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64 Cards in this Set

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What are the 4 cell types in the islets of Langerhans? What do they secrete?

Where are the alpha cells located in the islet?
Beta cells: insulin secreting
Alpha cells: glucagon secreting
Delta cells: somatostatin secreting
PP cells: pancreatic polypeptide secreting

Alpha cells are mixed throughout the islet. Unknown if there is an alpha-beta interaction.
What are the exocrine cells of the pancreas and what do they secrete?

How are these arranged?
Acinar cells: arranged in clusters secreting digestive enzymes.

Duct cells: HCO3- to neutralize chyme.

Exocrine glands empty into ducts joining to 1 duct (if not, pancreatic divism). Enzymes need to end up at apical portion facing the lumen of the acinar duct...if not - pancreatitis!
Why is an alkaline pH required in duodenum?
Needed for FAT absorption...lipase action and micelle formation. Acidic pH can destroy 2 of the 3 factors required for fat digestion!
There are 3 phases of pancreatic secretion: Cephalic, Gastric and Intestinal.
What happens in the cephalic phase of pancreatic secretion?
Efferent vagal stimulation stimulates enzyme release. Major pathway: reflex (taste, smell, chewing, swallowing, hypoglycemia) stimulates vagal nn, to synapse via Ach on ductal and acinar cells.
The intestinal phase of pancreatic secretion has a hormone component and a neural component.
Which 2 duodenal hormones mediate the intestinal phase of pancreatic secretion?

What triggers their release?
CCK and Secretin

Release in response to gastric acid, fat and protein (via neural (vago-vagal) cholinergic stimulation.
Where is CCK released from? What does it stimulate?

Where is Secretin released from? What does it stimulate?
I cells: Stimulates acinar cells indirectly. CCK is released and stimulates AFFERENT vagal fibers that stimulate EFFERENT vagal fibers to release Ach on Ach receptors on ACINI cells to release digestive enzymes. **No CCK receptors on acini!

S cells in response to acid, stimulating the duct to release HCO3- and H2O.

**CCK and Secretin potentiate each other's actions.
What is the negative feedback on CCK release from the I cells?

What is the negative feedback on HCO3- and H2O release from the S cells?
A: Trypsin, which cleaves CCK-releasing peptide.

S: HCO3- and H2O.
What 2 types of enzymes are produced in acinar cells?

How?
2: Lysozomal enzymes, and zymogen granules (inactive pro-enzymes activated by trypsin).

Produced in ER, packaged by golgi and sorted into lysosomal granules and zymogens. Zymogens go through a period of condensation and maturation.
What happens when CCK stimulates the acinar cells (via Ach)? Secretin?
CCK: IP3 mediates Ca++ to phosphorylate PKA to alter structural and regulatory proteins via phosphorylation.

Secretin: ATP activates cAMP to make PKA to phosphorylate structure and regulatory proteins for granule release.
What happens if apical cells are hyperstimulated (e.g. alcohol++?)

How is this prevented (2 things)?
Duct gets blocked, normal sorting does not occur, ending up in large cytoplasmic granules. These can be prematurely activated, leading to pancreatitis.

Prevented by having inactive enzymes in granules, but cationic trypsinogen PRSS1 gene mutations can lead to intracellular activation.

Also prevented by anti-proteases (SPRINK 1) in zymogen granules and cytoplasm, but these can also be mutated

Antiproteases SPINK1 "police" sorting.
Name 3 things that convert trypsinogen to active trypsin?
1. Enterokinase - normally found on brush border of intestinal cells.
2. Autoactivation - can occur in human trypsinogen
3. Cathepsin B - an enzyme in lysozomes.
Name 3 factors that prevent auto-digestion of acinar cells (which would otherwise lead to pancreatitis)?
1. Enzymes sorted into zymogen granules and lysosomal hydrolases - keep 'em separate.

2. Enzymes in zymogen granules are inactive. E.g. PRSS1 gene mutations lead to intracellular activation, a cause of hereditary pancreatitis.

3. Anti-proteases (SPINK) in ZYMOGEN and cytosol.

SORT-STORE-STOP
What do pancreatic duct cells secrete?

How? (3 ways)

Name 2 dx affecting ductal secretion.
Cl- and HCO3.

Cl-: Secretin increase cAMP activity, acting on the CFTR to increase Cl- secretion. **Non-functional in CF.

