What is diabetic gastroparesis?

Back 109

Gastroparesis can result in the formation of a bezor = conglomerated mass of undigested vegetable and fruit fiber

Front 110

Diabetes induced autonomic neuropathy can have similar effects as what?

Back 110

The surgical interruption of the vagus nerve

Front 111

What symptoms can autonomic neuropathy lead to?

Back 111

intestinal stasis
- overgrowth of bacteria
--nutrient malabsorption and diarrhea
severe constipation or diarrhea
loss of anal sphincter tone

Front 112

What is this caused by?

Back 112

Front 113

What is Achalasia?

Back 113

neuromuscular that affects LES
failure of LES to relax
-decrease NO and VIP signaling

Front 114

What is coffee ground emesis indicative of?

Back 114

blood digested in HCl and emesis means throw up

Front 115

What is tarry stool indicative of?

Back 115

bleeding in the upper GI tract

Front 116

What does orthostatic mean?

Back 116

bp drops upon standing
- due to the loss of blood

Front 117

Why is the secretion of intrinsic factor in the stomach so important?

Back 117

it is required for the absorption of vitamin B12

Front 118

What are the divisions of the stomach?

Back 118

endocrine region is in the antral mucosa = gastrin
endocrine - fundus and body = HCl, pepsin, and intrinsic factor

Front 119

What is one main characteristic of the fundus?

Back 119

Receptive relaxation

Front 120

What is the basic unit of the stomach?

Back 120

Front 121

Back 121

*Surface mucus cells- simple columnar = make a secrete mucus and alkaline fluid for protecting the stomach
* Gastric Pits- conduits for delivering the secretions (3-7 glands) - 50% of total luminal area
* Gastric gland - many different cell types- germinal cell proliferation in this area

Front 122

Parietal cells- where are they found and what do they produce?

Back 122

produce HCl acid and intrinsic factor
found in the upper gland

Front 123

Mucous cells- where are they and what do they produce?

Back 123

mucus neck cells are found in the upper gland and throughout the gland
make mucus and bicarbonate
* protect stomach against auto digestion
*mucus also acts as a lubricant

Front 124

Chief cells- where are they and what do they do?

Back 124

They are found near the base and make and secrete pepsinogen

Front 125

Mast cells- where are they and what do they do?

Back 125

basal side of the epithlium
*regulates gastric acid and pepsin secretions
*secrete histamine (juxtacrine) that affects gastric glands

Front 126

Endocrine glands - where are they and what do they do?

Back 126

are between chief and parietal cells
* play a major role in regulating chief and parietal cell secretory function
*secrete bioactive amines and peptides that stimulate the other cells through a paracrine action

Front 127

What are two specialized endocrine cells?

Back 127

G-cells are gastrin containing - regulate gastric acid
basal side contains secretory granules and apical side is narrow
* secreted from the endocrine portion of the stomach and reaches the exocrine portion of the stomach in this fashion

D cells- make and secrete somatostatin
dendritic like membranes - contacting adjacent cells - rapid delivery of somatostatin in paracrine fashion

Front 128

describe the morphological change parietal cells undergo?

Back 128

resting- tubovesiclular bodies and large mitochondria are present - canaliculi are lined by short stubby microvilli
activation - rapid transformation - prepare for acid secretion
tubovesicular bodies fuse with the canulicular or lumenal membrane and increase surface area 6-10 fold
**rapid insertion of proton pumps

Front 129

Describe all that is going on in this slide?

Back 129

this is an electroneutral membrane transporter
to move H+ in K+ is moved out = requires ATP - this pump is only active after the tubovesicular body has inserted into the canalicular membrane
* H+ is generated from carbonic acid due to the activity of carbonic anhydrase
*K+ needs to me on the side of the lumen to be pumped out so it moves down its conc. gradient into the lumen
* Cl helps maintain electroneutrality and also produces HCl on lumenal side

Front 130

Regulation of K+ and Cl channels on the canulicular membrane may help determine what?

Back 130

May determine rates of acid secretion

Front 131

How do Proton Pump inhibitors work?

Back 131

weal acids that are selectively taken up and concentrated in the acidic canaliculi or gastric parietal cells
- then converted to sulfonamides that react with the thiol groups
*bind to the alpha subunit of the proton pump and block its function

Front 132

What are the three major activators of acid secretion for the parietal cell?

Back 132

Gastrin, Histamine, and Acetylcholine

Front 133

describe the histamine receptor

Back 133

Histamine stimulates the H2-type receptor and activates adenylate cyclase
*increases cAMP- dependent protein kinase = initiating acid secretion

Front 134

Describe the gastrin receptor

Back 134

gastrin stimulates the gastrin receptor which are coupled to the PIP2 hydrolysis
Increase in cytosolic Ca++ (IP3)
activate Ca -dependent protein kinases
synergistic with cAMP pathways

Front 135

Describe the Ach receptor

Back 135

Ach stimulates a type 3 muscurinic receptor (M3) which are also coupled to PIP2 hydrolysis - increasing cytosolic Ca

Front 136

What accompanies gastric acid secretion?

Back 136

generating a proton for acid secretion through carbonic anhydrase also forms bicarbonate which moves into the blood stream

Front 137

What are the other important pathways regulating gastric acid secretion?

Back 137

1) gastrin secreted by antral G cells
2) Ac from cholinergic neurons - stimulate mast cells - secretion of histamine
3) Somatostatin is the major paracrine agent that inhibits gastric acid secretion

Front 138

PNH: Clinical Features

Back 138

(1) Chronic intravascular hemolysis causing chronic paroxysmal hemoglobinuria, elevated LDH;
(2) Normochromic, normocytic anemia (unless IDA is also present);
(3) Pancytopenia;
(4) Thrombosis of venous systems can occur - eg. of the hepatic veins (Budd-Chiari syndrome);
(5) May evolve into aplastic anemia, myelodysplasia, myelofibrosis, and acute leukemia;
(6) Abdominal, back, and musculoskeletal pain

Front 139

The Gastric Acid secretion can be divided into how many phases?

Back 139

3 phases
-cephalic
-gastric
-intestinal

Front 140

Describe the cephalic phase of gastric secretion?

Back 140

evoked by a stimuli from the central nervous system - can be initiated by sight, smell, and taste of food

Front 141

What are the three important areas of the brainstem that relay messages to the stomach?

Back 141

Postrema
nucleus tractus solitarii (NTS)
dorsal motor nucleus (DMN)
*preganglionic vagal nerves relay message to the enteric neurons - stimulating gastrin realeasing peptide and ACh -= release gastrin from antral G-cells

Front 142

Describe the gastric phase of gastric acid secretions?

Back 142

accounts for 50% of total acid
starts when fluid or food enter stomach
* as distention increases - gastric output increases (antrum)
- response mediated by vagal nerve fibers and local factors (gastrin)

Front 143

The presence of {peptides and amino acids} or {carbohydrates and fats} stimulate further gastric acid secretions?

Back 143

peptides and amino acids further stimulate gastric acid secretions

Front 144

Describe the intestinal phase of gastric acid secretion?

Back 144

least important phase <10%
stimulated by luminal distention and absorption of amino acids

Front 145

What can the cephalic phase of gastric acid secretion be inhibited by?

Back 145

intracerebral-ventricular injection of agents like:
-bombesin
-neurotensin
-cotricotropin-releasing factor (CRF)
* important modulators

Front 146

What can the gastric phase of gastric acid secretion be inhibited by

Back 146

increased luminal acidity (especially in the antrum)
- mediated by enteric neurons and increased release of somatostatin by D cells

Front 147

What can the intestinal phase of gastric secretion by inhibited by?

Back 147

luminal presence of acid
hyperosmolar solutions
luminal fat
* stimulates: GIP, neurotensin,somatostatin, secretin, VIP,, PYY

Front 148

What is the most important digestive enzyme secreted by gastric chief cells?

Back 148

Pepsinogen

Front 149

Regulation of pepsinogen secretion

Back 149

pepsiogen secretion parallels gastric acid secretion since many of the regulating agents are the same

Front 150

What does an increase in cAMP do for the chief cell?

Back 150

stimulates the release of pepsinogen but also increases pepsinogen synthesis
(VIP, secretin, PGE, Beta-antagonist)

Front 151

How is luminal pepsiogen activated?

Back 151

pH of 2 - active
*acid is required for acitivation
conformational change - opens catalytic site
*pepsin has a positive feedback effect

Front 152

What does pepsin do?

Back 152

it hydrolyzes ingested proteins into peptons - which are potent signals for gastrin and CCK
*pepsin has a high affinity for collagen (works more on meat than vegetables)

Front 153

What function does mucus serve in the stomach?

Back 153

Protects against autodigestion
*Mucin- glycoproteins that are heavily glycosylated - linked through disulfide bonds
*forms a gel (80% water)

Front 154

Purpose of bicarbonate secretion?

Back 154

lining cells and creating buffer zone
* dependent on carbonic anhydrase
*stimulated by vagal nerves and E-series prostaglandins

Front 155

What is the mucus gel buffer zone?

Back 155

mucus gel forms a semi-impermeant layer that protects underlying cells from the acidic lumen and retains bicarbonate secreted from underlying epithelial cells (alkaline)

Front 156

Factors affecting the buffer zone...leading to peptic ulcer development?

Back 156

Balance between aggressive and protective factors

Front 157

What is used to treat peptic ulcer disease?

Back 157

Front 158

How do proton pumps work?

Back 158

Made as a pro-drug then collect and aggregate where pH is less than 3
customized drugs that will accumulate in the lumen
*acid converts them to active form - sulfinamide- which bind the thiol groups of the pump and inactivate it

Front 159

What is H. pylori?

