Pbl Exam 5 Case 6

Front 1

1. How are carbs formed in our diet?

Back 1

Almost all the carbs of the diet are either large polysaccharides or disaccharides, which are combos of monosaccharides bound to one another by condensation.

In other words, a hydrogen ion has been removed from one of the monosaccharides, and a hdroxyl ion has been removed from the next one.

The two monosaccharides then combine w/each other at these sites of removal, and the hydrogen and hydroxyl ions combine to form water.

Front 2

2. What happens when carbs are digested?

Back 2

When carbs are digested, the process is reversed, and the carbs are converted into monosaccharides.

Specific enzymes in the digestive juices of the GI tract return the hydrogen and hydroxyl ions from water to the polysaccharides, and thereby separate the monosaccharides from each other.

This process is called hydrolysis.

Front 3

3. What is the hydrolysis of fats?

Back 3

Digestion of TAGS: the fat digesting enzymes return three molecules of water to the TAG molecule and thereby split the fatty acid molecules away from the glycerol.

Front 4

4. What is the hydolysis of proteins?

Back 4

The proteolytic enzymes return hydrogen and hydroxyl ions from water molecules to the protein molecules to split them into their constituent AAs.

Front 5

5. What are the three major sources of carbs in the diet?

Back 5

1. Sucrose
2. Lactose
3. Starches.

The diet also contain a large amt of cellulose, however; no enzymes are capable of hydrolyzing cellulose in the human GI tract

Front 6

6. What happens when food is chewed?

Back 6

When food is chewed, it is mixed w/saliva, which contains ptyalin (an α-amylase) secreted mainly by the parotid glands.

This enzyme hydrolyzes starch into the disaccharide maltose and other small polymers of glucose that contain 3-9 glucose molecules.

However, the food remains in the mouth for only a short time, so that probably not more than 5% of the starches will become hydrolyzed.

Front 7

7. Can starch digestion occur elsewhere?

Back 7

Starch digestion sometimes continues in the body and fundus of the sotmach for as long as 1 hour before the food becomes mixed w/the stomach secretions.

Then activity of the salivary amylase is blocked by acid of the gastric secretions b/c the amylase is nonactive when the pH falls below 4.0.

However, as much as 30-40% of the starches will have been hydrolyzed mainly to form maltose in the stomach.

Front 8

8. What is pancreatic amylase?

Back 8

Pancreatic secretion, like saliva, contains a large amt of α-amylase that is almost identical to the enzyme in saliva but is more powerful.

Therefore, w/in 15-30 minutes after the chyme empties from the stomach into the duodenum and mixes w/pancreatic juice, virtually all the carbs will have become digested.

In general, the carbs are almost totally converted into maltose and/or very small glucose polymers before passing beyond the duodenum or upper jejunum.

Front 9

9. What four enzymes in the enterocytes lining the walls of the small intestine hydrolyze disaccharides and small glucose polymers?

Back 9

1. Lactase
2. Sucrase
3. Maltase
4. α-dextrinase

These enzymes are capable of splitting the disaccharides lactose, sucrose, and maltose, plus other small glucose polymers, into their constituent monosaccharides.

These enzymes are located in the enterocytes covering the intestinal microvilli brush border.

Front 10

10. What happens to lactose, fructose, maltose, and other small glucose polymers?

Back 10

Lactose splits into a molecule of galactose and a molecule of glucose.

Sucrose splits into fructose and glucose

Maltose and other small glucose polymers all split into multiple molecules of glucose.

Thus, the final products of carb digestion are all monosaccharides. They are all water soluble and are absorbed immediately into the portal blood.

Front 11

11. What initiates protein digestion in the stomach?

What is one important feature of this enzyme?

Back 11

Pepsin. This enzyme requires the acidic pH of the gastric juices to become active.

One of the important features of pepsin digestion is its ability to digest the protein collagen. Collagen is a major part of the intercellular connective tissue of meats; therefore, for the digestive enzymes to penetrate meats and digest other meat proteins, it is first necessary to digest the collagen fibers.

Front 12

12. What digests proteins in the GI tract?

Back 12

Pepsin usually provides 10-20% of the total protein digestion in the stomach.

Most protein digestion occurs in the upper small intestine, in the duodenum and jejunum, under the influence of proteolytic enzymes from pancreatic secretion.

The pancreatic secretions contain trypsin, chymotrypsin, carboxypolypeptidase, and proelastase.

Front 13

13. What do each of these pancreatic enzymes do?

Back 13

1. Both trypsin and chymotrypsin split protein molecules into small polypeptides
2. Carboxypolypeptidase then cleaves individual AAs from the carboxyl ends of the polypeptides
3. Proelastase, in turn, is converted into elastase, which then digests elastase fibers that partially hold meat together

Front 14

14. What is the last digestive stage of the proteins in the intestinal lumen?

Back 14

The last stage is achieved by the enterocytes that line the villi of the small intestine, mainly in the duodenum and jejunum.

These cell have a brush border that has microvilli to increase surface area.

In the membrane of each of these microvilli are multiple peptidases that protrude through the membranes to the exterior where they come into contact w/the intestinal fluids.

Front 15

15. What are the two types of peptidase enzymes that are important?

Why?

Back 15

1. Aminopolypeptidase
2. Several dipeptidases

These enzymes succeed in splitting the remaining larger polypeptides into tri- and dipeptides and a few into AAs. Both the AAs plus the di- and tripeptides are easily transported thru the microvillar membrane to the interior of the enterocyte.

Front 16

16. What happens inside the cytosol of the enterocyte?

Back 16

There are multiple other peptidases that are specific for the remaining types of linkages between AAs.

Virtally all the last di- and tripeptides are digested to the final stage to form single AAs; these then pass on thru to the other side of the enterocytes and then into the blood.

Front 17

17. Does fat digestion take place in the stomach?

Back 17

A small amt of TAGs are digested in the stomach by lingual lipase that is secreted by lingual glands in the mouth and swallowed w/the saliva.

This amt of digestion is less than 10% and is generally unimportant. Instead, all fat digestion occurs in the small intestine.

Front 18

18. What is the first step of fat digestion?

Back 18

Phsyically to break the fat globules into very small sizes so that the water-soluble digestive enzymes can act.

This is called emulsification, and it begins by agitation in the stomach to mix the fat w/the products of stomach digestion.

Front 19

19. Where does most of the emulsification occur?

Back 19

In the duodenum under the influence of bile,.

Bile contains a large quantity of bile salts as well as the phospholipid lecithin. The polar parts of the bile salts and lecithin molecules are highly soluble in water, whereas most of the remaining portions are highly soluble in fat.

Therefore, these molecules interact w/the fat to greatly decrease the interfacial tension of the fat and make it soluble as well.

Front 20

20. What is a major function of the bile salts and lecithin?

Back 20

To make the fat globules readily fragmentable by agitation w/the water in the small bowel. This action is the same as detergents that are used in the wash.

Each time the diameters of the fat globules are significantly decreased as a result of agitation, the total surface area of the fat increases manyfold.

The lipase enzymes are water-soluble compounds and can attack the fat globules only on their surfaces. Thus, this is why this emulsification process is important.

Front 21

21. What does pancreatic lipase do?

What is enteric lipase?

Back 21

The most important enzyme for digestion of the TAGs is pancreatic lipase.

Present in pancreatic juice, it can digestion within 1 minute all TAGs that it can reach.

In addition, the enterocytes of the small intestine contain still more lipase, known as enteric lipase, but is is usually not needed.

Front 22

22. What are the end products of fat digestion?

Back 22

Free fatty acids and 2-monoglycerides

Front 23

23. What is another role of bile salts?

Back 23

TO remove the monoglycerides and free fatty acids from the vicinity of digesting fat globules almost as rapidly as these end products are formed.

Bile salts in water form micelles. The developing sterol nucleus emcompasses the fat digestate, forming a small fat globule in the middle of a resulting micelle, with polar groups of bile salts projecting outward to cover the surface of the micelle.

This allows the entire micelle to dissolve in the water of the digestive fluids and to remain in stable solution until the fat is absorbed into the blood.

Thus, the bile salt micelles also act as a transport medium to carry the monoglycerides and free fatty acids (ferrying)

Front 24

24. How does digestion of cholesterol esters and phospholipids occur...?

Back 24

Both cholesterol esters and the phospholipids are hydrolyzed by two other lipases in the pancreatic secretion that free the fatty acids: the enzyme cholesterol ester hydrolase, and phospholipase A2.

Front 25

25. Does the stomach have a good absorptive area?

Back 25

No, the stomach is poor in absorption b/c it lacks the typical villus type of absorptive membrane, and also b/c the junctions between the epithelial cells are tight junctions.

Only a few highly lipid-soluble substances, such as alcohol and some drugs like aspirin, can be absorbed in small quantities.

Front 26

26. What are the valvulae conniventes (or folds of Kerckring)?

Back 26

These folds are in the small intestinal mucosa villi, and they increase the surface area of the absorptive mucosa about 3x.

These folds extend circularly most of the way around the intestine and are especially well developed in the duodenum and jejunum.

Front 27

27. Where are the villi located in the GI tract?

Back 27

On the epithelial surface of the small intestine all the way down to the ileocecal valve.

These project about 1 mm from the surface of the mucosa. They lie so close to one another that they touch in most areas, but their distribution is less profuse in the distal small intestine.

The presence of villi on the mucosal surface enhances the total absorptive areas another 10x.

Front 28

28. What is the brush border?

Back 28

Each intestinal epithelial cell on each villus is characterized by a brush border.

This increases the surface area exposed to the intestinal materials at least another 20x.

Front 29

29. What is three important features of the villus?

Back 29

1. The advantageous arrangement of the vascular system for absorption of fluid and dissovled material into the portal blood

2. The arrangement of the central lacteal lymph vessel for absorption into the lymph

3. Extending from the epithelial cell body into each microvillus of the brush border are multiple actin filaments that contract rhythmically to cause continual movement of the microvilli, keeping them constantly exposed to new quantities of intestinal fluid.

Front 30

30. What is greater - absorption or absorptive capacity of the small intestine?

Back 30

Absorptive capacity.

Front 31

31. How does absorption of water occur in the small intestine?

Back 31

Water is transported thru the intestinal membrane entirely by diffusion. It obeys osmosis.