HCO3-: secreted by Cl-HCO3-exchanger. **Decreased in chronic pancreatitis.

Carbonic Anhydrase increases cytosolic HCO3-

2 dx: chronic pancreatitis decreases HCO3- and H20, F508-CFTR = decreased Cl- secretion
Which parts of the intestine do secretin and CCK act in?
Major action in duodenum, but continued action as far down as ileum.
Name 4 primary actions of CCK.

Other actions on:
Stomach?
Intestine?
Pancreas?
Brain?
1. Gallbladder contraction.
2. GI motility
3. Pancreatic exocrine secretion
4. Satiety

Stomach: decrease emptying and decrease acid secretion.

Intestine: increase enteropeptidase and motility.

Pancreas: increase glucagon secretion

Brain: decrease food intake, increase anxiety ,analgesia.
GGPS
How does CCK ligand differ to potentiate many different actions?

How does the CCK receptors differ?
Where is CCK-A found?
Where is CCK-B found?
Ligand: One gene, altered by length and modification, acts in multiple locations.

Receptor: 2 genes, multiple forms, multiple locations, with multiple signaling pathway.

CCK-A: GI, periphery
CCK-B: in brain - binds CCK-4 and CCK-8, gastrin.
What are the 2 primary actions of secretin?

Actions of secretin on:
Liver?
Stomach (2 actions)?
1. Stimulate HCO3 release from pancreatic ducts.
2. Potentiate Ach action on acinar enzyme secretion.

Liver: stimulates HCO3 and bile secretion.

Stomach: Inhibits gastric emptying and inhibits acid secretion.
What are the 2 key nerves providing extrinsic innervation of the GI tract?

What are the 2 nerve plexi associated with the GI tract?
Vagus and pelvic nerves.

PlexI: Submucosal (b/w circular mm layer and submucosa) and myenteric (b/w longitudinal and circular mm layers)
What are the 3 components of the functional motor unit of the GI tract?
1. Nerve
2. Smooth Muscle Cell
3. Interstitial cells of Cajal (ICC)...pacemaker cells for gut contraction, assoc. with smooth mm cells.
What effect does sympathetic stimulation have on gut motility? Parasympathetic?

What is the excitatory neurotransmitter of the gut? Inhibitory nt?
S: decreased peristalsis, increased sphincter tone.
Para: increased peristalsis, decreased sphincter tone.

Excitatory: Ach
Inhibitory: NO.
Describe excitation-contraction coupling in the gut in terms of slow-wave and spike potentials.
Slow wave - ongoing, weak contractions mediated by ICC associated with myenteric plexus of stomach and submucosal plexus of colon. Varies with location.

Ca++ influx via L-type (voltage-gated) channels causes AP (repolorization mediated by K+ influx). Contraction force proportional to number and amplitude of spikes.
What mediates primary, secondary, and tertiary esophageal peristalsis?
Primary: initiated by swallowing, spans the length of the esophagus.

Secondary: initiated by local distention, spans smooth mm region of esophagus, clears residual material.

Tertiary: spontaneous, at distal portion of esophagus for clearance and occurs in motor dysfunction.
Where does esophageal contraction originate (in brain)?

Give examples of diseases associated with esophageal dysmotility at the pharynx, esophagus and lower esophagus.
Via nucleus solitarius via vagal nn
Dorsal vagal nuclei

Dx: Pharynx: CNS associated dx: stroke, Parkinson's, dementia.

Esophagus: Esophageal spasm - achalasia, DM and schleroderm.

Bottom: achalasia, GERD, DM, schleroderma.
What are the motor functions of the stomach? (2).

What does emptying require?
Relaxation - receptive relaxation and accommodation at fundus
Grinding - at corpus and antrum

Emptying- requires antropyloric duodenal coordination.
How is peristalsis initiated in the intestine?

Which part of the nervous system initiates this?
Local distention initiates ascending excitation (Ach) and descending inhibition (NO) reflex.

Enteric nervous system can initiate this, it is automatic and involuntary, and modulated by physiological and emotional factors.
What are migrating motor complexes?

What interrupts these?
MMC: occur in phase III - fasting phase in stomach to the proximal colon every 75-90 min. Provide more productive movement of contents. Phase III = intestinal housekeeper.