Back 159

most common cause of duodenal ulcer disease
*can survive in harsh acid milieu due to its expression of urease, an enzyme that makes NH3 that can buffer protons
** stimulates a mucosal inflammatory response, stimulates acid secretion, and compromises barrier function

Front 160

What does NSAIDs do to the GI tract?

Back 160

aspirin and motrin cause GI bleeding
*NSAIDs also stimulate acid secretion

Front 161

What is Gastrinomas?
*Clinically described as Zollinger-Ellison syndrome

Back 161

endocrine tumors that secrete gastrin and cause hypergastrinemia
* consequences: hyper-secretion of acid and pepsin
*leading to diarrhea and recurrent peptic ulcer disease

Front 162

Composition of the pancreas?

Back 162

exocrine and endocrine function
80% of the total volume is due to glandular tissue
endocrine cells only account for 2%

Front 163

What is the primary functional unit of the pancreas?

Back 163

Acinus - composed of contiguous, pyramid-shaped glandular cells with apex facing the lumen

Front 164

Are acini polarized cells?

Back 164

Yes. They have distinct functional and structural differences in the apical and basolateral domains

*have developed RER and Golgi for synthesis and storage of digestive proteins
*Zymogen or storage granules are found in the apical or luminal pole- released into the ductule by exocytosis - then membrane vesicles are recycled

Front 165

What do the acinar cells produce?

Back 165

digestive enzyme proteins that are eventually transported through the ductular system into the duodenum to be mixed with intestinal chyme

Front 166

How is acinar cell secretion regulated?

Back 166

ACh, CCK, Bombesin, Sub P act on PIP2 increasing Ca
*cholinergic muscarinic receptors appear to be the dominant pathway for Ca-mediated

Secretin and VIP - A.C - increasing cAMP

Front 167

When calcium is released what does it trigger?

Back 167

Ca stimulates nitric oxide synthase (NOS), leading to the formation of NO
* NO activates guanylate cyclase activity to increase cellular cGMP levels which release zymogen granules

Front 168

Which is more powerful for pancreatic secretions: cAMP or Ca++?

Back 168

Ca+ mediated agonist is more importnat than cAMP mediated agonists in regulating acinar cell functions

Front 169

Types of Pancreatic enzymes?

Back 169

most digestive enzymes are made and stored in their inactive proenzyme form
*once secreted into duodenal they are converted to their active forms

Front 170

What is the master pancreatic enzyme?

Back 170

Trypsin- essential for hydrolytic activation of other proenzymes in the duodenal lumen

Front 171

Where do exopeptidases and carboxypeptidases cleave?

Back 171

They cleave proteins fro their ends

Front 172

Proteolytic enzymes make up ___% of all the protein found in pancreatic juice?

Back 172

80%

Front 173

What are the lipolytic enzyme and what do they do?

Back 173

involved in lipid digestion
-lipase
-phospholipase
-carboxyesterase

Front 174

What do amylolytic enzymes work on?

Back 174

spillting 1-4 glycosidic linkages
- important for carbohydrate digestion

Front 175

What do nucleases do?

Back 175

digest nucleic acids

Front 176

What is the purpose of trypsin inhibitor?

Back 176

provides extra protection to acinar cells in the event active trypsin forms within zymogen granules - this would have devastating events

Front 177

How does the pancreas protect itself from pancreatic enzymes?

Back 177

1)made in pro-enzyme
2) packaged into zymogen granules
3) co-packing with trypsin inhibitor
4) geographical (pancreas-duct- duodenum)

Front 178

Trypsinogen is activated how?

Back 178

Enterokinase (enteropeptidase) is a brush border enzyme that converts trypsinogen to trypsin

Front 179

What does trypsin do?

Back 179

activates other proenzyme

Front 180

What is the difference between ductular and acinar secretions?

Back 180

ductular secretion is HCO3-rich
whereas acinar fluid has a plasma like electrolyte composition

Front 181

Why are ductular secretions high in HCO3?

Back 181

important for neutralizing gastric acid entering the duodenum

Front 182

What is the purpose of acinar fluid?

Back 182

essential for transporting secreted enzymes into the ductular system

Front 183

What determines the final concentration of pancreatic juices?

Back 183

Front 184

explain this slide?

Back 184

- at low flow rates, pancreatic juice is mostly NaCl with small K and HCO3
- as rates increase, an inverse relationship between Cl and HCO3 - juice becomes progressively more alkaline
* K and Na concentrations are independent of secretory rate

Front 185

explain this slide?

Back 185

- at low flow rates, pancreatic juice is mostly NaCl with small K and HCO3
- as rates increase, an inverse relationship between Cl and HCO3 - juice becomes progressively more alkaline
* K and Na concentrations are independent of secretory rate

Front 186

What is the major regulator of ductular fluid secretion?

Back 186

Secretin
- made by endocrine cells and is a potent stimulus of pancreatic bicarbonate secretion

Front 187

What are the phases of pancreatic function?

Back 187

1) cephalic - 50%
2) gastric - 10%
3) intestinal - most important

Front 188

Describe the cephalic phase of pancreatic function?

Back 188

initiated by the CNS
-activation of pancreatic functions occurs by stimuli from efferent vagal fibers
-promotes secretion of enzymes and bicarbonate

Front 189

Describe the gastric phase of pancreatic function?

Back 189

least important phase - 10%
* initiated by stomach distention and by the presence of aa and peptides
** have little effect on bicarbonate secretion

Front 190

Describe the intestinal phase of pancreatic secretion

Back 190

initiated by gastric chyme into the intestinal lumen (especially fat acids)
*fatty acids and H+ stimulate mucosal endocrine cells secretion of CCK and secretin (juxtacrine action)
-- activates cholinergic enteric neurons

Front 191

Back 191

bicarbonate release is proportional to acid load
* this process is tightly regulated by secretin - also has an inhibitory effect on gastric acid secretion and motility - allowing time for digestion
**pH of the duodenum is neutral

Front 192

How is pancreatic function returned to normal?

Back 192

Through feedback inhibition of pancreatic function
* presence of active pancreatic protease inhibit pancreatic enzyme secretion

Front 193

What are the advantages of maintaining duodenal pH near neutral?

Back 193

Front 194

Back 194

Front 195

Back 195

enterokinase is absent so the pancreatic enzymes are low because they are all still in their zymogen form
* enterokinase converts trypsinogen to trypsin which further activates the zymogens

Front 196

Back 196

Chronic pancreatitis

Front 197

What are the causes of chronic pancreatitis?

Back 197

Front 198

What is the pathophysiology of chronic pancreatitis?

Back 198

Front 199

Back 199

vagal nerve is essental for mediating CCK-stimulated acinar-cell zymogen secretions (secretin - bicarbonate)
* CCK is released by endocrine cells of the duodenal mucosa in response to luminal fat then CCK stimulates afferent vagal fibers that initiate the majority of stimulated acinar cell secretions

Front 200

What the three situations in which amylase will be in the urine?

Back 200

1) duct obstruction
2) rupture
3) pancreatic destruction

Front 201

What can one suspect when amylase>> creatine in the urine?

Back 201

Pancreatitis
- used as a diagnostic tool

Front 202

How does fluid absorption differ throughout the small intestine?

Back 202

2L by mouth
7L by secretions = 9 L /day
* most fluid is removed by Duod/Jej/Ileum
8.8 L gets absorbed of the 9 L that enters
*just 1% off = then you will have symptoms

Front 203

Describe the permeability throughout the stomach?

Back 203

* small bowel must be "leakier" to accommodate rapid changes in water and electrolyte fluxes after a meal
*permeability of the colon and rectum must be less leaky to prevent back flux of absorbed water in electrolytes - property required for solidification of stool

Front 204

What are defensins?

Back 204

They are secreted by paneth cells
* have antimicrobial properties

Front 205

What are enterocytes responsible for?

Back 205

They are at the top of the villi and do the most secretion

Front 206

What are the functional differences between crypt cells and villi cells?

Back 206

Crypt - short, immature, cubodial, rudimentary microvilli, and terminal web -- and tight junction complexes
* Permeability high to accommodate secretions

Villi cells- tall columnar, mature cells, well developed terminal web,tight junctions
*solubility low to protect against back flow

Front 207

Back 207

Appreciate the difference

Front 208

What role do blood vessels and lymphatics play for the intestine?

Back 208

intestinal water and electrolyte transport
- absorption - carry away nutrients, water, electrolytes
-secretion - deliver fluid and electrolytes

Front 209

In the proximal small intestine how is Na absorbed?

Back 209

Na-H exchangers function independently in the proximal small intestine

Front 210

In the Ileum how is Na absorbed?

Back 210

Na-H exchange is coupled with anion exchanger (solute and Cl)

Front 211

In the Colon how is Na absorbed?

Back 211

through the help of an Na-H exchanger (Cl)

Front 212

How is Na absorbed in the Rectum?

Back 212

Na-H exchanger coupled to Cl and also through an Na channel

Front 213

Back 213

Summary

Front 214

Where is Chloride absorbed at?

Back 214

throughout the GI tract
passively

-coupled Na and Cl absorption Duodenum- ileum
- HCO3 dependent Cl absorption - distal ileum to rectum

Front 215

Potassium transport throughout the small intestine occurs how?

Back 215

most is absorbed passively
** in the colon however active K secretion and absorption are observed

Front 216

Back 216

Na is high on the luminal side right after a meal
- uses a low Na gradient in exchange for a proton
*Amiloride (diuretic) sensitive luminal membrance transporter that mediates the exchange of one proton with on Na ion
- Na, K-ATPase extrudes the Na out the other side

Front 217

Why have two exchangers that do the same thing?