Thus, when the chyme is dilute enough, water is absorbed thru the intestinal mucosa into the blood and vice versa.

Within minutes, sufficient water usually will be transferred by osmosis to make the chyme isosmotic w/the plasma.

Front 32

32. How does sodium get absorbed?

Back 32

The motive power for doium absorption is provided by active transport of sodium form inside the epithelial cells thru the basal and side walls of these cells into paracellular spaces.

This active transport obeys the usual laws of active transport; it requires energy, and the energy process is catalyzed by ATPase in the cell membrane.

Part of the sodium is absorbed along w/chloride ions; in fact, the negatively charged chloride ions are mainly passively "dragged" by the positive electrical charges of the sodium ions.

Front 33

33. How is the sodium concentration in the cell of the enterocytes affected?

Back 33

It gets reduced to 50 mEq/L

B/c the sodium concentration in the chyme is normally isosmotic with that of plasma (142 mEq/L), sodium moves down this steep electrochemical gradient from the chyme thru the brush border of the epithelial cell into the epithelial cell cytoplasm. This provides still more sodium ions to be transported by the epithelial cells into the paracellular spaces.

Front 34

34. What is the next step in the transport process of sodium?

Back 34

Osmosis of water into the paracellular spaces. This occurs b/c a large osmotic gradient has been created by the elevated concentration of ions in the paracellular space.

Much of this osmosis occurs thru the tight junctions between the apical borders of the epithelial cell, but much also occurs thru the cells themselves. Also, osmotic movement of water creates flow of fluid into and thru the paracellular spaces, and finally, into the circulating blood of the villus.

Front 35

35. How does aldosterone affect sodium absorption?

How is this important in the colon?

Back 35

When a person becomes dehydrated, excess aldosterone is secreted by the adrenal glands. This increases all aspects of sodium absorption by the intestinal epithelium. And the increased sodium absorption in turn causes secondary increases in absorption of chloride ions, water, and some other substances.

This effect is especially important in the colon b/c it allows virtually no loss of NaCl in the feces and also little water loss.

Front 36

36. Where does absorption of chloride ions occur?

Back 36

In the duodenum and jejunum.

In the upper part of the small intestine, chloride ion absorption is rapid and occurs mainly by diffusion. Then chloride ions move along the electrical gradient caused by sodium ions to follow the sodium ions.

Front 37

37. Where does absorption of bicarbonate ions occur?

Back 37

Also in the duodenum and jejunum.

Large quantities of bicarb ions must be reabsorbed from the upper small intestine b/c large amts of bicarb have been secreted by the the pancreas and bile.

Front 38

38. How does bicarbonate ion absorption occur?

Back 38

Indirectly. When sodium ions are absorbed, moderate amts of hydrogen ions are secreted into the lumen of the gut in exchange for some of the sodium. These hydrogen ions in turn combine with the bicarb ions to form carbonic acid which then dissociates to form water and carbon dioxide.

The water remains as part of the chyme in the intestines, but the CO2 is readily absorbed into the blood and then expired thru the lungs.

Front 39

39. Where does the bicarbonate-chloride ion exchange take place?

Back 39

In the ileum and large intestine.

The epithelial cells in the villi of the ileum as well as on all surfaces of the large intestine have a special capability of secreting bicarbonate ions in exchange for absorption of choloride ions.

This is important b/c it provides alkaline bicarbonate ions that neutralize acid products formed by bacteria in the large intestine.

Front 40

40. Diarrhea and secretion of ions

Back 40

Deep in the spaces between the intestinal folds are immature epithelial cells that continually divide to form new epithelial cells. These in turn spread outward over the luminal surfaces of the intestine.

While still in the deep folds, the epithelial cells secrete NaCl and water into the intestinal lumen. This secretion in turn is reabsorbed by the older epithelial cells outside the folds, thus providing flow of water for absorbing intestinal digestates.

Front 41

41. What is cholera?

Back 41

Extreme diarrheal secretion is initiated by entry of a subunit of cholera toxin into the epithelial cells.

This stimulates the formation of excess cAMP, which opens tremendous numbers of chloride channels, allowing chloride ions to flow rapidly from inside the cell into the intestinal crypts.

In turn, this is believed to activate a sodium pump that pumps sodium ions into the crypts to go along with the chloride ions. Finally, all this extra NaCl causes extreme osmosis of water form the blood, thus providing rapid flow of fluid along with the salt.

All this excess fluid washes away most of the bacteria and is of value to combating the disease; however, too much of a good thing can be lethal

Front 42

42. Where are calcium ions absorbed?

Back 42

In the duodenum, and the most of calcium ion absorbed is very controlled to supply exactly the daily need of the body for calcium.

This is controlled by PTH and vitamin D.

PTH activates vitamin D, and the activated vitamin D in turn greatly enhances calcium absorption.

Front 43

43. Where are iron ions absorbed?

Back 43

Iron ions are also actively absorbed from the small intestine.

Front 44

44. Where are potassium, magnesium, phosphate, and other ions absorbed?

Back 44

These ions are actively absorbed thru the intestinal mucosa.

In general, the monovalent ions are absorbed w/ease and in great quantities. Conversely, bivalent ions are normally absorbed in only small amts; for example, max absorption of calcium ions is only 1/50th as great as the normal absorption of sodium ions.

Front 45

45. What is the most abundant of the absorbed monosaccharides?

Why?

Back 45

Glucose, usually accounting for more than 80% of the carb calories absorbed.

The reason for this is that glucose is the final digestion product of our starches in the diet, which is our most abundant carb.

The remaining 20% of absorbed monosaccharides are composed almost entirely of galactose and fructose.

Front 46

46. How is glucose transported?

Back 46

In the absence of sodium transport thru the intestinal membrane, virtually no glucose can be absorbed. The reason is that glucose absorption occurs in a co-transport mode w/active transport of sodium.

Front 47

47. What are the two stages in the transport of sodium thru the intestinal membrane?

Back 47

1. Active transport of sodium ions thru the basolateral membranes of the intestinal epithelial cells into the blood, thereby depleting sodium inside the epithelial cells.

2. Decrease of sodium inside the cells causes sodium from the intestinal lumen to move thru the brush border of the epithelial cells to the cell interiors by a process of facilitated diffusion.

Thus, a sodium ion combines w/a transport protein, but the transport protein will not transport the sodium to the interior of the cell until the protein itself combines with glucose.

Fortunately intestinal glucose also combines with the same transport protein, and then both the sodium ion and glucose molecule are transported to the interior of the cell.

Front 48

48. Glucose-sodium transport summary

Back 48

Thus, the low concentration of sodium inside the cell literally drags sodium to the interior of the cell and along with it the glucose at the same time.

Once inside the epithelial cell, other transport proteins and enzymes cause facilitated diffusion of the glucose thru the cell's basolateral membrane into the paracellular space and from there into the blood.

It is the initial active transport of sodium thru the basolateral membranes of the intestinal epithelial cells that provides the eventual motive force for moving glucose also thru the membranes.

Front 49

49. How are the other monosaccharides absorbed?

Back 49

Galactose is transported by almost exactly the same emchanism as glucose.

Conversely, fructose transport does not occur by the sodium co-transport mechanism. Instead, fructose is transported by facilitated diffusion all the way thru the intestinal epithelium but not coupled w/sodium transport.

Much of the fructose, on entering the cell, becomes phosphorylated, then converted to glucose, and finally transported in the form of glucose the rest of the way into the blood. B/c fructose is not co-transported w/sodium, its overall rate of transport is only 1/2 that of glucose or galactose.

Front 50

50. How are proteins absorbed?

Back 50

They are absorbed thru the luminal membranes of the intestinal epithelial cells in the form of di- and tripeptides and a few AAs. The energy for most of this transprot process is supplied by a sodium co-transprot mechanism in the same way that sodium co-transport of glucose occurs.

That is, most peptide or AA molecules bind int he cells microvillus membrane w/a specific transport protein that requires sodium binding before transport can occur.

After binding, the sodium ion then moves down the gradient to the interior of the cell and pulls the AA or peptide along with it. This is called co-transport.

Front 51

51. How are fats absorbed?

Back 51

After entering the epithelial cell, the fatty acids and monoglycerides are taken up by the cells smooth ER; here, they are mainly used to form new TAGs athat are subsequently released in the form of chylomicrons thru the base of the epithelial cell, to flow upward thru the thoracic duct and empty into the circulating blood.

Front 52

52. Can some fats be absorbed directly into the protal blood?

Back 52

Small quantities of short and medium chain fatty acids, such as those from butterfat, are absorbed directly into the portal blood rather than being converted into TAGs first.

The cause of this difference between short and long chain fatty acid absorption is that the short chain fatty acids are more water soluble and mostly are not reconverted into TAGs by the ER.

This allows direct diffusion of these short chain fatty acids from the intestinal epithelial cells directly into the capillary blood of the intestinal villi.

Front 53

53. Where does absorption occur in the large intestine?

Back 53

Most of the absorption occurs in the proximal half of the colon, whereas the distal half functions principally for feces storage.

Front 54

54. How are electrolytes and water absorbed and secreted in the large intestine?

Back 54

The tight junctions between the epithelial cells of the large intestinal epithelium are much tighter than those of the small intestine. This prevents significant amts of back-diffusion of ions thru these junctions, thus allowing the large intestinal mucosa to absorb sodium ions far more completely - that is, against a much higher concentration gradient than can occur in the small intestine.

In addition, the mucosa of the large intestine secretes bicarb ions while it simultaneously absorbs an equal number of chloride ions in an exchange transport process.

Absorption of sodium and chloride ions creases an osmotic gradient across the large intestinal mucosa, which in turn causes absorption of water.

Front 55

55. What is the max absorption capacity of the large intestine?

Back 55

The large intestine can absorb a max of 5-8 L of fluid and electrolytes each day.

When the total quantity entering the large intestine thru the ileocecal valve or by way of large intestine secretion exceeds this amt, the excess appears in the feces as diarrhea.

Front 56

56. What bacterial are present in the colon?

Back 56

Numerous bacteria, especially colon bacilli, are present even normally in the absorbing colon. They are capable of digesting small amts of cellulose.