Interrupted by Phase I - feeding!
How does slow wave propagation differ in the right and left colon? What happens in each if the colon is missing?
Right colon - key for absorption of water and electrolytes, watery diarrhea if missing.

Left colon - key role is forming and storing feces. Alter transit (e.g. IBS) = diarrhea or constipation.
Motor dysfunction of the colon is classified as affecting TRANSIT or OUTLET. Give examples of dx associated with each.
Transit: medication (#1!), diet, neuropathy (DM), scleroderm, obstruction, Hirschsprung's dx, Changa's Dx.

Outlet: Hirschsprung's dx, pelvic floor trauma, prolapse (eww!), enterocele, large rectocele, anal stenosis, rectal ulcer syndrome.
Bile is _________ with blood plasma. Bile salts are derivatives of _________.

Bile involves secretion from 2 sources. What are they? What is the feedback control on each?
Bile is ISOSMOTIC with blood plasma. Bile salts are derivatives of CHOLESTEROL.

1. Ductal epithelial cells - alkaline, HCO3- rich, 25% of bile. Provides right pH. Feedback via secretin.

2. Hepatocytes - secrete inorganic ions and organic substances (bile salts, cholesterol), bile pigments (bilirubin), detoxified metabolites. GB contracts via CCK.
Give the 2 types of bile acids.

What is the polarity of bile acids?

Functions?
1. Primary - cholinic, synthesized by hepatocytes.

2. Secondary - deoxychonlic acid, lithocholic), dehydroxylation of primary acids by colonic bacteria. Can irritate epithelium, causing secretory diarrhea.

Polarity: amphophilic.

Functions: emulsify fat, facilitate solubilization and digestion of lipids (micelles), eliminate excess cholesterol.
Outline the steps of enterohepatic circulation by....

1. Liver
2. Small Intestine
3. Distal Ileum
4. Portal Vein
1. Liver - bile acids are synthesized, conjugated and secreted.

2. SI - bile acids solubilize fats and products of fat digestion.

3. Distal Ileum - bile acids ACTIVELY reabsorbed.

4. Portal Vein - returned to liver for resecretion (95%)
Describe the structure of a simple micelle.

What is critical micellar concentration?

What is a mixed micelle?

What is the Krafft point?
Hydrophobic non-polar hydrocarbon chain with a hydrophilic polar head. Hydrophilic head points out.

CMCL minimum [ ] of a BA required for micelle formation.

Mixed micelle has holesterol at the centre and phospholipids inserted between the polar heads.

Krafft:T below which micelles of a given BA will NOT form.
What is the most common gallstone?

What happens in the gallbladder when there is too much cholesterol?
Cholesterol gallstone.

If there is too much cholesterol, cholesterol is secreted out in a unilaminar vesicle. This is unstable, and will form a complex or crystal in the mixed micelle, and is no longer soluble, precipitation out. **Why obesity is a risk factor.

Depends on: The cholesterol saturation index > 1!
Give the other 2 types of gallstones and what they contain.
Black pigment stones: associated with hemolysis and cirrhosis. Results from excessive bilirubin excretion in the bile.

Brown pigment stones: associated with biliary stasis (block = no flow!) and infection, contain calcium bilirubinate. Mix of black pigment and cholesterol.
What is bilirubin?

Steps in billirubin production?
Breakdown product of Hg or myoglobin in reticuloendothelial system.

Heme released from RBC --> heme oxygenase converts it to biliverdin --> biliverdin reductase converts it to bilirubin
Unconjugated bilirubin is ________ soluble and bound to ______. In the liver, it is conjugated with ___________ to form __________, making it _______ soluble. Enzyme: __________.
Unconjugated bilirubin is LIPID soluble and bound to ALBUMIN. In the liver, it is conjugated with GLUCARONIC ACID to form BILIRUBIN DIGLUCARONIDE, making it WATER soluble. Enzyme: glucaronyl transferase.
Bilirubin is deconjugated in the intestine by bacteria. What are the 3 possible outcomes? Where do they end up?
Bilirubin or Urobilinogen. Once unconjugated, it is lipophillic and can pass back into blood stream.

If stays in intestine, stercobilinogen, giving poop colour.

Billirubin is recirculated, urobilinogen is excreted in urine.
What is jaundice?

What form must bilirubin be in for urinary excretion?
Jaundice = failure to excrete bile pigments, leading to hyperbilirubinema. Yellow!