Back 217

THe NHE3 is the fine tuning of exchange because it is more tightly regulated that NHE2
* these exchangers are NOT in the crypts

Front 218

Back 218

Na-H coupled to Cl (anion exchanger)
Cl is also absrobed
- net effect - absorbing both Na and Cl
- bicarbonate being extruded into the intestinal lumen

Front 219

Back 219

*SGLT1 is an Na-Glucose co-transporter
* Glucose extis the cell by Glut2, whereas Na is pumped out by the Na pump
Effective way of getting Na and glucose into the blood stream
- moving 2+ charges so the blood side is more positive than the lumen
- NaCl absorbed in the presence of glucose
** In contrast to other Na absorptive pathways, glucose and aa stimulated Na absorption are NOT affected by enterotoxins such a cholera toxin or enterotoxin

Front 220

Back 220

powerful pump
- pump out sodium...water will follow and then the luminal contents will solidify

Front 221

What is the rationale behind using sugar or aminoacid-based oral rehydration solutions for treatment of cholera or traveler's diarrhea?

Back 221

Glucose and Na absorption though SGLT1 isn't affected by enterotoxins (cholera or ST-alpha)
* use sugar or aminoacid-based oral rehydration solutions
**rice also very effective

Front 222

what is intestinal secretion driven by?

Back 222

secretion of Cl or HCO3
- Cl enters the cell via basolateral membrane Na/K/2Cl
- Cl enter lumen through CFTR
- opening of these channels is done by protein kinases
** active Cl secretion in the gut is regulated by numerous neurotransmitters and gut peptides

Front 223

What are the two divisions of regulatory mediators of intestinal water and electrolyte transport?

Back 223

2 groups:
1) secretagogues
2) proabsorptive agents

Front 224

How doe secretagogues agents work?

Back 224

they stimulate net intestinal secretion by activating active anion secretion and inhibiting NaCl absorption
- Serotonin, CCK, Gastrin, Guanylin, arachiodnate metabolites (NO), stimulate enteric neurons, Blood (VIP, Calcitonin)

Front 225

How do Pro-absorptive agents work?

Back 225

somatostatin, catecholamines, and adrenal steroid hormones

Front 226

Can the intestinal mucosa change?

Back 226

*starvation- there is nothing there to absorb so don't put energy into maintaining villi
* diabetes (short bowel)- elongation- body doesn't think that glucose is there so they hypertrophy

Front 227

Acute regulation of intestinal water and transport makes rapid changes by?

Back 227

cellular regulations of transport protein activity and NOT by altered expression of their abundance
*when signals cease the transport rates return to normal

Front 228

Do pro-absorptiev agents inhibit the release of secretagogues?

Back 228

Yes.
Ex: adrenergic agents stimulate pre-synaptic alpha-2 adrenergic receptors INHIBITING Ach release for enteric neurons

Front 229

By what mechanism do pro-secretory agents work?

Back 229

increase cyclic nucleotide or cytosolic Ca
*Adenylate cyclase- VIP and prostaglandin E2 = increase cAMP

*PIP2- Ach and serotonin = increases in Ca

Front 230

How does Guanylin work?

Back 230

secreted into the intestinal lumen
binds surface receptors that have guanylate cyclase activity
* increase in cGMP = net secretion
- increased anion secretion and inhibiting NaCl absorption

Front 231

By what mechanism does enterotoxin of E.Coli?

Back 231

binds to the guanylin receptor
* causing profuse diarrhea that is common for traveler's diarrhea

Front 232

What are three examples of chronic regulation so intestinal water and electrolyte transport?

Back 232

"intestinal adaptation"
1) massive small bowel resection or disease
2) plasma volume depletion
3) SCFA

Front 233

What effect does massive small bowel resection or disease have?

Back 233

increase in villus width and height are adaptive responses = increase in absorptive capacity
** increase in enterocyte Na absorptive capacity due to increased gene expression of Na-H exchangers

Front 234

What is the adaptation in plasma volume depletion?

Back 234

intestine increases its ability to absorb fluid and electrolytes
**increased plasma levels of aldosterone
- increases expression of luminal membrane Na-H exchangers (NHE3)- proximal colon
* increase in Na channel and Na pump in distal colon and rectum
* GAPDH is unchanged
***allows the increased extraction of water and electrolytes

Front 235

What is colonic CHO metabolized to?

Back 235

CO2, SCFA,H2 (gas)

Front 236

What are colonocytes?

Back 236

are mature, non-dividing epithelial cells forming the colonic epithelium. These columnar epithelial cells belong to one of several epithelial cell lineages in the gastrointestinal tract, which differ from each other in morphology and function (

Front 237

What are the effects of SCFA on intestinal mucosal function?

Back 237

1) preferred metabolic fuel soruce for coloncytes
2) promote mucosal proliferation and differentiation
3) stimulate intestinal Na absorption
4) chronic upregulation of eletroneutral Na absorption in colonic mucosa

Front 238

Back 238

high fiber diet (pectin)
* marked increase in the protein expression of colonic NHE3
** mediated by SCFA- stimulated increases in NHE3 gene expression
*only occurs in the colon because that is where the bacteria are located

Front 239

Back 239

when you start changing dietary habits
- dump a larger load on bacteria and overwhelms them
- but continue diet and then the bacteria will accomodate
* possibly due to increase transporters like NHE3 to accommodate the uptake of more fluid

Front 240

what are the major pathophysicological mechanisms causing diarrhea?

Back 240

Front 241

Back 241

STalpha binds to guanylate cyclase - increase in cGMP = active secretion of anions and inhibiting uptake of Na and Cl
** no mucosal inflammation of destruction

Front 242

Do increased propulsive motor contractions cause diarrhea?

Back 242

Not by themselves but usually associated with diarheally cases
* reduce the contact time between luminal fluid and the absorptive surface area (can cause nutrient malabsorption)

Front 243

Back 243

Cholera binds GM1- ganglioside receptor of the enterocyte
* inserts its alpha sub-unti into the cell
* irreversibly activating adenylate cyclase through Gs reg. subunit
- increases in cAMP causes net secretion by inhibiting NaCl absorption and stimulates active anion secretion

Front 244

Is nutrient dependent Na absorption affected by cholera toxin

Back 244

No

Front 245

What are the solutions to helping cholera toxin?

Back 245

low bicarbonate due to secretion
- can use oral replacement therapy so that numbers go back to normal
*BUT you can't do anything to help the diarrhea you might actually make it worse
- need cells to renew so wait 5 days

Front 246

What occurs in cystic fibrosis?

Back 246

CF patients are unable to secrete chloride through CFTR
- leads to very viscous secretions
* can lead to mucus obstruction in intestinal lining = meconium ileus
* can also see blocking of pancreatic ducts
* pulmonary infections are common

Front 247

What occurs during diabetic diarrhea?

Back 247

uncommon
* diarrhea, anal incontinence, and autonomic neuropathy
due to: diabetes- associated destruction of noradrenergic autonomic nerves to the gut
*nerves have a pro-absorptive role
Treatment: alpha-2- adrenergic receptor agonist, clonidine, Octreotide

Front 248

Back 248

SUMMARY

Front 249

What does salivary amylase break down?

Back 249

starch

Front 250

What does lipase break down?

Back 250

fat

Front 251

What does HCl acid and pepsin break down?

Back 251

protein

Front 252

What are the three phases of the events in the small intestine?

Back 252

1)intraluminal digestion
2)mucosal absorption
3) nutrient delivery

Front 253

What does digestion consist of?

Back 253

characterized by pancreatic enzyme secretion and the release of bile salts that are critical for micellar solubilization of lipid
* Key events - release of CCK and secretin - stimulate bile salt and pancreatic secretion

Front 254

When is CCK released from the proximal small intestine?

Back 254

in response to amino acids and fatty acids in the lumen
*CCK acts indirectly through the release of Ach which act on M3 receptors in the pancreas

Front 255

What does CCK do?

Back 255

1) stimulates pancreatic enzyme secretion (amylase, lipase, and protease) from pancreatic acinar cells
2) causes contraction of the gallbladder
3) relaxation of Sphincter of Odi

Front 256

What does secretin do?

Back 256

stimulates bicarbonate secretion from pancreatic duct cells
*neutralization of the acid

Front 257

Main source of calories in the diet?

Back 257

Front 258

CCK stimulates secretion of which enzymes?

Back 258

protease is the only one secreted in an inactive form

Front 259

Back 259

Nutrients are absorbed the entire length of the small intestine
*exception of folate and iron which are just absorbed in the proximal duodenum and jejunum
*biles salts and cobalamin can only be absorbed in the distal ileum
*Ca can be absorbed throughout at high concentrations

Front 260

What factors affect or influence the efficiency of nutrient uptake in the mucosa?

Back 260

1) number of villus absorptive cells present
2) presence of brush border hyrolases
3) specific nutrient transport proteins on the brush border membrane
4) transit time (motility) - determines the amount of time of contact

Front 261

length of small intestine in child and adult

Back 261

Front 262

How is the surface area of the small intestine amplified?

Back 262

-folded on itself
-off each fold there are villi
- on each villi there are microvilli (brush border)

Front 263

Explain how absorption of water and electrolytes are coupled to nutrient absorption?

Back 263

Sodium-glucose ligand transporter 1 (SGLT1)
- Na and glucose move into the cell
- glucose then transported across the basolateral membrane into paracellular space
* net result: water and electrolyte absorption

Front 264

How much energy do dietary carbohydrates provide?

Front 265

How much energy do dietary carbohydrates provide

Back 265

about half of an american's diet

Front 266

Definition of Dietary fiber?

Back 266

dietary fibers are mainly constituents of plant cell walls that resist digestion by enzymes of the human GI tract

Front 267

How does digestion of starches occur?

Back 267

Through alpha amylases (salivary amylase and pancreatic amylase)

Front 268

What are the products of alpha-amylase digestion?

Back 268

1) maltose
2) maltotriose
3) branched alpha-limit dextrin
4) oligosacchardies

Front 269

What must happen to oligosaccharides before digestion?