Other important substances formed as a result of bacterial activity are vitamin K, B12, thiamine, riboflavin, and various gases that contribute to gas in the colon.

Front 57

57. What is the composition of feces?

Back 57

They are normally 3/4ths water and 1/4th solid matter that itself is composed of about 30% dead bacteria, 10-20% fat, 10-20% inorganic matter, 2-3% protein, and 30% undigested roughage from the food and dried constituents of digestive juices.

Front 58

58. What gives shit the brown color?

Bad smell?

Back 58

Color caused by stercobilin and urobilin, derivatives of bilirubin.

The odor is caused by products of baterial action; they include indole, skatole, mercaptans, and hydrogen sulfide.

Front 59

59. What can cause paralysis of the swallowing mechanism?

Back 59

Damage to CN V, IX, or X can cause paralysis of significant portions of the swallowing mechanism.

Also, a few diseases, such as polio and encephalitis, can prevent normal swallowing by damaging the swallowing center in the brain.

Finally, paralysis of the swallowing muscles, as occurs in muscular dystrophy or in failure of the NMJ transmission in myasthenia gravis or botulism, can also prevent normal swallowing.

Front 60

60. When the swallowing mechanism is partially or totally paralyzed, what abnormalities can result?

Back 60

1. Complete abrogation of the swallowing act so that swallowing cannot occur
2. Failure of the glottis to close so that food passes into the lungs instead of the esophagus
3. Failure of the soft palate and uvula to close the posterior nares so that food refluxes into the nose during swallowing.

Front 61

61. How is the swallowing mechanism affected during deep anesthesia?

Back 61

Often, while on the operating table, the patient vomits large quantities of materials from the stomach into the pharynx; then, instead of swallowing the materials again, they simply suck them into the trachea b/c the anesthetic has blocked the reflex mechanism of swallowing. As a result, such patients occasionally choke to death on their own vomit.

Front 62

62. What is gastritis?

Back 62

Inflammation of the gastric mucosa.

Mild to moderate chronic gastritis is exceedingly common int he population as a whole, especially in the middle to later years of adult life.

The inflammation may be only superficial, or it can penetrate deeply into the gastric mucosa, in many long-standing cases causing almost complete atrophy of the gastric mucosa. In a few cases, it can be acute and severe, w/ulcerative excoriation of the stomach mucosa by the stomach's own peptic secretions.

Front 63

63. What can cause gastritis?

Back 63

Caused by chronic bacterial infection of the gastric mucosa. This often can be treated w/antibacterial therapy.

In addition, certain ingested irritant substances can be damaging to the protective gastric mucosal barrier - often leading to severe acute or chronic gastritis.

Two of the most common of these substances are excesses of EtOH or aspirin.

Front 64

64. What are two reasons for the low level of absorption in the stomach?

Back 64

Caused by two specific features of the gastric mucosa:

1. it is lined w/highly resistant mucous cell that secrete a viscid and adherent mucus

2. it has tight junctions between the adjacent epithelial cells

These two together plus other impediments to gastric absorption are called the gastric barrier.

Front 65

65. What is gastric atrophy?

Back 65

In many people w/chronic gastritis, the mucosa gradually becomes more and more atrophic until little or no gastric gland digestive secretion remains.

It is also believed that some people develop autoimmunity against the gastric mucosa, this also leading eventually to gastric atrophy.

Loss of the stomach secretions in gastric atrophy leads to achlorhydria and occasionally to pernicious anemia.

Front 66

66. What is achlorhydria?

Back 66

Achlorhydria means simply that the stomach fails to secrete HCl.

It is diagnosed when the pH of the gastric secretions fails to decrease below 6.5 after max stimulation.

Front 67

67. What is hypochlorhydria?

Back 67

Hypochlorhydria means diminished acid secretion.

When acid is not secreted, pepsin is also usually not secreted; even when it is, the lack of acid prevents it from functioning b/c pepsin requires an acidic medium for activity.

Front 68

68. Why is pernicious anemia a freq concern in gastric atrophy?

Back 68

Pernicious anemia is a common feature of gastric atrophy and achlorhydria. Normal gastric secretions contain a glycoprotein called intrinsic factor, secreted by the same parietal cells that secrete HCl.

Intrinsic factor must be present for adequate absorption of vitamin B12 from the ileum. That is, intrinsic factor combines w/B12 in the stomach and protects it from being digested and destroyed as it passes into the small intestine. Then, when the intrinsic factor-vitamin B12 complex reaches the terminal ileum, the intrinsic factor binds w/receptors on the ileal epithelial surface. This in turn makes it possible for the vitamin B12 to be absorbed.

In the absence of intrinsic factor, only 1/50th of the B12 is absorbed. The result is pernicious anemia.

Front 69

69. What is a peptic ulcer?

Where are they most commonly formed?

Back 69

A peptic ulcer is an excoriated area of stomach or intestinal mucosa caused principally by the digestive action of gastric juice or upper small intestinal secretions.

The most freq site is within a few cm of the pylorus. In addition, peptic ulcers freq occur along the lesser curvature of the antral end of the stomach, or more rarely, in the lower end of the esophagus where stomach juices freq reflux.

A type of peptic ulcer called a marginal ulcer also often occurs wherever a surgical opening such as a gastrojejunostomy has been made between the stomach and the jejunum of the small intestine.

Front 70

70. What is the basic cause of a peptic ulceration?

Back 70

The usual cause is an imbalance between the rate of secreiton of gastric juice and the degree of protection afforded by (1) the gastroduodenal mucosal barrier and (2) the neutralization of the gastric acid by duodenal juices.

In other words, a peptic ulcer is caused by (1) excess secretion of acid and pepsin by the gastric mucosa or (2) diminished ability to protect against the digestive properties of the gastric juices.

Front 71

71. How is the stomach and upper duodenum protected by a mucosal barrier?

Back 71

All areas normally exposed to gastric juice are well supplied with mucous glands, beginning with compound mucous glands in the lower esophagus plus the mucous cell coating of the stomach mucosa, the mucous neck cells of the gastric glands, the deep pyloric glands that secrete mainly mucus, and, finally, the glands of Brunner of the upper duodenum, which secrete a highly alkaline mucus.

Front 72

72. How is the duodenum protected?

Back 72

Via the alkalinity of the small intestinal secretions. Especially important is pancreatic secretion that neutralizes the HCl, thus also inactivating pepsin and preventing digestion of the mucosa.

In addition, large amts of bicarb ions are provided int the secretions of the large Brunner's glands in the first few cm's of the duodenal wall, and in bile coming form the liver.

Front 73

73. What two feedback control mechanisms ensure that the neutralization of gastric juices is complete?

Back 73

1. When excess acid enters the duodenum, it reflexly inhibits gastric secretion and peristalsis in the stomach, both by nervous reflexes and by hormonal feedback from the duodenum, thereby decreasing the rate of gastric emptying.

2. The presence of acid int he small intestine liberates secretin from the intestinal mucosa, which then passes by way of the blood to the pancreas to promote rapid secretion of pancreatic juice. This juice also contain s a high concentration of sodium bicarb, thus making still more sodium bicarb available for neutralization of the acid.

Front 74

74. What is H. pylori?

Back 74

Many peptic ulcer patients have chronic infections of the terminal portions of the gastric mucosa and initial portions of the duodenal mucosa most often caused by infection of H. pylori.

Often the bacterium is capable of penetrating the mucosal barrier both by virtue of its physical capability to burrow through the barrier and by releasing bacterial digestive enzymes that liquefy the barrier. As a result, the strong acidic digestive juices of the stomach secretions can then penetrate into the underlying epithelium and literally digest the GI wall.

Front 75

75. What are other causes of ulceration?

Back 75

1. Smoking, presumably b/c of increased nervous stimulation of the stomach secretory glands

2. EtOH, b/c it tends to break down the mucosal barrier

3. Aspirin and other NSAIDs that also have a strong propensity for breaking down this barrier.

Front 76

76. What are two agents that treat peptic ulceration?

Back 76

1. Use of antibiotics along w/other agents to kill infectious bacteria

2. Administration of an acid-suppressant drug, especially ranitidine, an antihistamine that blocks the stimulatory effect of histamine on gastric gland histamine receptors, thus reducing gastric acid secretion by 70-80%

Front 77

77. Lack of pancreatic secretion occurs in what three situations?

Back 77

1. In pancreatitis
2. When pancreatic duct is blocked by a gallstone at the papilla of Vater
3. After the head of the pancreas has been removed b/c of malignancy

Front 78

78. Loss of pancreatic juice means what...?

Back 78

Loss of trypsin, chymotrypsin, carboxypolypeptidase, pancreatic amylase, pancreatic lipase, and a few other enzymes. As a result, a large portion of the ingested food cannot be used for nutrition, can copious, fatty feces are excreted.

Front 79

79. What is the most common cause of pancreatitis?

Second most common?

Back 79

1. Drinking excess alcohol
2. Blockage of the papilla of Vater by a gallstone

These two together account for more than 90% of all cases.

Front 80

80. What is nontropical sprue?

Back 80

AKA celiac disease, results from the toxic effects of gluten present in certain types of grains, especially wheat and rye.

Only some people are susceptible to this effect, but in those who are susceptible, gluten has a direct destructive effect on intestinal enterocytes. In milder forms of the disease, only the microvilli of the absorbing enterocytes on the villi are destroyed, thus decreasing the absorptive surface area by 2x.

In the more severe forms, the villi themselves become blunted or disappear altogether, thus still further reducing the absorptive are of the gut.

Front 81

81. What is tropical sprue?

Back 81

A different type of sprue called tropical sprue frequently occurs in the tropics and can often be treated with antibacterial agents.

Even though no specific bacterium has been implicated as the cause, it is believed that this variety of sprue is usually caused by inflammation of the intestinal mucosa resulting from unidentified infectious agents.

Front 82

82. In the early stages of sprue, what digestive product absorption is most impaired?

Back 82

In the early stages of sprue, intestinal absorption of fat is more impaired than absorption of other digestive products.

The fat that appears in the stool is almost entirely in the form of salts of fatty acids rather than undigested fat, demonstrating that the problem is one of absorption, not of digestion. This is called steatorrhea.