Conjugated - H2O soluble. This means hyperbilirubinemia.
What are the 3 types of jaundice?
1. pre-hepatic (hemolytic) - excessive hemolysis, largely unconjugated bilirubin (occurs BEFORE liver).

2. Hepatic - in liver dx, acute hepatitis.

3. Post-hepatic (obstructive) - blockage of intra or extrahepatic bile ducts, bile refluxes back into blood (gallstones)
What occurs at the 2 phases of detoxification at the liver?
Phase 1: Occurs in E.R., an enzymatic process involving CYP 450, commonly involves oxidation, (also reduction and hydrolysis.

Phase 2: conjugation, leading to excretion in urine and bile.
What happens to glucose at the liver in the absorptive state?

Post-absorptive state?
Taken up by liver and glycogenesis occurs. Some is converted to TRIACYLGLYCEROL (TAG), released into the blood and taken up by adipose tissue (excess glucose).

Post-absorptive: Glycogenolysis (breakdown of glycogen to glucose), Gluconeogenesis - synthesis of glucose from lactate, aa, pyruvic acid and glycerol.
What happens to fat in the absorptive state?
Absorptive: lipogenesis - triglycerides are synthesized from glucose and aa.

Post-absorptive: lipolysis - fat stores broken down into FFA which can go to muscle as E source, and to liver to be converted to ketone bodies. *Not eating = see ketone bodies in urine, major E source for other tissues.
What is the 1/2 life of albumin?

Which 2 clotting factors are not made in the liver?
21 days.

Factor 8 and VWF.
What 2 products does the liver catabolize AA into?

How does the liver facilitate ammonia clearance?
Ketoacids and ammonia. The ketoacids provide E for liver cells in absorptive state.

Clearance: coverts ammonia to urea for excretion by kidneys.
What are some of the limitations for liver biochemistry tests?
-Normal ranges defined on a population before FLDx and HepC found
-Can differ by age, gender, race, nutrition status (fed vs. fasting) and pregnancy (increase ALP, made by placenta)
-Cannot tell difference between damage or if increased enzymes is due to regeneration.
-Normal tests can appear in some progressive liver dx.
What do elevated liver enzymes indicate?

What are the 2 liver enzymes tested?

What is there association with liver function?
Indicate: hepatocyte damage = enzymes normally inside leak and backflow into circulation.

2 Enyzmes: Alanine Aminotransferase (ALT): low [ ] also in skeletal muscle = can be elevated by exercise, drug induced myolysis, e.g. when using STATIN for cholesterol.

Aspartate Aminotransferase (AST): also found in cardiac and skeletal muscle and rbcs. This is NOT liver specific and is inducible.

None!
Damage to the bile duct can lead to backflow of the enzymes in the bile duct. What are the 3 enzymes which would rise?
1. Alkaline Phosphatase (ALP) - found in the microvilli of the bile canalicular membrane, also found in bone, intestines and placenta (*= rises in pregnancy)

2. gamma-glutamyltransferase (GGT). NON-SPECIFIC for bile duct, found in membranes of highly secretive or absorptive cells, e.g. kidney, pancreas, intestine, prostate, BUT it is NOT found in bone = can distinguish with ALP. Inducible - EtOH, meds.

3. 5'-Nucleotidase (5'NT) - only in bilary epithelium. $$$, not readily available.
How would hepatocellular injury present biochemically?

A problem with bile flow? (Cholestatic)?
Elevated AST, ALT

Elevated ALP, GGT, Bilirubin and 5-NT.

*Can also have a mixed picture.
What are the 4 tests for liver function?
Bilirubin, INR (liver makes all clotting factors except 8 and VWF), glucose, albumin (transport protein and important for oncotic P).
What is the rate limiting step in bilirubin production?

Which clotting factor made in the liver has the shortest 1/2 life?
Excretion of the conjugated product (water soluble). This is the last thing to go = Hyperbilirubinemia: higher proportion in early liver dx.

Factor 7, 7 hours. Within several hours, it is not available = INR will decrease first. = THE FIRST NUMBER TO BECOME ABNORMAL IN ACUTE LIVER INJURY. (Albumin t1/2 = 21 days = will not go first).
What are the 3 main consequences of liver dysfunction?
1. Impaired excretion of bile (conjugation) = jaundice.