Back 269

must be digested to sugar monomers before they are absorbed
*hydrolyzed by brush border enzymes
*activity of oligosaccharides is greatest in the proximal small intestine

Front 270

digestion of alpha-limit dextrins (branched)?

Back 270

removal of glucose from non-reducing end by GLUCOAMYLASE
ISOMALTASE cleaves the alpha 1-6 linkage
* digestion of maltotriose and maltose to glucose by SUCRASE OR GLUCOAMYLASE

Front 271

Absorption of glucose or galactose occurs how?

Back 271

Through SGLT1 transporter
- along with 2 Na+ ions
= secondary active transport

Front 272

Under high luminal glucose conditions which other mechanism is at work for absorption of monosacchardies?

Back 272

Glut2 insertion in the apical membrane = regulated by Ca, intestinal taste receptors,insulin, glucagon-like peptide 2, and stress
*

Front 273

Under high luminal glucose conditions which other mechanism is at work for absorption of monosacchardies?

Back 273

Glut2 insertion in the apical membrane = regulated by Ca, intestinal taste receptors,insulin, glucagon-like peptide 2, and stress
*

Front 274

Glut5 vs. Glut2

Back 274

monosaccharide transporter for fructose by facilitated diffusion on lumen side

* Glut 2 does (glucose, galatose, and fructose)

Front 275

What are the sites of sugar absorption?

Back 275

transporters are regulated along the longitudinal axis (highest in jejunum and lowest in ileum) and horizontal axis

Front 276

Acquired lactase deficiency?

Back 276

expression of lactase beings in late gestation
and then declines after weaning down to only 10%
*decreased synthesis of the enzyme
**acquired lactase deficiency develop abdominal gas/bloating, cramps, and diarrhea
* unabsorbed lactose draws water into the lumen
*lactose - SCFA- methane, CO2, and H2

Front 277

Congenital glucose- galactose malabsorption?

Back 277

Rare autosomal recessive disease (missence mutation in SGLT1)
* glucose isn't being taken up with 2 Na+
*increased concentrations in the lumen will increase amount of water that stays in the lumen
*Fructose is well tolerated and can be feed to infants with this disorder

Back 278

Fiber that gets down to the colon where bacteria can digest it
*generate short chain fatty acids and gas
*bacteria help salvage these nutrients

Front 279

Back 279

fiber that isn't soluble gets down to the colon
*bacteria can digest it
* generate SCFA,CO2, H2
*bacteria salvage these nutrients

Front 280

Back 280

Lactase is inefficient
if you aren't absorbing the SCFA that the bacteria make then the pH of your stool with decrease

Front 281

Sources of proteins?

Back 281

1) the diet
2) endogenous proteins in digestive secretions
3) proteins present in exfoliated intestinal cells

Front 282

If gastric pepsins are absent, is protein digestion and absorption affected?

Back 282

* No, gastric pepsin only accounts for 15% or dietary proteins
* pepsins are irreversibly denatured in mildly alkaline fluid, and thus little peptic digestion occurs past the duodenum

Front 283

Back 283

Front 284

How are pepsins made?

Back 284

synthesized in gastric chief cells as inactive pro-enzymes
-signal sequence directs the protein to golgi
- condensed into secretory granules
- secretion of granules by exocytosis occurs through increases in cAMP or Ca
- cleavage of 44 aa at N-terminus in acidic environment = active

Front 285

endopeptidase and exopeptidases?

Back 285

endo- trypsin, chymotrypsin, elastase
exo- carboxypeptideases A and B - remove aa from carboxy-terminus

Front 286

After pancreatic proteases, how is further digestion of oligopeptides occur?

Back 286

through brush border membrane peptidases
-20 different (1 of 4 groups_
*endopeptidases
* aminopeptidases
* carbozypeptidases
* dipeptidase

Front 287

Back 287

The brush border peptidases are mainly active against peptides of four or more aa to produce free amino acids as well as di and tri-peptides
** either small peptides of aa can be absorbed by enterocytes
* single membrane transport system with broad specificity

Front 288

The jejunum, transport of ____ is the most significant

Back 288

transport of di and tri-peptides is more significant than free aa

Front 289

The ileum is more active in the uptake of ____ than the jejunum?

Back 289

more active in the uptake of single amino acids
- free aa are transported across the brush border

Front 290

Intracellular peptidase and transport across the basolateral membrane occurs how?

Back 290

enterocyte contains at least four intracellular peptidases that are involved in digestion of di and tri- peptides
* 90% or more of the products of protein digestion appear in the portal blood as free aa
* 5 classes of transporters on basolateral side
- 3 Na independent and 2 Na dependent

Front 291

How do acidic aa move across the basolateral side of the enterocyte?

Back 291

no known basolateral transporters for acidic aa (glutamine, glutamate, aspartate)
** shunted into the pathways of energy metabolism

Front 292

What is Hartnup's disease?

Back 292

rare autosomal recessive disorder that involves defective renal and intestinal transport of neutral aa
** malabsorbed tryptophan is metabolized by gut bacteria to various indoles and excreted in feces and urine
* Tryptophan is a precursor for Niacin

Front 293

What is Cystinuria?

Back 293

defect in the dibasic brush border aa transporter in the small intestine and renal proximal tubule

Front 294

Back 294

in lysinuric protein intolerance, a rare autosomal recessive defect in the transporter present in the basolateral membrane of intestinal villus and renal tubular epithelial cells
*unlike cystinuria or hartnup - babies with lysinuric intolerance have severe growth retardation and failure to thrive
**in the prior two disease the defect can be bypassed
* but in lysinuric, the transport across the basolateral membrane can not occur- and therefore are never absorbed

Front 295

What is the primary lipid consumed in the diet?

Back 295

Long chain triglycerides and smaller amount of cholesterol, phospholipids, and fat-soluble vitamins.

Front 296

Where does the digestion of lipids begin?

Back 296

In the stomach with gastric lipase
* hydrolyzes the 3-position fatty acid

Front 297

What produces gastric lipase? Characteristics of gastric lipase?

Back 297

chief cells in the fundus of the stomach
* its secretion is stimulated by cholinergic agents (gastrin and CCK)
* active over a broad range of pH (2-6)
*resistant to pepsin
*inhibited by bile salts

Front 298

Back 298

most dietary triglycerides are composed of long chain fatty acids (C14-22) saturated or unsaturated
* polyunsaturated are preferentially located in the 2 position of the glycerol backbone

Front 299

Back 299

The churning action of gastric peristalsis against the closed pylorus results in the formation of oil emulsions containing triglycerides in its core

Front 300

Gastric lipase is responsible for what percentage of total intraluminal lipid digestion?

Back 300

20-30%
*fat emulsion is then emptied into the duodenum

Front 301

Fat in the duodenum strongly inhibits what action?

Back 301

gastric emptying
*this is to ensure that fat is not emptied more rapidly than the duodenum can accommodate

Front 302

Back 302

Summary

Front 303

Properties of Gastric Lipases?

Back 303

Front 304

Gastric acid in duodenum stimulates secretion of what?

Back 304

Secretin - peptide hormone from neuroendocrine cells
*secretin stimulates secretions of bicarbonate rich fluid by pancreatic ductular cells

Front 305

Back 305

1) hormone secreted from gut when fatty acids and aa are present 2) hormone circulates in blood
3) CCK induces discharge of enzyme
4) induces gallbladder contraction and sphincter relaxation

Front 306

How much lipase is secreted for fat digestion?

Back 306

Front 307

What is the product after pancreatic lipase has worked on the triglyceride?

Back 307

3 fatty acids
Now these products are soluble in micelles where triglycerides are not

Front 308

Tegmentum:

Back 308

The intermediate level of the midbrain containing nuclei for cranial nerves and part of the reticular formation

Front 309

What is this showing?

Back 309

Bile salts with lecithin - coat and stabilize the fat emulsion
*inhibits pancreatic lipase activity
* therefore, pancreatic colipase is required to displace the bile salts
**colipase also serves as an anchor the lipase then you can have cleavage of the triglyceride

Front 310

Properties of Pancreatic lipase

Back 310

Front 311

What are bile-salt activated lipases? What function do they have?

Back 311

ex: phopholipase A2 and cholesterol esterase
*require bile salts for their activity
* will catalyze hydrolysis of many ester bonds (unlike pacreatic lipases)
**bile salts induce conformational changes in the enzyme that provides access to bulky substrates

Front 312

Why doesn't human milk which contains lipases, catalyze hydrolysis of lipids in the breast tissue

Back 312

There is a bile-salt requirement for human milk

Front 313

In adult, pancreatic lipase or bile-salt activated lipase has more of an effect?

Back 313

pancreatic lipase 10-60x more lipolytic activity
*majority of triglyceride digestion

* in neonates, pancreatic lipase is immature compensated with gastric lipase and milk bile salt activated lipase

Front 314

Back 314

Summary

Front 315

Back 315

suggests pancreatic insufficiency
* fat malabsorption due to decreased lipase secretion = impaired lipolysis
* unabsorbed triglycerdie emulsion causes large bulky stools (don't stimulate fluid secretion)
* pancreatic insufficiency usually due to CF or hereditary pancreatitis

2) oral pancreatic enzymes are denatured at acid pH
- lack bicarbonate secretion all of the enzymes are being destroyed by acidic environment
*improve by blocking acid secretion H2 or PPI

Front 316

Back 316

Major component of bile
*above critical concentration- bile salts form micelles

Front 317

Back 317

mixed micelles are multi-molecular aggregates of varying size depending on the ratio between bile salts and lipolytic product

Front 318

What is the rate limited step of lipid uptake?

Back 318

the diffusion of mixed micelles across this unstirred water layer
*pH gradient exists across this layer- the fluid is in immediate contact with the brush border is about 1 pH more acidic
*lower pH may enhance absorption (as protonated FA are more soluble than ionized forms)

Front 319

How are fatty acids and 2 monoglycerides taken into the enterocyte?