Front 83

83. What are four consequences of malabsorption in sprue?

Back 83

1. Severe nutritional deficiency, often developing wasting of the body
2. Osteomalacia
3. Inadequate blood coagulation caused by lack of vitamin K
4. Macrocytic anemia of the pernicious anemia type, owing to diminished vitamin B12 and folic acid absorption.

Front 84

84. What can cause constipation?

Back 84

Any pathology of the intestines that obstructs movement of intestinal contents, such as tumors, adhesions that constrict the intestines, or ulcers, can cause constipation.

A freq functional cause of constipation is irregular bowel habits that have developed thru a lifetime of inhibition of the normal defecation reflexes.

Can also result from spasm of a small segment of the sigmoid colon.

Front 85

85. What is megacolon?

What is a freq cause?

Back 85

Occasionally, constipation is so severe that bowel movements occur only once every several days or sometimes only once a week. This allows tremendous quantities of fecal matter to accumulate in the colon, causing the colon sometimes to distend to a diameter of 3 to 4 inches. The condition is called megacolon, or Hirschsprung’s disease.

A frequent cause of megacolon is lack of or deficiency of ganglion cells in the myenteric plexus in a segment of the sigmoid colon. As a consequence, neither defecation reflexes nor strong peristaltic motility can occur in this area of the large intestine. The sigmoid itself becomes small and almost spastic while feces accumulate proximal to this area, causing megacolon in the ascending, transverse, and descending colons.

Front 86

86. What is enteritis?

Back 86

Means inflammation usually caused either by a virus or by bacteria in the intestinal tract. In usual infectious diarrhea, the infection is most extensive in the large intestine and the distal end of the ileum.

Everywhere the infection is present, the mucosa becomes extensively irritated, and its rate of secretion becomes greatly enhanced. In addition, motility of the intestinal wall usually increases manyfold. As a result, large quantities of fluid are made available for washing the infectious agent toward the anus, and at the same time strong propulsive movements propel this fluid forward.

Front 87

87. What is psychogenic diarrhea?

Back 87

Periods of nervous tension can be accompanied by diarrhea.

This is caused by excessive stimulation of the parasympathetic nervous system, which greatly excites both (1) motility and (2) excess secretion of mucus in the distal colon.

Front 88

88. What is ulcerative colitis?

Back 88

Ulcerative colitis is a disease in which extensive areas of the walls of the large intestine become inflamed and ulcerated.

The motility of the ulcerated colon is often so great that mass movements occur much of the day rather than for the usual 10 to 30 minutes.

Also, the colon’s secretions are greatly enhanced. As a result, the patient has repeated diarrheal bowel movements.

Front 89

89. What causes ulcerative colitis?

Back 89

The cause of ulcerative colitis is unknown. Some clinicians believe that it results from an allergic or immune destructive effect, but it also could result from chronic bacterial infection not yet understood. Whatever the cause, there is a strong hereditary tendency for susceptibility to ulcerative colitis.

Once the condition has progressed very far, the ulcers seldom will heal until an ileostomy is performed to allow the small intestinal contents to drain to the exterior rather than to pass through the colon.

Even then the ulcers sometimes fail to heal, and the only solution might be surgical removal of the entire colon.

Front 90

90. What reflex initiates defecation?

Back 90

It is normally initiated by accumulating feces in the rectum, which causes a spinal cord-mediated defecation reflex passing from the rectum to the conus medullaris of the spinal cord and then back to the descending colon, sigmoid, rectum, and anus.

Front 91

91. What happens to defecation when the spinal cord is injured somewhere between the conus medullaris and the brain?

Back 91

The voluntary portion of the defecation act is blocked while the basic cord reflex for defecation is still intact.

But, b/c the cord defecation reflex can still occur, a small enema to excite action of this cord reflex, usually given in the morning, can often cause adequate defecation.

Front 92

92. What is vomiting?

Back 92

Vomiting is the means by which the upper gastrointestinal tract rids itself of its contents when almost any part of the upper tract becomes excessively irritated, overdistended, or even overexcitable.

Excessive distention or irritation of the duodenum provides an especially strong stimulus for vomiting.

Front 93

93. What sensory signals initiate vomiting?

Back 93

They originate mainly from the pharynx, esophagus, stomach, and upper portions of the small intestines.

The nerve impulses are transmitted by both vagal and sympathetic afferent nerve fibers to multiple distributed nuclei in the brain stem that are together are called the "vomiting center".

From here, motor impulses that cause the actual vomiting are transmitted from the vomiting center by way for the 5th, 7th, 9th, 10th, and 12th cranial nerves to the upper GI tract, through vagal and sympathetic nerves to the lower tract, and through spinal nerves to the diaphragm and abdominal muscles.

Front 94

94. What is antiperistalsis?

Back 94

The prelude to vomiting.

In the early stages of excessive GI irritation or overdistention, antiperistalsis begins to occur often many minutes before vomiting appears. Antiperistalsis means peristalsis up the digestive tract rather than downward. This may begin as far down in the intestinal tract as the ileum, and the antiperistaltic wave travels backward up the intestine at a rate of 2-3 cm/sec.

This process can push a large share of the lower small intestinal contents all the way back to the duodenum and stomach within 3-5 minutes. Then, as these upper portions of the GI tract, especially the duodenum, become overly distended, this distention becomes the exciting factor that initiates the actual vomiting act.

Front 95

95. At the onset of vomiting, what occurs?

Back 95

Strong intrinsic contractions occur in both the duodenum and the stomach, along w/partial relaxation of the esophageal-stomach sphincter, thus allowing vomitus to being moving form the stomach into the esophagus.

From here, a specific vomiting act involving the abdominal muscles takes over and expels the vomitus to the exterior.

Front 96

96. What four things occur during the vomiting act?

Back 96

1. A deep breath
2. Raising of the hyoid bone and larynx to pull the upper esophageal sphincter open
3. Closing of the glottis to prevent vomitus flow into the lungs
4. Lifting of the soft palate to close the posterior nares

Next comes a strong downward contraction of the diaphragm along w/simultaneous contraction of all the abdominal wall muscles. This squeezes the stomach between the diaphragm and the abdominal muscles, building the intragastric pressure to a high level. Finally, the lower esophageal sphincter relaxes completely, allowing expulsion of the gastric contents upward through the esophagus.

Front 97

97. What is the chemoreceptor trigger zone?

Back 97

Vomiting can also be caused by nervous signals arising in areas of the brain. This is true for a small area located bilaterally on the floor of the fourth ventricle.

Electrical stimulation of this area can initiate vomiting; but, more important, administration of certain drugs, including apomorphine, morphine, and some digitalis derivatives, can directly stimulate this chemoreceptor trigger zone and initiate vomiting.

Front 98

98. How can motion sickness cause vomiting?

Back 98

It is well known that rapidly changing direction or rhythm of motion of the body can cause certain people to vomit.

The mechanism for this is the following: The motion stimulates receptors in the vestibular labyrinth of the inner ear, and from here impulses are transmitted mainly by way of the brain stem vestibular nuclei into the cerebellum, then to the chemoreceptor trigger zone, and finally to the vomiting center to cause vomiting.

Front 99

99. What is nausea and what three things can cause it?

Back 99

Nausea is the conscious recognition of subconscious excitation in an area of the medulla closely associated w/or part of the vomiting center.

It can be caused by:
1. Irritative impulses coming from the GI tract
2. Impulses that originate in the lower brain associated w/motion sickness
3. Impulses from the cerebral cortex to initiate vomiting

Front 100

100. What are four common causes of GI obstructions?

Back 100

1. Cancer
2. Fibrotic constriction resulting from ulceration or from peritoneal adhesions
3. Spasm of a segment of the gut
4. Paralysis of a segment of the gut

Front 101

101. What happens if an obstruction occurs at the pylorus?

Back 101

This results often from fibrotic constriction after peptic ulceration, persistent vomiting of stomach contents occurs.

This depresses bodily nutrition; it also causes excessive loss of hydrogen ions form the stomach and can result in various degrees of whole-body alkalosis.

Front 102

102. What happens if the obstruction is beyond the stomach?

Back 102

Antiperistaltic reflux from the small intestine causes intestinal juices to flow backward intot he stomach, and these juices are vomited along w/the stomach secretions.

In this instance, the person loses large amts of water and electrolytes, so that he or she becomes severely dehydrated, but the loss of acid from the stomach and base from the small intestine are about equal so no acid-base balance occurs.

Front 103

103. What happens if the obstruction is near the distal end of the large intestine?

Back 103

Feces can accumulate in the colon for a week or more. The patient develops an intense feeling of constipation but at first vomiting is not severe.

After the large intestine has become completely filled and it finally becomes impossible for additional chyme to move from the small intestine into the large intestine, severe vomiting does then occur.

Prolonged obstruction of the large intestine can finally cause rupture of the intestine itself or dehydration and circulatory shock resulting from severe vomiting.

Front 104

104. Amylose vs. amylopectin

Back 104

In amylose, the glucosyl residues form a straight chain linked via α-1,4-glycosidic bonds.

In amylopectin, the α-1,4-chains contain branches connected via α-1,6-glycosidic bonds.

Front 105

105. What is dietary fiber composed of?

Back 105

Composed principally of plant polysaccharides and a polymer called lignan.

Front 106

106. Digestion of dietary carbs

Back 106

In the digestive tract, dietary polysaccharides and disaccharides are converted to monosaccharides by glycosidases, enzymes that hydrolyze the glycosidic bonds between the sugars.

All of these enzymes exhibit some specificity for the sugar, the glycosidic bond (α or β), and the number of saccharide units in the chain.

The monosaccharides formed by glycosidases are transported across the intestinal mucosal cells into the interstitial fluid and subsequently enter the bloodstream.

Undigested carbs enter the colon, where they may be fermented by bacteria.

Front 107

107. Where does digestion of starch begin?

Back 107

The digestion of starch (amylopectin and amylose) begins in the mouth, where chewing mixes the food with saliva. The salivary glands secrete salivary α-amylase and other components.

Front 108

108. What is α-amylase?

Back 108

α-amylase is an endoglucosidase, which means that it hydrolyzes internal α-1,4-bonds between glucosyl residues at random intervals in the polysaccharide chains.