2. Impaired drug metabolism --> toxicity

3. Impaired control of E metabolism - raised INR, low albumin = adema, ascites, hepatic encephalopathy (ammonia), CHO/Fats (hypoglycemia in very late stage...glucose metabolism is last to go!)
What are signs of portal hypertension?

What is the hepatic venous pressure gradient?
Decreased platelet count

Splenomegaly - blood backflow to spleen = congestion, congestion can also cause esophageal varicies.

Ascites - distorted sinusoidal
architecture leads to increased resistance

HVPG = wedged hepatic portal vein pressure = free hepatic portal vein pressure.
Explain how ascites in cirrhosis results from hepatic venous outflow block.
Hepatic venous outflow block: leads to increased sinusoidal pressure (HVPG > 10-12 mmhg), body interprets this and reduces pressure by vasodilation (NO) and increases arteriolar resistance. This decreases the effective arterial volume, activates RAAS, leading to sodium and H2O retention.
Why does liver dysfunction cause more thrombocytopenia than other causes of splenomegaly?
Platelets are sequestered in spleen and there is decreased hepatic thrombopoietin synthesis.
What is the Child-Pugh-Turcotte Score?
Calculation based on INR, albumin and bilurubin levels and ascites and encephaly to classify severity of cirrhosis from A-C C (score 10-15) = worst, no surgery here unless life-saving...*high surgical mortality.

*Cirrhosis = increased risk of liver failure with stress.
What is the mechanism of action of antacids?

What are the 3 major forms of antacids?
Neutralize formed acid.

3 Forms:

Aluminum-se: osteomalacia, hypophosphatemia, constipation

Magnesium-se: diarrhea, accumulation in pt. w. renal insufficiency
Mg-Al mixture (Malox): < side effects

Ca++-se: may increase CA in urine, renal stones.
What is the mechanism of action of antisecretory GI drugs (2 types).

Which are more effective?
1. H2 blockers: block H2 channel blockers (mediated via histamine) on parietal cells, **end in "-tidine".

2. Proton pump inhibitors: block H+/K+ ATPase by BINDING IRREVERSIBLY. "-prazole" ending

Problem: negative feedback can up-regulate acid production with H2 blockers via other mechanisms. **PPI are most effective - irreversibly block the final output source.
Antispasmodics are smooth muscle relaxants for the GI tract. What are the 3 main types of these?
1. L-type (voltage-gated) calcium channel blockers. se: cardiac, limited efficacy.

2. Highly selective to GI Ca++ channel blockers (dicetel)

3. Nitroglycerin or glycerin trinitrate which convert to NO and relax smooth mm.
How do anticholiergic antispasmodic agents work?

When should these NOT be Rx?
Block muscarinic receptors on smooth muscle cells, blocking the stimulatory effects of ACh. These relax GI tract, bladder, and reproductive organs.

No Rx: closed-angle glaucoma, mega colon.
What is visceral hyperalgesia?

Treatment? (2 forms)
Hyper-pain sensation in gut, leading to abdominal pain, dyspepsia (discomfort in upper abdomen), bloating, IBS, NCCP

Tx: 1. TCAs (Tricyclic antidepressants),

2. SSRI (selective serotonic reuptake inhibitors)...continuous signal (afferent) to brain causes reflex motor activity.
Nausea originates in the vomiting centre. What 4 areas send information to this centre?
Cortex, vestibular apparatus, vagus nerve and GI tract, and the area postrema: chemoreceptor trigger zone outside the blood brain barrier which samples peripheral blood **Has 5-HT3 receptors.

NOTE:
Dopamine antagonists act in the brain and are used to treat nausea and vomiting

5-HT3 receptor antagonists - these block serotonin receptors in the central nervous system and GI
Which agents are anti-emetic?
Metoclopramide - acts as a dopamine receptor antagonist centrally and peripherally, causing ACh release from neurons.

Domperidone: does not cross bbb, acts peripherally.
What effect does erythromycin have on the GI?
Acts on motilin receptors of smooth muscle to initiate MMC in upper buy, increasing antral contractions and antrodudenal coordination, reduces fundic volume.
How do 5-HT4 agonists work? (e.g. cisapride, tegaserod).
Increase Ach release in enteric NS.
Used to treat reflux and constipation. Cisapride - can cause cardiac arhythmia and sudden death by blocking K_ channel, prolonging QT interval.