Back 319

Through the microvillus membrane fatty acid transporter FATP4

the mechanism for 2 monoglycerides is probably by simple diffusion across brush border- high lipid solubility

Front 320

Back 320

Summary

Front 321

Back 321

chylomicrons undergo further processing in the golgi
followed by fusion into secretory vesicles and exocytosis at the basolateral membrane of enterocyte
expels into the extracellular space

Front 322

What are the two families of cytosolic fatty acid-binding proteins?

Back 322

Fabpi- specific for long chain
Fabpl- broader specificity

Front 323

What do lipids need to be bound to intracellular Fabps?

Back 323

prevents lipids form forming lipid droplets in the cytosol and directs them to the SER for triglyceride resynthesis

Front 324

What happens when the free fatty acids reach SER?

Back 324

the fatty acids and 2 monoglycerides are re-esterified to form triglycerides
*large lipid droplets are formed at the apex of the enterocyte following a fatty meal

Front 325

Lipid droplets are converted into chylomicrons by what?

Back 325

Phospholipids and apolipoproteins A,B, and C

Front 326

What are the two pathways for Triglyceride synthesis?

Back 326

Front 327

Back 327

Chylomicrons are spherical and vary greatly in size
-90% of their mass is accounted for by triglycerides
- too large to transverse the mucosal capillaries
-leave the intestine in fenestrated lacteals and ultimately delivered to the venous circulation by the thoracic duct

Front 328

Back 328

MCT (6-12C) - small amt of diet
*digestion and absorption of MCTs differ significantly
MCTs are:
1) hydrolyzed more rapidly
2) more H2O soluble
3) don't need bile salts to be taken up by enterocyte
4) directly released
*not resynthesized
* no chylomicrons

Front 329

Back 329

MCT (6-12C) - small amt of diet
*digestion and absorption of MCTs differ significantly
MCTs are:
1) hydrolyzed more rapidly
2) more H2O soluble
3) don't need bile salts to be taken up by enterocyte
4) directly released
*not resynthesized
* no chylomicrons

Front 330

Pros and Cons of MCT?

Back 330

Pro: useful in people with digestion and absorption issues
- nutritional supplement in patients with GI disorders

Con: MCT do not contain essential polyunsatruated fatty acids, which are the precursors for prostaglandins, leukotrienes, etc.

Front 331

Back 331

these finds suggest failure or transport of chylomicrons from the basolateral membrane of villus cells
* decreased lipids in the blood = cause lipid membrane abnormalities (RBC)
**ABETALIPOPROTEINEMIA

Front 332

What is abetalipoproteinemia?

Back 332

rare autosomal disease due to failure in secretion of chylomicrons in the intestine
*mutation in gene for microsomal triglyceride transfer protein (MTTP) - protein required fro the assembly and secretion of apo-B containing lip-proteins
*triglycerides are lost in the stool as the enterocytes are sloughed as part of normal turnover

Front 333

Why is bile needed?

Back 333

the physicochemical properties of bile salts make micellar solubilization of lipid possible in the aqueous environment of both bile and intestinal fluid

Front 334

How much bile is secreted daily?

Back 334

1L/day in adults

Front 335

Composition of hepatic bile?

Back 335

97.5% water / bile salts/ mucin / lipid

Front 336

How are bile salts synthesized?

Back 336

synthesized from cholesterol

Front 337

What are the two bile salts directly formed from cholesterol?

Back 337

The primary bile salts:
* sodium cholate
* sodium chenodeoxycholate
**synthesis is regulated by feedback inhibition

Front 338

What is the rate limiting step of bile salt synthesis?

Back 338

at the site of microsomal enzyme 7alpha-hydroxylase
= rate limiting in the synthesis of bile salts from cholesterol

Front 339

Bile salts returning to the liver can also have an inhibiting effect...how?

Back 339

act at the rate-limiting enzyme in the cholesterol synthesis, HMG-CoA reductase

Front 340

How much bile salts are made daily?

Back 340

.3-.6 / day
but this can increase 5-10x in the case of bile salt depletion

Front 341

l'espoir (m.)

Back 341

hope

Front 342

honteux (-euse)

Back 342

shameful

Front 343

What purpose does cholyl amidase serve?

Back 343

bacterial enzyme i the terminal ileum that can cleave the extremely strong amide conjugation

Front 344

Back 344

Conjugation of bile salts lowers the pKa
* allowing bile salts to remain in solution at normal duodeanl-jejunal pH (6.5) - will not precipitate out

Front 345

Enterohepatic circulation?

Back 345

conserves bile salts within the intestine by the action of the enterohepatic circulation

Front 346

Back 346

Normal conditions: bile salts are efficiently reabsorbed by the apical sodium-dependent bile transporter (ABST) located in the ileum

Front 347

Why is there a little jejunal absorption of bile salts?

Back 347

Due to the glycine conjugates being at a higher pKa
*this allows a little jejunal absorption by passive nonionic diffusion

Front 348

How much of the intraluminal concentration of bile salts is reabsrobed?

Back 348

90% is re-absorbed
*but by recycling 5-10x /day the physiological pool of bile salts becomes much greater

Front 349

2 ways that bile salts are attacked in the intestinal lumen?

Back 349

1) deconjugation (cholyl amidases)
2) dehydroxylation - to produce the following secondary bile salts

Front 350

What are the secondary bile salts?

Back 350

1) sodium deoxycholate
* from cholate conjugates
2) sodium lithocholate
*from chenodeoxycholate conjugates

Front 351

After a single enterohepatic circulation how many bile acids are no longer conjugated?

Back 351

10-20% of the portal venous bile acids are no longer conjugated after a single circulation

Front 352

Where are bile salts re-conjugated?

Back 352

The bile salts are reconjugated after being taken up by the liver and then re-excreted into the bile

Front 353

Do secondary bile salts (like primary) undergo enterohepatic circulation?

Back 353

Yes!
* significant amounts of deoxycholate are reabsorbed
* but only trace amounts of lithocholate appear in bile

Front 354

What is the normal distribution of bile salts?

Back 354

40% cholate
40% chenodeoxycholate
20% deoxycholate
13% lithocholate

Front 355

What are the 4 things that normal bile salt kinetics depend on:

Back 355

1) hepatic synthesis
2) secretion into bile
3) appropriate intestinal mileu
4) intact enterohepatic circulation

Front 356

Bile salts act as a detergent to do what function?

Back 356

solubilize fats for their efficient absorption

Front 357

Bile salt synthesis is tightly regulated... why?

Back 357

Because bile salts are cytotoxic at high concentrations
*want to prevent liver damage

Front 358

What are nuclear hormone receptors?

Back 358

transcription factors that are activated by ligands
*nuclear receptor FXR forms a heterodimer with RXR to increase transcription of bile salt metabolism

Front 359

FXR up-regulates expression of bile salt transporters on what membrane of the cell?

Back 359

Both the basolateral and the canalicular hepatocyte membranes

Front 360

When to micelles form?

Back 360

When hydrophilic properties predominate
ex: bile salts

Front 361

When do bilaminar sheets of crystals form?

Back 361

when hydrophobic and hydrophilic are about equal

Front 362

When do hydrophobic properties form?

Back 362

in a molecule that is insoluble
ex: cholesterol

Front 363

What happens when the critical micellar concentration is exceeded?

Back 363

micelles form when the concentrations of bile salts exceed this threshold

Front 364

Mixed micelles?

Back 364

larger lipid-soluble core than a pure bile salt solution
*solubilization of lipid in the inner lipid core for him
*formation of mixed micelles is crucial to solubilizing cholesterol in the bile and dietary fat

Front 365

What actions can biliary ductules preform?

Back 365

capable of both reabsorption and secretion

Front 366

What is the function of the gallbladder?

Back 366

mucosa of the normal gallbladder is capable of concentrating bile salts, pigments, and lipid constituents

Front 367

Sources of Intraluminal cholesterol?

Back 367

1) diet
2) intestinal turnover
3) bile

Front 368

Explain intraluminal digestion of cholesterol?

Back 368

hydrolysis of cholesterol esters by cholesterol esterase
* then solubilized into micelles

*uptake across the brush border
* reseterfication of enterocytes with fatty acids

Front 369

What are the two functions mentioned for phospholipids?

Back 369

1) cell membranes
2) chylomicron assembly

Front 370

Intraluminal digestion of phospholipids?

Back 370

hydrolysis by phopholipase A2 to yield a LCFA and lysolecithin

*lysolecithin- water soluble
and rapidly absorbed by diffusion
*LCFA are solubilized in micelles

Front 371

What are the fat-soluble vitamins?

Back 371

E, D, A, K

Front 372

Biochemical functions of fat-soluble vitamins?

Back 372

Front 373

What are the food sources for fat-soluble vitamins?

Back 373

Front 374

Describe the intraluminal digestion of Vitamin A?

Back 374

retinyl esters are hydrolyed by pancreatic esterase to retinols and carotenoids

Front 375

Back 375

summary

Front 376

Vitamin D is absorbed how?

Back 376

-solubilized in micelles
-uptake across mucosa is by passive diffusion
-packaged into chylomicrons
-exocytosis into the liver and kidney

Front 377

Where does D3 interaction with Vitamin D?

Back 377

1, 25 (OH)2D3 interaction with a vitamin D receptor

Front 378

What is the intraluminal digestion of Vitamin E?

Back 378

*de-esterfication of pancreatic esterase and solubilized inot micelles
* passie diffusion into enterocytes, re-esterfied, into chylomicrons, and delivered to circulation via lymphatics

Front 379

Absorption of Vitamin K?

Back 379

phylloquinones from the diet are solubilized into micelles and taken up into enterocytes by passive diffusion

Front 380

Back 380

summary

Front 381

Back 381

summary

Front 382

Back 382

summary

Front 383

Back 383

summary

Front 384

Back 384

summary

Front 385

What are the water-soluble vitamins?