The shorted polysaccharide chains that are formed are called α-dextrins. Salivary α-amylase is largely inactivated by the acidity of the stomach contents, which contain HCl secreted by the parietal cells.

Front 109

109. What does pancreatic α-amylase do to starches and glycogen?

Back 109

It continues to hydrolyze the starches and glycogen, forming the disaccharide maltose, the trisaccharide maltotriose, and oligosaccharides. These oligosaccharides, called limit dextrins, are usually 4-9 glucosyl units long and contain one or more α-1,6-branches. The two glucosyl residues that contain the α-1,6-glycosidic bond eventually become the disaccharide isomaltose, but α-amylase does not cleave these branched oligosaccharides all the way down to isomaltose.

Front 110

110. Specificity of α-amylase

Back 110

α-amyalse has no activity toward sugar-containing polymers other than glucose linked by α-1,4-bonds.

α-amylse displays no activity toward the α-1,6-bond at branch points and has little activity for the α-1,4-bond at the nonreducing end of the chain.

Front 111

111. What disaccharidases are present in the intestinal brush border membrane?

Back 111

The dietary disaccharides lactose and sucrose, as well as the products of starch digestion, are converted to monosaccharides by glycosidases attached to the membrane in the brush border of absorptive cells.

The different glycosidase activities are found in four glycoproteins; glucoamylase, the sucrase-isomaltase complex, the smaller glycoprotein trehalase, and lactase-glucosylceramidase. These glycosidases are collectively called the small intestinal disaccharidases, although glucoamylase is really an oligosaccharidase.

Front 112

112. What is glucoamylase?

Back 112

Glucoamylase and the sucrase-isomaltase complex have similar structures and exhibit a great deal of sequence homogeneity.

A membrane-spanning domain near the N-terminal attaches the protein to the luminal membrane. The long polypeptide chain forms two globular domains, each with a catalytic site.

In glucoamylase, the two catalytic sites have similar activities, w/only small differences in substrate specificity. The protein is heavily glycosylated with oligosaccharides that protect it from digestive proteases.

Front 113

113. What is the specificity of glucoamylase?

Back 113

Glucoamylase is an exoglucosidase that is specific for the α-1,4-bonds between glucosyl residues. It begins at the nonreducing end of a polysaccharide or limit dextrin, and sequentially hydrolyzes the bonds to release glucose monosaccharides.

It will digest a limit dextrin down to isomaltose, the glucosyl disaccharide with an α-1,6-branch, which is subsequently hydrolyzed principally by the isomaltase activity in the sucrase-isomaltase complex.

Front 114

114. What is the sucrase-isomaltase complex?

Back 114

The structure of the sucrase-isomaltase compelx is very similar to tha tof glucoamylase, and these two proteins have a high degree of sequence homology. Hwoever, after the single polypeptide chain of sucrase-isomaltase is inserted through the membrane and the protein protrudes into the intestinal lumen, an intestinal protease clips it into two separate subunits that remain attached to each other. Each subunit has a catalytic site that differs in substrate specificty from the other through noncovalent interactions.

Front 115

115. What accounts for all of the intestine's ability to hydrolyze sucrose in addition to maltase activity?

Back 115

The sucrase-maltase site accounts for approx 100% of the intestine's ability to hydrolyze sucrose in addition to maltase activity; the isomaltase-maltase site accounts for almost all of the intestine's ability to hydrolyze α-1,6-bonds, in addition to maltase activity.

Together, these sites account for approx 80% of the maltase activity of the small intestine. The remainder of the maltase activity is found int he glucoamylase complex.

Front 116

116. What is trehalase?

Back 116

Trehalase is only half as long as the other disaccharidases and has only one catalytic site. It hydrolyzes the glycosidic bond in trehalose, a disaccharide composed of two glucosyl units linked by an α-bond between their anomeric carbons.

Trehalose, which is found in insects, algae, etc... is not a major dietary compoennt in the US. However, unwitting consumption of trehalose can cause nausea, vomiting, and other symptoms of severe GI distress if consumed by an individual deficient in the enzyme.

Front 117

117. What is the β-glycosidase complex (lactase-glucosylceramidase)?

Back 117

The β-glycosidase complex is another large glycoprotein found in the brush border that has two catalytic sites extending in the lumen of the intestine. However, its primary structure is different, and it is attached to the membrane thru its carboxyl end by a phoshatidylglycan anchor.

The lactase catalytic site hydrolyzes the β-bond connecting glucose and galactose in lactose. The major activity of the other catalytic site in humans is the β-bond between glucose or galactose and ceramide in glycolypids.

Front 118

118. The production of maltose, maltotriose, and limit dextrins by pancreatic α-amylase occurs where?

Where is sucrase-isomaltase activity highest?

β-glycosidase activity?

Glucoamylase?

Back 118

Production of those sugars occurs in the duodenum, the most proximal portion of the small intestine.

Sucrase-isomaltase activity is highest in the jejunum, where the enzymes can hydrolyze sucrose and the products of starch digestion

β-glycosidase activity is highest in the jejunum.

Glucoamylase activity increases progressively along the length of the small intestine, and its activity is highest in the ileum.

Front 119

119. What do the colonic bacteria metabolize?

What major gases are formed?

Back 119

Colonic bacteria rapidly metabolize the saccharides, forming gases, short-chain fatty acids, and lactate.

The majory short-chain fatty acids formed are acetic acid (2 C's), propionic acid (3 C's), and butyric acid (4 C's).

The short chain fatty acids are absorbed by the colonic mucosal cells and can provide a substantial source of energy for these cells.

The major gases formed are hydrogen gas, carbon dioxide, and methane. These gases are released thru the colon, resulting in flatulence.

Front 120

120. What is the nonpersistent lactase phenotype?

Back 120

Lactase activity increases in the human for about 6-8 weeks of gestation and it rises during the late gestational phase (27-32 weeks) thru full term. It remains high for 1 month after birth and then begins to decline.

For most of the world's population, lactase activity decreases to adult levels at approximately 5-7 years of age. Adult levels are less than 10% of those present in infants. These populations have adult hypolactasia and exhibit the lactase nonpersistent phenotype.

This is the normal condition of most of the world's population.

Front 121

121. What is the persistent lactase phenotype?

Back 121

In people who are derived mainly from western northern Europeans, and milk-dependent nomadic tribes of Saharan Africa, the levels of lactase remain at, or only slightly below, infant levels throughout adulthood.

Front 122

122. What intestinal diseases can cause lactase deficiency?

Back 122

Intestinal diseases that injure the absorptive cells of the intestinal villi diminish lactase activity along the intestine, producing a condition known as secondary lactase deficiency.

Kwashiorkor (protein malnutrition), colitis, gastroenteritis, tropical and nontropical sprue, and excessive alcohol consumption fall into this category.

These disease also affect other disaccharadases, but sucrase, maltase, isomaltase, and glucoamylase activities are usually present at such excessive levels that there are no pathologic effects.

*Lactase is usually the first activity lost and the last to recover.

Front 123

123. What is one benefit of dietary fiber?

Back 123

In diverticular disease, in which sacs or pouches may develop in the colon b/c of a weakening of the muscle and submucosal structures. Fiber is thought to soften the stool, thereby reducing pressure on the colonic wall and enhancing expulsion of feces.

Front 124

124. Why are oats good for our health?

What about pectins?

Back 124

β-glucan (obtained from oats) has also been shown to reduce cholesterol levels thru a reduction in bile acid resorption in the intestine.

Pectins also may have a beneficial effect in the diet of individuals w/DM by slowing the rate of absorption of simple sugars and preventing high blood glucose levels after meals.

Front 125

125. What foods have the highest glycemic index?

The lowest?

Back 125

Glucose and maltose have the highest glycemic indices (142, w/white bread defined as an index of 100).

Cornflakes and potatoes have high glycemic indices, whereas yogurt and skim milk have particularly low glycemic indices.

Front 126

126. What determines the glycemic response?

Back 126

Depends not only on the glycemic index of the foods but also on the fiber and fat content of the food, as well as its methods of preparation.

Front 127

127. Glucose absorption by intestinal epithelium

Back 127

Glucose is transported thru the absorptive cells of the intestine by facilitated diffusion and by Na⁺-dependent facilitated transport.

Glucose, therefore, enters the absorptive cells by binding to transport proteins, membrane-spanning proteins that bind the glucose molecule on one side of the membrane and release it on the opposite side. Two types of glucose transport proteins are present in the intestinal absorptive cells: the Na⁺-dependent glucose transporters and the facilitative glucose transporters.

Front 128

128. What are the Na⁺-dependent transporters?

Back 128

Na⁺-dependent glucose transporters, which are located on the luminal side of the absorptive cells, enable these cells to concentrate glucose from the intestinal lumen. A lower intracellular Na⁺ concentration is maintained by a Na⁺,K⁺-ATPase on the serosal (blood) side of the cell that uses the energy from ATP cleavage to pump Na⁺ out of the cell into the blood.

Thus, the transport of glucose from a low concentration in the lumen to a high concentration in the cell is promoted by the cotransport of Na⁺ from a high concentration in the lumen to a low concentration in the cell (secondary active transport).

Front 129

129. What are the facilitative glucose transporters?

Back 129

Facilitative glucose transporters, which do not bind Na⁺, are located on the serosal side of the cells. Glucose moves via the facilitative transporters from the high concentration inside teh cell to the lower concentration in the blood without the expenditure of energy. In addition to the Na⁺-dependent glucose transporters, facilitative transporters for glucose also exist on the luminal side of the absorptive cells.

Front 130

130. What are the best-characterized facilitative glucose transporters?

Back 130

Those found in the plasma membranes of cells (referred to as GLUT 1 - 5)

One common structural theme to these proteins is that they all contain 12 membrane-spanning domains.

Front 131

131. Glucose transport in the kidney

Back 131

The epithelial cells of the kidney, which reabsorb glucose from the lumen of the renal tubule back into the blood, have Na⁺-dependent glucose transporters similar to those of intestinal epithelial cells.

They are thus also able to transport glucose against its concentration gradient. Other types of cells use mainly facilitative glucose transporters that carry glucose down its concentration gradient.