Back 385

Front 386

Function of water soluble vitamins?

Back 386

function as coenzymes

Front 387

What are the minerals that are absorbed in the small intestine?

Back 387

Calcium, phosphorus, magnesium, and sulfur

Front 388

What are the trace elements that are necessary for biochemical processes?

Back 388

Calcium
Phosphorus
Magnesium
*provide structural support (skeleton)

Front 389

Function of Vitamins and Minerals

Back 389

Front 390

What are the exceptions to absolute dietary vitamin requirements?

Back 390

Front 391

What is cobalamin?

Back 391

has two portions
nucleotide and porphyrin-like corrin ring- contains cobalt at center

Front 392

What are some of the ligands that are attached to the cobalt in the corrin ring?

Back 392

1) methyl- biological
2) 5-deoxyadenosyl group
3) cyanide group- commercial

Front 393

Is Cobalamin conserved?

Back 393

Yes. Cbl is excreted into the bile and then reabsorbed
Daily losses: 1-3 ug
*Due to large stores in the liver reabsorption in the intestine it could take 2-12 years for a Cbl deficiency to be detected

Front 394

Foods containing B12

Back 394

Front 395

Cobalamin-Binding Protein: Intrinsic factor

Back 395

Source: Partietal cells
Required for: uptake of Cbl by ileum

Front 396

Cobalamin-Binding Protein: R binders

Back 396

Source: Many cells, all secretions
Required for: Unknown

Front 397

Cobalamin-Binding Protein: Cubulin

Back 397

Source: ileal cells, endocytic receptor
Required for: Uptake of Cbl-IF

Front 398

Cobalain binding Protein: IF Aminoless

Back 398

Source: endocytic receptor
Required for: complex by ileum

Front 399

Cobalain binding Protein: Transcobalamin II

Back 399

Source: liver, intestinal mucosa, macrophages
Required for: Transport of Cbl out of gut and into cells

Front 400

Once cobalamins are liberated from bonds in proteins, the Cbl is bound to one of two different proteins...what are they? How do they differ?

Back 400

at lower pH (stomach) more Cbl is attached to R-proteins
but
once the Cbl enter the small intestine- R proteins are degraded by proteases freeing Cbl to bind to IF

Front 401

Back 401

Summary

Front 402

once the IF- Cbl complex has formed where does it travel?
what occurs?

Back 402

To the distal ileum
- where it is exposed to specific endocytic receptors (cubulin and aminonless) which are expressed at the apical surface of ileal cells
*absorb IF-Cbl

Front 403

What is Imerslund-Grasbeck Syndrome?

Back 403

Syndrome seen in Finnish population that supports the role of cubilin in vitamin B12 absorption

Front 404

What happens to Cbl-IF once internalized?

Back 404

IF is degraded
*then Cbl is complexed with transcobalamin II in the portal circulation

Front 405

What does TCII do?

Back 405

Transports cobalamins to tissues such as bone marrow and the nervous system

Front 406

What is cobalamin essential for?

Back 406

- synthesis of succinyl CoA
- methionine (aa, purine, pyrimidine)
- conversion of homocystenine to methionine
** deficiencies can disrupt DNA synthesis
***leading to megoblastic anemia and neuropsychiatric disturbances

Front 407

Common causes of Cobalamin deficiency?

Back 407

1) chronic atrophic gastritis
2) ileal disease (Crohn's, tropical sprue, ileal resection
3) bacterial overgrowth
*lack or abnormal IF
* decrease surface receptors for Cbl-IF complex
* lack or abnormal TCII

Front 408

What purpose does folate serve in the body?

Back 408

* bacteria in the colon can also produce folate
* acts to transfer 1 carbon unit for a number of enzymatic reactions involved in DNA, RNA, and protein synthesis

Front 409

Symptoms of folate deficiency?

Back 409

megaloblastic anemia and neural tube defects in pregnancy

Front 410

Back 410

*folate taken in by diet is predominately in the polyglutamate form
*glutamate carrboxypeptidase II cleaves the molecule at the brush border to produce monoglutamate
*uptake by folate carrier (RFC1)
*in enterocyte, it is methylated and reduced
*transported across basolateral membrane to the portal circulation and liver

Front 411

What are the two forms that iron is present as?

Back 411

The iron heme- 10%
nonheme (ionic form) -90%
* intestinal absorption of heme iron is more efficient

Front 412

What is the mechanism for absorption of heme iron?

Back 412

* at duodenal pH, heme is split from globin
* absorbed as metalloporphyrin into enterocytes
* once in cell iron is released from heme by heme oxygenase
*Iron is transported bound to transferrin in the plasma
*delivered to tissues for use or storage

Front 413

Back 413

* Nonheme iron mostly like Fe3+
* complexed with aa, sugars, asorbic acid to keep Fe in solution at duodenal pH
* Fe3+ converted to Fe2+ @ brush border (ferrireductase)
* Nramp2 allows absorption into enterocyte
* transported across cell to basolateral side where it crosses through IREG1
- ferroxidase hephaestin required for export
* bound to transferrin in serum
** TfR1 is the receptor that allows Fe uptake into cells

Front 414

Regulation of Iron absorption is tightly regulated... how?

Back 414

*decrease Fe in diet the Nramp2 receptor is unregulated
* increase Fe in diet the Nramp2 receptors is downregulated

** iron absorption is overall regulated by the liver

Front 415

Role of Hepcidin on IREG1

Back 415

*Hepcidin - secreted by hepatocytes, inhibits iron absorption in intestine
* directly interacts with IREG1 at membrane
*interaction results in the internalization and degradation of IREG1 = reducing iron export

Front 416

Three molecules that regulate hepatic hepcidin?

Back 416

HFE
transferrin receptor 2
hemojuvelin

*HFE/TfR1 and TfR2 - sense changes in blood transferrin concentrations

Hint 416

** low blood concentrations of diferric transferrin result in decreased hepcidin release from liver and increased Fe uptake

Front 417

Where is calcium absorbed?

Back 417

throughout small intestine at high levels - passively paracellular route

low levels - active saturable energy driven transcellular route (need Vit D3)
*in duodenum

Front 418

Transcellular calcium transport involves 3 steps:

Back 418

1) entry into the cell via calcium channel (TRPV6 - expression Vit D dependent) - present on brush border
2)Translocation through enterocyte bound to calbindin D9K
3) extrusion at the basolateral membrane against an electrochemical gradient via a calcium ATPase and Na/Ca exchanger
*ATPase stimulated by Vit D3

Front 419

Back 419

Autoimmune inflammation of the stomach is a rather common cause of vit. B12 deficiency in older women
*inflammation results in parietal cell damage and loss of acid production - loss of IF
*can't cleave B12 from food due to decreased acid
*later the loss of IF - further failure to absorb

Front 420

Back 420

Review

Front 421

Back 421

high % saturation in the blood due to primary hemachromatosis
- iron overload due to increased absorption of iron

Treatment: phlebotomy and iron-chelation therapy

Front 422

Back 422

round ligament contained in the falciform ligament
*right lobe (caudate and quadrate as well)
* surrounded by fibrous Glisson's capsule which is richly innervated

Front 423

Back 423

Segmentation of the liver into 8 parts
*each with its distinct blood supply

Front 424

What is the vascular anatomy

Back 424

*Oxygenated blood is supplied by the right and left branches of the hepatic artery (from celiac)
*Oxygen poor blood is supplied by the right and left branches of the portal vein draining to celiac, SMA, IMA

**bile ducts supplied solely by hepatic artery

Front 425

Describe the vascular anatomy

Back 425

portal vein drains the GI tract of blood
*vascular drainage through hepatic veins to the IVC

**dual blood supply- very resistant to anoxia

Front 426

What are the cells types that compose the liver?

Back 426

*kupffer cells-comprise the liver's immune defense - clears dead cells and debris

Front 427

what is a liver lobule

Back 427

histologic and functional unit of the liver
-hexagonal with portal triads (artery, vein, bile duct)
- continuous system of communicating hepatocytes
- sinusoids - fenestrated capillary lining and no bm - separate these columns of parenchymal cells

Front 428

What is the space of Disse?

Back 428

the space between the hepatocytes and the sinusoidal endothelial cells

Front 429

Back 429

portal triad is at center with the terminal hepatic venules at the periphery
* Zone 1 - cells closest- first to receive oxygenated blood and nutrient rich blood = last to develop hypoxia - first to regenerate

Zone 3 - last to receive blood, most sensitive to toxic or vasculature injury

Front 430

What are the main activities of Zone 1 cells?

Back 430

glucose synthesis and release
oxidative energy metaboism
aa utilization
bile acid and biliruben excretion
ammonia detoxification

Front 431

What are the main activities of Zone 3 cells?

Back 431

hepatocyte are most active in glucose uptake and utilization and biotransformation

Front 432

Trace blood flow through liver starting at hepatic artery or portal vein?

Back 432

-hepatic artery and portal vein in zone 1 along sinusoids
-drains into terminal hepatic venules
- terminal vein
- terminal vein unites with hepatic vein
-IVC

Front 433

Trace the flow of bile?

Back 433

-bile canaliculi (smallest branches in the biliary tree) from zone 3 to zone 1 of the acinus
- enters small terminal bile ductules
- empty into small bile duct located in portal triad

Front 434

Back 434

under right lobe of liver
30-50 ml of bile
-blood supply for cystic artery
-common hepatic duct to common bile duct

Front 435

Describe normal hepatic blood flow?

Back 435

- liver has no active role in regulating portal inflow = passive recipient of blood
- wide range of portal blood flow without effect on pressure
* decrease in portal venous flow or sinusoidal pressure = reflex in the increase of hepatic arterial flow

Front 436

Why is radius the most important determinate of resistance?