Front 132

132. Galactose absorption

Back 132

Galactose is absorbed thru the same mechanisms as glucose. It enters the absorptive cells on the luminal side via the Na⁺-dependent glucose transporters and facilitative glucose transporters and is transported thru the serosal side on the facilitative glucose transporters.

Front 133

133. Fructose absorption

Back 133

Fructose both enters and leaves absorptive epithelial cells by facilitated diffusion, apparently via transport proteins that are part of the GLUT family.

The transporter on the luminal side is GLUT 5. Although this transporter can transport glucose, it has a much higher activity w/fructose. Other fructose transport proteins also may be present. Also, fructose is absorbed at a much more rapid rate when it is ingested as sucrose than when it is ingested as a monosaccharide.

Front 134

134. How does the transport of monosaccharides differ among tissues?

Back 134

The properties of the GLUT transport proteins differ among tissues, reflecting the function of glucose metabolism in each tissue. In msot cell types, the rate of glucose transport across the cell membrane is not rate-limiting for glucose metabolism. This is b/c the isoform of transporter present in these cell types has a relatively low Km for glucose (i.e. a low concentration of glucose will result in half the maximal rate of glucose transport) or is present in relatively high concentrations in the cell membrane so that the intracellular glucose concentration reflects that in the blood.

B/c the hexokinase isozyme present in these cells has an even lower Km for glucose, variations in blood glucose levels do not affect the intracellular rate of glucose phosphorylation. However, in several tissues, the rate of transport becomes rate-limiting when the serum level of glucose is low or when low levels of insulin signal the absence of dietary glucose.

Front 135

135. What tissue is an example of a tissue in which glucose transport is not rate-limiting?

Back 135

The erythrocyte (RBC). Although the glucose transporter (GLUT 1) has a Km of 1 to 7 mM, it is present in extremely high concentrations, constituting approx 5% of all membrane proteins.

Consequently, as the blood glucose levels fall from a postprandial level to the normal fasting level or even hypoglycemic level, the supply of glucose is still adequate for the rates at which glycolysis and the pentose phosphate pathway operate.

Front 136

136. What about glucose transport in the liver?

Back 136

The Km for the glucose tranporter (GLUT 2) in the liver is relatively high compared with that of other tissues. This is in keeping w/the liver's role as the organ that maintains blood glucose levels. Thus, the liver wiill convert glucose into other energy storage molecules only when blood glucose levels are high.

Front 137

137. What about glucose transport in muscle and adipose tissue?

Back 137

In muscle and adipose tissue, the transport of glucose is greatly stimulated by insulin.

The mechanism involves the recruitment of glucose transporters (specifically GLUT 4) from intracellular vesicles into the plasma membrane.

In adipose tissue, the stimulation of glucose transport across the plasma membrane by insulin increases its availability for the synthesis of fatty acids and glycerol from the glycolytic pathway.

In skeletal muscle, the stimulation of glucose transport by insulin increases its availability for glycoslysis and glycogen synthesis.

Front 138

138. What elicits the hypoglycemic response?

Back 138

A decrease in blood glucose concentration to some point between 18-54 mg/dL.

The hypoglycemic response is a result of a decreased supply of glucose to the brain and starts w/light-headedness and dizziness and may progress to coma.

The slow rate of transport of glucose thru the blood-brain barrier (from the blood into the CSF) at low levels of glucose is thought to be responsible for this neuroglycopenic response.

Glucose transport from the CSF across the plasma membranes of neurons is rapid and is not rate-limiting for ATP generation from glycolysis.

Front 139

139. How does glucose pass into the brain?

Back 139

in the brain, the endothelial cells of the capillaries have extremely tight junctions, and glucose must pass from the blood into the extracellular CSF fluid by GLUT 1 transporters in the endothelial cell membranes and then through the basement membrane.

Measurements of the overall process of glucose transport from the blood into the brain (mediated by GLUT 3 on neural cells) shows a Km of 7 - 11 mM and a max velocity not much greater than the rate of glucose utilization by the brain.

Thus, decreases of blood glucose below the fasting level are likely to significantly affect the rate of glucose metabolism int he brain, b/c of reduced glucose transport into the brain.

Front 140

140. What causes hyperglycemia in poorly controlled diabetics?

Back 140

This is often attributable to a lack of circulating, active insulin, which sitmulates glucose uptake (through the recruitment of GLUT 4 transporters from the ER to the plasma membrane) by the peripheral tissues (heart, muscle, and adipose tissue).

Without uptake by these tissues, glucose tends to accumulate w/in the bloodstream, leading to hyperglycemia.

Front 141

141. How does cholera cause illness?

Back 141

After being ingested, the V. cholerae organisms attach to the brush border of the intestinal epithelium and secrete an exotoxin that binds irreversibly to a specific chemical receptor (Gm1 ganglioside) on the cell surface.

This exotoxin catalyzes an ADP-ribosylation reaction that increases adenylate cyclase activity and thus cAMP levels in the enterocyte.

As a result, the normal absorption of sodium, anions, and water from the gut lumen into the intestinal cell is markedly diminished. The exotoxin also stimulates the crypt cells to secrete chloride, accompanied by cations and water, from the bloodstream into the lumen of the gut.

Front 142

142. How do starch blockers work and why were they discontinued?

Back 142

Starch blockers were based on a protein found in beans, which blocked the action of amylase.

They were discontinued b/c they were never shown to be effective in weight loss. This was probably b/c of a combination of factors, such as inactivation of the inhibitor by the low pH in the stomach, and an excess of amylase activity compared w/the amt of starch blocker ingested.

Front 143

143. Amylase activity and cystic fibrosis

Back 143

Amylase activity in the gut is abundant and is not normally rate limiting for the process of digestion. EtOH induced pancreatitis or surgical removal of part of the the pancreas can decrease pancreatic secretion.

Pancreatic exocrine secretion into the intestine can also be reduced as a result of CF, in which mucus blocks the pancreatic duct, which eventually degenerates.

However, pancreatic exocrine secretion can be decreased to 10% of normal and still not affect the rate of starch digestion, b/c amylases are secreted in the saliva and pancreatic fluid in excessive amounts. In contrast, protein and fat digestion are more strongly affected in cystic fibrosis.

Front 144

144. What is sucrase-isomaltase complex deficiency?

Back 144

Individuals with genetic deficiencies of the sucrase-isomaltase complex show symptoms of sucrose intolerance but are able to digest normal amounts of starch in a meal without problems.

The maltase activity in the glucoamylase complex, and residual activity in the sucrase-isomaltase complex (which is normally present in excess of need), is apparently sufficient to digest normal amts of dietary starch.

Front 145

145. What is the basis of the hydrogen breath test?

Back 145

If a sugar is not absorbed, it is metabolized in the intestinal lumen by bacteria that produce various gases, including hydrogen.

The test is often accompanied by measurements of the amt of sugar that appears in the blood or feces, and the acidity of the feces.

Front 146

146. What can cause lactase intolerance?

Back 146

Can either be a result of a primary deficiency of lactase production in the small bowel, or it can be secondary to an injury to the intestinal mucosa, where lactase is normally produced.

The osmotic effect of the lactose and lactic acid in the bowel lumen is responsible for the diarrhea that is often seen as part of this syndrome.

Front 147

147. What malabsorptive disorders are most commonly encountered in the US?

Back 147

Celiac disease, pancreatic insufficiency, and Crohn disease

Pancreatic insufficiency, primarily from chronic pancreatitis or CF, is a major cause of defective intraluminal digestion.

Front 148

148. What is celiac disease?

Back 148

Celiac disease (AKA sprue) is a chronic disease, in which there is a characteristic mucosal lesion of the small intestine and impaired nutrient absorption, which improves on withdrawal of wheat gliadins and related grain proteins from the diet.

It occurs largely in whites and occurs in the range of 1/100 to 1/200.

Front 149

149. What is the pathogenesis of celiac disease?

What is the hallmark of this disease?

Back 149

The fundamental disorder is a sensitivity to gluten, which is the alcohol soluble, water insoluble protein component (gliadin) of wheat and closely related gains (oat, barley, and rye).

The hallmark of this disease is a T-cell mediated chronic inflammatory reaction w/an autoimmune component, which most likely develops as a consequence of a loss of tolerance to gluten.

The small intestinal mucosa, when exposed to gluten, accumulates intraepithelial CD8+ T cells and large numbers of lamina propria CD4+ T cells, which are sensitized to gliadin.

Front 150

150. What genetic factors are associated w/celiac disease?

Back 150

Almost all individuals w/celiac share the MHC complex class II HLA-DQ2 or HLA-DQ8 haplotype.

It has been suggested that gliadin is deamidated by the enzyme transglutaminase and that deaminadated gliadin peptides bind to DQ2 and DQ8.

Recognition of these peptides by CD4+ T cells leads to secretion of interferon γ, which damages the intestinal wall.

Front 151

151. Why is celiac disease associated w/lymphoma?

Back 151

The epithelial cells secrete large amts of IL-15 that activates CD8+ T cells and increases the risk of lymphoma development.

Front 152

152. What is the morphology of celiac disease?

1/2

Back 152

By endoscopy, the small intestinal mucosa appears flat or scalloped, or may be visually normal. Biopsies demonstrate diffuse enteritis, with marked atrophy or total loss of villi.

The surface epithelium shows vacuolar degeneration, loss of the microvillus brush border, and an increased number of intraepithelial lymphocytes.

The crypts, on the other hand, exhibit increased mitotic activity and are elongated, hyperplastic and tortuous, so that the overall mucosal thickness remains the same.

Front 153

153. What is the morphology of celiac disease?

2/2

Back 153

The lamina propria has an overall increase in plasma cells, lymphocytes, macrophages, eosinophils, and mast cells. All these changes are usually more marked in the proximal small intestine than in the distal, since it is the duodenum and proximal jejunum that are exposed to the highest concentration of dietary gluten.

Although these changes are characteristic of celiac disease, they can be mimicked by other diseases, most notably tropical sprue.

Mucosal histology usually reverts to normal or near-normal following a period of gluten exclusion from the diet.

Front 154

154. What are the clinical features of celiac disease?

Back 154

The symptoms vary from patient to patient. Symptomatic diarrhea and failure to thrive may be evident during infancy, yet adults may seek attention much later in life.