Back 436

Front 437

What is normal portal venous wedge pressure and how do you obtain this value?

Back 437

5-8 mmHg
*measure wedge hepatic venous pressure
-- internal jugular or femoral vein

Front 438

What is the hepatic venous pressure gradient?

Back 438

when comparing the pressure difference between the wedge hepatic venous pressure and the free hepatic venous pressure (IVC)
**should only be a 1-4 mm Hg difference when normal
** not normal when ascites (large amounts of intraabdominal fluid) is present

Front 439

What are the pressure measurements for PVP and HVPG?

Back 439

Front 440

Define Portal Hypertension?

Back 440

Front 441

In cirrhosis, how does the relationship between flow and pressure change?

Back 441

small increases in portal venous inflow may be associated with significant increases in portal vein pressure

Front 442

Common causes for portal hepatic disease and their classifications

Back 442

intrahepatic has further classifications that can be based on the wedge hepatic venous pressure

Front 443

Prehepatic Causes

Back 443

Front 444

Intrahepatic cause

Back 444

Front 445

What are the characteristics of Cirrhosis?

Back 445

Front 446

Posthepatic Causes

Back 446

Front 447

What is portosystemic collaterals?

Back 447

collateral blood vessel from between the portal system and the systemic vasculature du to an increase in portal pressure
*seen in: esophagus, stomach, abdomen,periumblical area, and rectum

Front 448

Example of Caput medusa (periumblicial collateral) formation

Back 448

Front 449

Is portal HTN a common complication of cirrhosis?

Back 449

YES! Cirrhosis - process of diffuse fibrosis following hepatocyte destruction and nodular regeneration - leading to distorted liver architecture

Front 450

What are some cases where cirrhosis might result?

Back 450

chronic viral hepatitis
alcohol
inherited metabolic disease
biliary disease
autoimmune disorders
drugs and toxins

Front 451

The two major path-physiologic consequences of cirrhosis?

Back 451

1) Portal HTN
2) hepatic failure

Front 452

What is splenomegaly and hypersplenism?

Back 452

spelnomegaly- increased splenic vein pressure
hypersplenism- sequesteration

Front 453

When do varcies form?
when do you have a bleeding risk?

Back 453

Varices from when portal pressure is at least 10 mm Hg

Bleeding is likely when the portal pressure is at least 12 mm Hg

Front 454

What is bleeding for a variex governed by?

Back 454

Front 455

How are bleeding esophageal varices treated?

Back 455

1) sclerotherapy
2) banding

Front 456

How can an acute reduction in portal pressures be achieved?

Back 456

1) vasopressin
2) octerotide
*via splanchnic arteriolar constriction

Front 457

How can chronic reduction in portal pressure be achieved?

Back 457

Beta- adrenergic bockers

* another approch is to divert blood flow away from the portal system into systemic venous system by the surgical creation of shunts = transjugular intrahepatic portosystemic shunting (TIPS)

Front 458

What is hepatic encephalopathy

Back 458

entry of ammonia and other toxins normally cleared by the liver but are reaching the systemic circulation instead due to build up of collateral arteries - this is how it reaches the brain
*causes astrocyte swelling and neurologic dysfunction

Front 459

Toxins implicated in hepatic encephalopathy

Back 459

Front 460

What are the stages of hepatic encephalopathy?

Back 460

Front 461

What is ascites?

Back 461

- increased in splanchnic vessels due to portal HTN results in increased fluid formation

Front 462

What is hypoalbuminemia?

Back 462

Also seen in with cirrhosis, results in decreased plasma oncotic pressure which favors an extravascular shift of fluid = Acties formation

Front 463

Pathophysiology of cirrhosis?

Back 463

Front 464

Pathophysiology of cirrhosis: the two main pahways- increased intrahepatic resistance and decrease arteriolar resistance (vasodilation)

Back 464

increased production of NO - vasodilation
*leads to decreased effective plasma volume
*activation of compensatory mechanisms
** increased in renin-angio and sympathetic nervous system leads to increased renal resistance and decreased glomerular filtration rate
* kidney compensates by retaining Na and H20 = ascites

Front 465

What is hematemesis?

Back 465

vomiting of blood

Front 466

How is portal hypertension managed?

Back 466

Front 467

Where does plasma protein synthesis occur?
Which proteins are made?

Back 467

most proteins are made in the liver
*albumin
*glycoproteins

Front 468

Where are the plasma proteins synthesized? What are the main plasma proteins?

Back 468

Liver
*albumin
*glycoproteins
-- liver also produces most of the coagulation factors

Front 469

What is albumin's half- life?

Back 469

~3 weeks

Front 470

What is typically produced from the breakdown of aa?

Back 470

Ammonia is also produced by bacterial degradation of urea (producing CO2 and NH3 - diffuse into portal circulation)

Front 471

What is the urea cycle regulated by?

Back 471

regulated by intracellular substrate levels on a short term basis and the amount of protein intake and rate of urea excretion on a long term basis

Front 472

What does hyperammonia causes what?
And what can lead to hyperammonia?

Back 472

Causes: neurological dysfunction
*inherited defects in the urea-cycle enzymes, hepatic dysfunction, and shunting of portal blood to the systemic circulation can lead to hyperammonemia

Front 473

Monosaccharide Metabolism

Back 473

Front 474

Metabolic pathways for hepatic utilization of glucose, fructose, and galactose

Back 474

Front 475

Under aerobic conditions, the liver uses what as its main source of energy?

Back 475

Fatty acids (instead of carbohydrates)
* the rate of glycolysis will be low

Front 476

What is glycogen synthesis

Back 476

Front 477

What is glycogenolysis

Back 477

Front 478

What is gluconeogenesis?

Back 478

- recycling alanine from muscles
- Cori cycle ( lack of glucose)

Front 479

Describe the intergration of the glucose- alanine cycle and the cori cycle?

Back 479

Front 480

What is lipogenesis?

Back 480

synthesis of fatty acids from carbohydrate precursor in the liver by their conversion to acetyl coenzyme a by the cytosolic fatty acid synthase complex

Front 481

Characteristics of lipoproteins

Back 481

Front 482

Triglycerides synthesized by the liver are secreted by...

Back 482

* portion of VLDL is converted to LDL
*VLDL and LDL are either stored as adipose tissue or used for energy production by muscle

Front 483

What is significant of good levels of HDL?

Back 483

HDL cleans up periphery by bring triglycerides to the liver = decrease risk of heart disease

* increase LDL and VLDL not a very good thing because you are producing triglycerides and placing them on the vessels

Front 484

When does lipolysis occur?

Back 484

during fasting or starvation, or in diabetes mellitus with insulin deficiency when carbs are in short supply
*then lipolysis of triglycerdies stored in the adipose tissue occurs

Front 485

What is ketogenesis? and what purpose do ketones serve?

Back 485

- ketones can be used as alternative energy source by muscle and brain

Front 486

The liver is also a major site for cholesterol synthesis from...

Back 486

*cholesterol important for:
- cell membrane
- steroids
- precursor for bile acid synthesis

Front 487

What are events that up-regulate cholesterol synthesis?

Back 487

*hepatocyte depletion of cholesterol, depletion of the bile acid pool
*hormones: thyroid hormone, cortiocosteroids, adn glucagon

Front 488

what are the things that down-regulate cholesterol synthesis?

Back 488

events that increase cellular cholesterol
- uptake of dietary cholesterol

Front 489

What is the target enzyme for many cholesterol lowering drugs?

Back 489

HMG-CoA Reductase

Front 490

What are the three metabolic conditions in humans?

Back 490

Front 491

What occurs in the fed state?

Back 491

dietary glucose is absorbed from the intestines and is readily available as an energy source to all tissues (especially brain and RBC)

muscle: stored as glycogen
liver: stored as glycogen

*dietary fat absrobed in the intestine is transported as triglycerides (incorporate in chylomicrons) to liver and peripheral tissues

Front 492

What occurs in the post -absorptive state?

Back 492

*liver maintains blood glucose level by glucogenolysis
* aa released by muscle are used for gluconeogenesis
* adipose tissue starts releasing fatty acids which are in turn oxidized by the live and muscle to produce energy

Front 493

Fasting state- what occurs?

Back 493

liver continues to supply lucose to RBC and brain
*hepatic stores of glycogen become depleted within 48 hrs
* gluconeogenesis from aa
* as fasting continues, fatty acids released from adipose tissue are oxidized to ketones

Front 494

What is the liver's biotransformation?

Back 494

The liver is responsible for the biotransformation and clearance of endogenous and exogenous toxic substances
* 2 different groups: phase I and phase II

Front 495

What are the two different groups for biotransformation?

Back 495

* phase I - make substances more polar and water-solublefor bile or urine excretion
- can lead to detox or more toxic intermediates
* phase II- conjugation of molecule to a drug
- enhances solubility and detoxifies compound
-- exception is methylation which can detox but compounds become less soluble

Front 496

What all can biotransformation led to?

Back 496

*Hepatocellular Injury occurs when the biotransformation leads to the formation of more toxic or carcinogenic metabolite

Front 497

Explain Acetamionphen's Biotransformation?

Back 497

conjugated with sulfate and glucoronic acid - each render it harmless
* BUT 5-15% is converted to reactive intermediate, NAPQI
* NAPQI will react with sulfhydryl groups in proteins and cause damage

Hint 497

*with normal doses most of the NAPQI can add glutathione making Mercapturic acid and be eliminated by the kidneys
*BUT if you overdose this pathway becomes saturated and glutathione stores become depleted
*NAPQI accumulates leading to cell injury, live failure, death

Front 498

What is the function, source, absorption, and transport of Vitamin A?

Back 498

Front 499

What is the function, source, absorption, and transport for Vitamin A?

Back 499

* retinol is a fat soluble vitamin
* once in enterocyte taken up by hepatocyte where it is stored as retinyl palmitate in Ito cel
* Vit A overdose can lead to toxicity and damage of cells

Front 500

What is the storage, mobilization, and circulation of Vitamin A?

Back 500

Front 501

What is the function, sources, and absorption of Vitamin D?

Back 501

* produced in skin as cholecalciferol in the presence of UV
* ergocalciferol can be absorbed from plants in the presence of bile salts
* majority incorporated into chylomicrons and secreted into intestinal lymphatics
* other portion is directly absorbed into portal circulation

Front 502

Describe the synthesis of Vitamin D?

Back 502

* liver does not significantly store vitamin D
* most of the regulation for vitamin D occurs primarily at the level of the kidney

Front 503

What is the function, sources, absorption, and transport of Vitamin K?

Back 503

*produced in intestinal bacteria
* once in chylomicron it is attached to a VLDL and secreted for distribution throughout the body
** the liver synthesizes the vitamin K dependent clotting factors

Front 504

Describe copper metabolism?

Back 504

* 10% of copper ingested is through the duodenal enterocyte
* bound to albumin and carried to portal circulation
* taken up by copper transporter CTR1
*ATP7B - regulates excreted bile
* transform copper into ceruloplasmin

Hint 504

*copper is an important coenzyme and component of proteins
* there are copper dependent catalytic enzymes yet excess copper can be toxic

Front 505

Wilson's Disease?

Back 505

* the main excretory pathway of copper is through bile
* mutation of ATP7B transporter leads to a reduction in conversion of apoceruloplamin to ceruplasmin, which carries 90% of circulating copper to peripheral tissues
* failure to excrete copper into bile will lead to accumulation of copper in hepatocytes
= liver injury and cirrhosis

Front 506

How can a reduction in copper lead to anemia?

Back 506

Copper helps maintain the integrity of blood cells
so if you decrease copper you will carry less oxygen

Front 507

Where is the major iron repository?

Back 507

The Liver

Front 508

What regulates the efflux of iron from macrophages and absorption of iron into the intestinal mucosa?

Back 508

Hepcidin

Front 509

What level is iron absorption mainly regulated at?

Back 509

duodenal enterocyte
- enterocyte produces TFR-1 and HFE protein in cytoplasm
- HFE and beta-microglobulin bind with TFR-1 on basolateral surface
- sensor for transferrin iron in blood and allows entry into enterocyte
- move to the apical surface together where iron absorption acutally occurs
** iron within the crypt enterocyte determines expression of DMT-1 and ferroportin proteins which are responsible for iron absorption on the apical surface

Front 510

Back 510

*Ferric form - ferrous form (duodenal cytochrome B)
* absorption into enterocyte (DMT-1)
*iron exported to portal circulation by ferroportin-1
* then converted back to ferric form so it can bind to apotransferrin (by hephaestin)
* Diferric transferrin circulates in portal circulation - reaches hepatocyte
* enters via TFR-1 or TFR-2
* amount of iron in the cell regulates expression of hecidin

Front 511

What is hepcidin? What does it do?

Back 511

a peptide messenger that conveys the need for iron absorption to the enterocytes
** a high hepcidin level results when there is increased amounts of intracellular iron to effect a reduction in iron absorption

Front 512

Back 512

Front 513

Back 513

Hint 513

The Manifestations of the patient's liver dysfunction?
* hypoglycemia
*hypoalbuminemia
* coagulopahty - prolonged prothrombin time
* hepatic encephalopathy

Front 514

What is bilirubin?

Back 514

It is the degradation product of heme
*85% is derived from senescent RBC
*15% derived from free heme

Front 515

How is bilirubin transported to the liver?

Back 515

bound to serum albumin
* undergoes conjugation in the hepatocytes and excretion into the bile via the bile canaliculus

Front 516

How much bilirubin is produced daily?

Back 516

Front 517

describe the metabolism of bilirubin?

Back 517

*heme - biliverdin (heme oxygenase in spleen)
*biliverdin - bilirubin (biliverdin reductase)
*bilirubin enter circulation bound to albumin (makes it more soluble)
*facilitated diffusion into liver
*bound to ligandin and Z protein and then undergoes conjugation
* conjugated bilirubin into bile canalicular membrane by MRP2 (active)
*becomes a component of bile

Front 518

What are the two different forms of bilirubin?

Back 518

* unconjugated can inhibit synthesis of RNA and proteins and metabolism of carbohydrate

Front 519

What is Kernicterus?

Back 519

When babies are switching for fetal hemoglobin to adult hemoglobin they have to deal with unconjugated bilirubin - causing jaundice and brain damage

Front 520

What is the chemical difference between conjugated and unconjugated bilirubin?

Back 520

Front 521

Once conjugated bilirubin reaches the intestines what is it converted to?

Back 521

*urobilinogens by bacteria
* then eliminated in stool and by kidneys
** small fraction may be reabsorbed and re-excreted in bile

Front 522

Why is urine yellow?

Back 522

Due to urobilin which is the oxidation product of urobiliogens

Front 523

What would be your first thought it you couldn't detect urobilinogen in the urine or stool?

Back 523

complete bile duct obstruction

Front 524

When is urobilinogen production increased?

Back 524

During liver disease or in over production of bilirubin

Front 525

What is the pathway for bilirubin in a fetus?

Back 525

Conjugated bilirubin excreted by the liver into the intestinal lumen is deconjugated by an intestinal Beta-glucoronidase. reabsorbed, and ultimately cleared by the placenta

Front 526

What is breast milk jaundice?

Back 526

* develop unconjugated hyperbilirubinemia due to breast feeding
- - beta-glucorinidase activity still present

Front 527

What can cause unconjugated Hyperbilirubinemia?

Back 527

Front 528

What is Gilbert's syndrome?

Back 528

This is type II- UDP-glucoronosyl transferase
- partial transferase activity

Front 529

What is type I Crigler-Najjar Syndrome?

Back 529

Type I UDP-glucoronosyl transferase
* resulting in severe hyperbilirubinemia
* death

Front 530

What are the defects in conjugated hyperbilirubinemia?

Back 530

* Dubin- Johnson is intermittent mild jaundice - MRP2 can't transport bilirubin across canalicular
*accumulation of dark pigment in the hepatic lysosomes

Front 531

What occurs in cholestasis and
hepatitis?

Back 531

regurgitation of bilirubin into the circulation due to failure of excretion from the liver

Front 532

Therapy for Unconjugated Hyperbilirubinemia?

Back 532

Front 533

How does phototherapy work?

Back 533

Front 534

What is the function of bile?

Back 534

Front 535

What is the composition of bile?

Back 535

Front 536

What allows bile acids to act like detergents?

Back 536

they have a hydrophilic and hydrophobic component
*facilitate intestinal absorption

Front 537

How are the primary bile acids made?

Back 537

Front 538

What are the canalicular transporter proteins involved in bile formation and transport

Back 538

* NTCP (Na dependent)- uptakes bile from the blood into hepatocyte (basolateral side)
* OATP (Na independent)
* bile salt transporters: BSEP, ABCG5/G8, MDR3, and MRP2
** once in hepatocyte have to move against large concentration gradient (active- BSEP-bile salts)
* MRP2 - bilirubin

Front 539

What occurs after canalicular secretion?

Back 539

* bile undergoes alkalinization and dilution
* the ductular cells absorb and secrete fluid and electrolytes
* bile ductular secretion and flow is stimulated by secretin

Front 540

What stimulates ductular flow?

Back 540

Front 541

Describe concentration and storage of bile?

Back 541

*gallbladder concentrates bile 5-10 fold
* after a meal, CCK promotes gallbladder contraction

Front 542

Special requirement ACMS cards (SR) are for what?

Back 542

ALSE, Avionics Support, Ground Support & Public Audit

Hint 542

PG 85-00-10 pg 5-1

Front 543

Route for Bile

Back 543

* this is the only route were cholesterol is eliminated from the body
*liver compensates for this loss by increasing cholesterol synthesis

Front 544

Primary bile salts are converted by intestinal bacteria to secondary bile acids

Back 544

*sulfolithocholic acid - is poorly absorbed and rapidly lost from the enterohepatic circulation

Front 545

How do the primary bile salts become secondary bile salts?

Back 545

* Sulfolithocholic acid is poorly absrobed and rapidly lost from the enterohepatic circulation

Front 546

What are the disorders of bile acid metabolism?

Back 546

Front 547

大どおり

Back 547

おおどおり

Hint 547

boulevard (Oh Oh Dori)

Front 548

How does cholestasis manifest?

Back 548

Front 549

What is choledochal cyst?

Back 549

Manifests due to a back up of bilirubin into the blood
- patient gets jaundice
- accumulation of bile acids in the skin causes histamine release and pruritus
- lipoprotein metabolism is deranged and hyperlipidemia occurs which may result in cutaneous xanthomata
- fat soluble vitamin malabsorption

Front 550

What happens when one has ileal inflammatory disease or ileal resection

Back 550

* bile acids aren't reabsorbed like they should be
* so when then they enter the colon and cause a secretory diarrhea
* increased bile acid loss so hepatic synthesis is increased to compensate
* if can't fully compensate then you might have malabsorption of bat soluble vitamins

Front 551

True or False:

Na+ ions are 'LESS' favorable with cell permeability in the 'CELL MEMBRANE' of a 'NEURON' than K+ ions?

(Na+ IONS MOVE 'INWARD' AND SLOWER THAN K+ IONS MOVE 'OUTWARD)

Back 551

True

Front 552

Back 552

Front 553

Back 553

Front 554

How was the diagnosis of primary sclerosing cholangitis made?

Back 554

Front 555

What are the other complications of the primary sclerosing cholangitis?

Back 555

Front 556

What is Charot's triad?

Back 556

fever
upper quadrant abdominal pain
jaundice