The classic presentation includes diarrhea, flatulence, weight loss, and fatigue. However, extraintestinal manifestations of malabsorption may overshadow the intestinal symptoms.

A characteristic skin blistering lesion, dermatitis herpetiformis, can occur in patients w/celiac disease.

Neurologic disorders are occasionally seen.

Front 155

155. Dx of celiac disease?

Definitive Dx depends on what 3 things?

Back 155

Detection of circulating anti-gliadin or "anti-endomysial" antibodies strongly favors the Dx; antibodies against tissue transglutaminase also may be detected, as this is the autoantigen recognized by anti-endomysial antibody.

Definitive Dx rests on:
1. Clinical documentation of malabsorption
2. Demonstration of the intestinal lesion by small bowel biopsy
3. Unequivocal improvement in both symptoms and mucosal histology on gluten withdrawal from the diet

Front 156

156. What is the prognosis of those w/celiac disease?

Back 156

Most patients w/celiac disease who adhere to a gluten free diet remain well indefinitely and ultimately die of unrelated causes.

However, there is a long term risk of malignant disease, which includes non-Hodgkin lymphoma, small intestinal adenocarcinoma, and esophageal squamous cell carcinoma.

Front 157

157. What is tropical sprue?

Back 157

This condition is a celiac like disease that occurs almost exclusively in people living in or visiting the tropics.

No specific causal agent has been clearly associated w/tropical sprue, but bacterial overgrowth by enterotoxigenic organisms (E. coli and Hemophilus) has been implicated.

Malabsorption usually becomes apparent w/in days or a few weeks of an acute diarrheal enteric infection in visitors to endemic locales and may persist if untreated. The mainstay of treatment is broad spectrum antibiotics.

Front 158

158. What is the morphology of tropical sprue?

Back 158

Intestinal changes are extremely variable, ranging from near normal to severe diffuse enteritis. Unlike celiac sprue, injury is seen at all levels of the small intestine.

Patients freq have folate and or vitamin B12 deficiency, leading to markedly atypical enlargement of the nuclei of epithelial cells (megaloblastic change), reminiscent of the changes seen in pernicious anemia.

Front 159

159. What is whipple disease?

Back 159

Whipple disease is a rare disease caused by the bacterium Tropheryma whippelii. It is a systemic condition that may involve any organ of the body, but principally affects the intestine, CNS, and joints.

The causal organism T. whippelii is a gram positive actinomycete, named on the basis of molecular phylogenetic analysis. The bacteria proliferate preferentially within macrophages and invoke no significant host immune reaction.

Front 160

160. What is the morphology of whipple disease?

What is the hallmark?

Back 160

The hallmark is a small intestinal mucosa laden with distended macrophages in the lamina propria. The macrophages contain PAS positive, diastase-resistant granules (which are lysosomes stuffed w/partially digested microorganisms) and rod-shaped bacilli on electron microscopy.

In untreated cases, the bacilli can be seen as well in neutrophils, the extracellular space of the lamina propria, and even in epithelial cells. Expansion of the villi by the dense infiltrate of macrophages imparts a shaggy gross appearance the the intestinal mucosal surface; edema of the mucosa thickens the intestinal wall. Accompanying these changes is involvement of the mesenteric lymph nodes by the same process and lymphatic dilation, suggesting lymphatic obstruction. The lymphatic blockade is believed to be responsible for lipid desposition in the villi, thus the origianl impression of intestinal lipodystrophy.

Bacilli-laden macrophages also can be found in the synovial membranes of affected joints, the brain, cardiac valves, and elsewhere. At each of these sites, inflammation is essentially absent. Functional impairment can be considerable at each affected site.

Front 161

161. What are the clinical features of Whipple disease?

Back 161

Whipple disease is principally encountered in whites in the fourth to fifth decade of life, with a strong male predominance of 10:1. Many cases come from rural regions, suggesting an environmental influence.

It usually present as a form of malabsorption with diarrhea and weight loss, sometimes of years' duration.

Arthropathy is often the inital presentation. Atypical presentations, with polyarthritis, obscure psychiatric complaints, cardiac abnormalities, and other symptom complexes are common. Lymphadenopathy and hyperpigmentation are present in over half the cases.

Currently the Dx rests on demonstration of small intestinal PAS-positive macrophages that contain rod-shaped organisms.

Response to antibiotic therapy is usually prompt, although some patients have a protracted, refractory course.

Front 162

162. What is abetalipoproteinemia?

Back 162

Inability to synthesize apolipoprotein B is a rare inborn error of metabolism transmitted by autosomal recessive inheritance.

It is characterized by a defect in the synthesis and export of lipoproteins from intestinal mucosal cells. Free fatty acids and monoglycerides that are produced by hydrolysis of dietary fat enter the absorptive epithelial cells and are re-esterified in the normal fashion but cannot be assembled into chylomicrons.

As a consequence, triglycerides are stored within the cells, creating lipid vacuolation that is readily evident under the light microscope, particularly with special fat stains. Concomitantly, there is complete absence in plasma of all lipoproteins containing apolipoprotein B (chylomicrons, very-low-density lipoproteins, and low-density lipoproteins).

The failure to absorb certain essential fatty acids leads to lipid membrane defects, readily evident in the characteristic acanthocytic erythrocytes (burr cells). The disease becomes manifest in infancy and is dominated by failure to thrive, diarrhea, and steatorrhea.

Front 163

163. What is idiopathic inflammatory bowel disease?

What are the two disorders in this classification?

Back 163

This is a set of chronic inflammatory conditions resulting from inappropriate and persistent activation of the mucosal immune system, driven by the presence of normal intraluminal flora.

The two disorder known as IBD are Crohn disease and ulcerative colitis.

These diseases share many common features but have distinctly different clinical manifestations.

Both CD and UC are chronic, relapsing inflammatory diseases of obscure origin. CD is an autoimmune disease that may affect any portion of the GI tract from esophagus to anus, but most often involves the distal small intestine and colon. UC is a chronic inflammatory disease limited to the colon and rectum. Both exhibit extraintestinal inflammatory manifestations.

Front 164

164. What is the pathogenesis of IBD?

What are the two key abnormalities?

Back 164

In IBD, the normal immune properties of the GI tract are disrupted, leading to two key pathogenic abnormalities: (1) strong immune responses against normal flora, and (2) defects in epithelial barrier function.

It is postulated that IBD results from unregulated and exaggerated local immune responses to commensal microbes in the gut, in genetically susceptible individuals. Thus, it involves failure of immune regulation, genetic susceptibility, and environmental triggers.

Front 165

165. What are the genetic susceptibility components to IBD?

Back 165

HLA associations: HLA-DR1/DR1/DQw5 allelic combination has been observed in 27% of white patients with CD, whereas HLA-DR2 is increased in patients with UC.

A gene called NOD2 *nucleotide-binding oligomerization domian) has recently been shown to be associated with CD.

Front 166

166. What does the NOD2 protein do?

Back 166

The NOD2 protein is expressed in many types of leukocytes as well as epithelial cells, and is thought to function as an intracellular receptor for microbes.

Upon binding microbial components, it may trigger the NF-κB pathway; recall that NF-κB is a transcription factor that triggers the production of cytokines and other proteins involved in innate immune defense against infectious pathogens.

Front 167

167. How are NOD2 mutations associated with CD?

Back 167

The NOD2 mutations that are associated with CD may reduce the activity of the protein, resulting in the persistence of intracellular microbes and uncontrolled, prolonged immune responses.

Front 168

168. What is the role of intestinal flora in IBD?

Back 168

Animal studies have definitively established the importance of gut flora in IBD. If gene-knockout mice that normally develop IBD are made germ-free, the disease disappears. However, the hunt for a specific microbe as the underlying cause has been largely fruitless.

There is also no clear evidence that reducing intestinal flora has a beneficial effect on the course of IBD in humans. Microbes could exacerbate immune reactions by providing antigens and inducing costimulators and cytokines, all of which contribute to T-cell activation. Defects in the barrier function of the intestinal epithelium could allow luminal flora to gain access to the mucosal lymphoid tissue, and thus trigger immune responses.

Front 169

169. What is the responsible party in the exaggerated local immune responses in IBD?

Back 169

It is believed that the exaggerated local immune response in IBD is a consequence of too much T-cell activation and/or too little control by regulatory T lymphocytes.

In both CD and UC, the prime culprits appear to be T-cells, particular CD4+ T-cells, and the lesions are likely caused by T-cells and their products.

Although antibodies against certain self-antigens, such as tropomyosin, have been detected in some patients with UC, it is not clear if these autoantibodies play a pathogenic role.

Front 170

170. What is the autoimmune basis behind CD?

Why?

Back 170

CD appears to be the result of a chronic delayed-type hypersensitivity reaction induced by IFN-γ-producing TH1 cells.

The nature of the inflammatory infiltrate, especially the presence of granulomas, is consistent with a TH1 response.

Front 171

171. What is the autoimmune basis behind UC?

Back 171

Although animal models suggest that ulcerative colitis is caused by excessive activation of TH2 cells, in human disease the signature TH2 cytokine, IL-4, has not been found in the lesions.

It may be that the lesions are caused by an atypical TH2 response, or that there is no consistent pattern of T cell activation or dominant cytokine production.

Front 172

172. How can we Dx IBD?

Back 172

Since the exact etiology of IBD is not known, the diagnosis of IBD and the distinction between CD and UC are dependent on clinical history, radiographic examination, laboratory findings, and pathologic examination of tissue. There is no single test upon which a diagnosis is made. Even with the best efforts, the distinction between the two diseases still cannot be made in some cases.

Pathologic appearance, both macroscopic and microscopic, plays a central role in establishing a definitive diagnosis.

Front 173

173. What two antibody tests are useful for the Dx of IBD?

Back 173

The pANCA (perinuclear antineutrophilic cytoplasmic antibody) is positive in 75% of patients with UC and in only 11% with CD.

Another test detects an antibody against the cell wall mannan polysaccharide of Saccharomyces cerevisiae (ASCA). This antibody appears to be elevated in CD patients. The clinical utility of these tests remains to be proven.

Front 174

174. What is Crohn disease?

What are the three pathological characterizations?

Back 174

When fully developed, CD is characterized pathologically by:

1. Sharply delimited and typically transmural involvement of the bowel by an inflammatory process w/mucosal damage
2. The presence of noncaseating granulomas
3. Fissuring w/formation of fistulae

Front 175

175. What is the prevalence of CD?

Back 175

3/100,000

It occurs at any age, from young childhood to advanced age, but peak ages of detection are the second and third decades of life with a minor peak in the sixth and seventh decades. Females are affected slightly more often than males. Whites appear to develop the disease two to five times more often than do nonwhites. In the United States, CD occurs three to five times more often among Jews than among non-Jews. Smoking is a strong exogenous risk factor.

Front 176

176. What is the morphology of CD?

Back 176

In CD, there is gross involvement of the small intestine alone in about 40% of cases, of small intestine and colon in 30%, and of the colon alone in about 30%. CD may involve the duodenum, stomach, esophagus, and even mouth, but these sites are distinctly uncommon.

In diseased bowel segments, the serosa is granular and dull gray, and often the mesenteric fat wraps around the bowel surface (creeping fat). The mesentery of the involved segment is also thickened, edematous, and sometimes fibrotic.

*The intestinal wall is rubbery and thick, as a consequence of edema, inflammation, fibrosis, and hypertrophy of the muscularis propria. As a result, the lumen is almost always narrowed; in the small intestine this is evidenced on xrays as the "string sign", a thin stream of barium passing thru the diseased segments. Strictures may occur in the colon but are usually less severe.

Front 177

177. What is a classic feature of Crohn disease?

Back 177

The sharp demarcation of diseased bowel segments from adjacent uninvolved bowel.

When multiple bowel segments are involved, the intervening bowel is essentially normal ("skip" lesions).

Front 178

178. What is a characteristic sign of early CD?

Back 178

Focal mucosal ulcers resembling canker sores (aphthous ulcers), edema, and loss of the normal mucosal texture.

Front 179

179. What happens as CD develops?

Back 179

With progressive disease, mucosal ulcers coalesce into long, serpentine linear ulcers, which tend to be oriented along the axis of the bowel. As the intervening mucosa tends to be relatively spared, the mucosa acquires a coarsely textured, cobblestone appearance.

*Narrow fissures develop between the folds of the mucosa, often penetrating deeply thru the bowel wall and leading to bowel adhesions and serositis.

Further extension of fissures leas to fistula or sinus tract formation, either to an adherent viscus, to the outside skin, or into a blind cavity. Free perforation or localized abscesses may also develop.

Front 180

180. What are the six histologic changes in CD?

Back 180

1. Mucosal inflammation
2. Chronic mucosal damage
3. Ulceration
4. Transmural inflammation affecting all layers
5. Noncaseating granulomas
6. Other mural changes

Front 181

181. Mucosal inflammation in CD

Back 181

The earliest lesion in CD appears to be focal neutrophilic infiltration into the epithelial layer, particularly overlying mucosal lymphoid aggregates. As the disease becomes more established, neutrophils infiltrate isolated crypts; when a sufficient number of neutrophils have traversed the epithelium of a crypt (both in the small and large intestines), a CRYPT ABSCESS is formed, usually w/ultimate destruction of the crypt.

Front 182

182. Chronic mucosal damage in CD

Back 182

The hallmark of inflammatory bowel disease, both CD and UC, is chronic mucosal damage.

Architectural distortion is manifested in the small intestine as variable villus blunting; in the colon, crypts exhibit irregularity and branching. The degree of the glandular architectural distortion in CD is usually less severe than in UC.

Crypt destruction leads to progressive atrophy, particularly in the colon. The mucosa may undergo metaplasia; this may take the form of gastric antral type glands (pyloric metaplasia) or the development of Paneth cells in the distal colon, where they are normally absent (Paneth cell metaplasia).

Front 183

183. Ulceration in CD

Back 183

Ulceration is the usual outcome of severe active disease. It may be superficial, may undermine adjacent mucosa in a lateral fashion, or may penetrate deeply into underlying tissue layers.

There is often an abrupt transition between ulceration and adjacent normal mucosa.

Front 184

184. Noncaseating granulomas in CD

Back 184

In about 1/2 of the cases, sarcoid-like granulomas may be present in all tissue layers, both w/in areas of active disease and in uninvolved regions of the bowel.

Granulomas have been documented throughout the GI tract, from mouth to rectum, in patients with CD limited to one bowel segment.

Conversely, the absence of granulomas does not preclude the Dx of CD.

Front 185

185. What are the other mural changes in CD?

Back 185

In diseased segments, the muscularis mucosa usually exhibits reduplication, thickening, and irregularity.

Fibrosis of the submucosa, muscularis propira, and mucosa eventually leads to stricture formation.

Less common findings are mucosal and submucosal lymphangiectasia, hypertrophy of mural nerve fibers, and localized vasculitis.

Front 186

186. What are the clinical features of CD?

Back 186

The clinical manifestations of Crohn disease are extremely variable. They are generally more subtle than those of UC. The disease usually begins with intermittent attacks of relatively mild diarrhea, fever, and abdominal pain, spaced by asymptomatic periods lasting for weeks to many months.

Often the attacks are precipitated by periods of physical or emotional stress. Although emotional influences are thought not to have any direct role in the initiation of the disease, they may contribute to flare-ups.

In those with colonic involvement, occult or overt fecal blood loss may lead to anemia over time, but massive bleeding is uncommon.

In about one-fifth of patients the onset is more abrupt, with acute right lower quadrant pain, fever, and diarrhea sometimes suggesting acute appendicitis or an acute bowel perforation. The course of the disease includes bouts of diarrhea with fluid and electrolyte losses, weight loss, and weakness.

Front 187

187. What complications may arise from long term CD?

Back 187

Fribrosing strictures, particularly of the terminal ileum, and fistrulas to other loops of bowel, the urinary bladder, vagina, or perianal skin, or into a peritoneal abscess.

Extensive involvement of the small bowel, including the terminal ileum, may cause marked loss of albumin, generalized malabsorption, specific malabsorption of B12, or malabsorption of bile salts, leading to steatorrhea.

Front 188

188. What are ten extraintestinal manifestations of CD?

Back 188

1. Migratory polyarthritis
2. Sacroiliitis
3. Ankylosing spondylitis
4. Erythema nodosum
5. Clubbing of the fingertips
6. Hepatic primary sclerosing cholangitis occurs, but the association is not as strong as in UC
7. Uveitis
8. Nonspecific mild hepatic pericholangitis
9. Renal disorders secondary to trapping of the ureters in the inflammatory process sometimes develop
10. Systemic amyloidosis is a rare late complication

Front 189

189. What is ulcerative colitis?

How is it similar/different to CD?

Back 189

UC is an ulceroinflammatory disease limited to the colon and affecting only the mucosa and submucosa except in the most severe cases.

Unlike CD, UC extends in a continuous fashion proximally from the rectum. Well-formed granulomas are absent. Like CD, UC is a systemic disorder associated in some patients with migratory polyarthritis, sacroiliitis, akylosing spondylitis, uveitis, hepatic involvement, and skin lesions.

Front 190

190. What is the prevalence of UC?

Back 190

4-12/100,000

In the United States it is more common among whites than among blacks, and females are affected more often than males. The onset of disease peaks between ages 20 and 25, but the condition may arise in both younger and considerably older individuals.

Nonsmoking is associated with UC; ex-smokers are at higher risk for developing UC than never-smokers.

Front 191

191. What is the morphology of UC?

Back 191

UC involves the rectum and extends proximally in a retrograde fashion to involve the entire colon ("pancolitis") in the more severe cases.

It is a disease of continuity and no skip lesions are found. In 10% of those with severe pancolitis, the distal ileum may develop mucosal inflammation ("backwash ileitis"). This is probably due to the incompetence of the iliocecal valve, resulting in reflux of the inflammatory material from the colon.

In contrast to CD, the ileitis is often diffuse and limited to within 25 cm from the ileocecal valve. The appendix may be involved w/both CD and UC.

Front 192

192. What is the colonic involvement with UC like as the disease progresses?

1/2

Back 192

In the course of the colonic involvement w/UC, the mucosa may exhibit slight reddening and granularity w/friability and easy bleeding. W/fully developed severe active inflammation, there may be extensive and broad based ulceration of the mucosa int eh distal colon or throughout its length.

Isolated islands of regenerating mucosa bulge upward to create pseudopolyps. Often the undermined edges of adjacent ulcers interconnect to create tunnels covered by tenuous mucosal bridges.

Front 193

193. What is the colonic involvement with UC like as the disease progresses?

2/2

Back 193

As with CD, the ulcers of UC are frequently aligned along the axis of the colon, but rarely do they replicate the linear serpentine ulcers of CD.

With indolent chronic disease or with healing of active disease, progressive mucosal atrophy leads to a flattened and attenuated mucosal surface.

Unlike CD, mural thickening does not occur in UC, and the serosal surface is usually completely normal. Only in the most severe cases of ulcerative disease (UC, CD, and other severe inflammatory diseases) does toxic damage to the muscularis propria and neural plexus lead to complete shutdown of neuromuscular function. In this instance the colon progressively swells and becomes gangrenous (toxic megacolon)

Front 194

194. What is the course of mucosal inflammation in UC?

Back 194

First, a diffuse predominantly mononuclear inflammatory infiltrate in the lamina propria is almost universally present, even at the time of clinical presentation. Neutrophilic infiltration of the epithelial layer may produce collections of neutrophils in crypt lumina (crypt abscesses). These are not specific for UC and may be observed in CD or any active inflammatory colitis. Unlike CD, there are no granulomas, although rupture of crypt abscesses may incite a foreign body reaction in the lamina propria.

Second, further destruction of the mucosa leads to outright ulceration, extending into the submucosa and sometimes leaving only the raw, exposed muscularis propria.

Third, with remission of active disease, granulation tissue fills in the ulcer craters, followed by regeneration of the mucosal epithelium. Submucosal fibrosis and mucosal architectural disarray and atrophy remain as residua of healed disease.

Front 195

195. What is a key feature of UC?

Back 195

The mucosal damage is continuous from the rectum and extending proximally.

In CD, mucosal damage in the colon may be continuous but is just as likely to skip areas. It should be noted that quiescent UC, particularly treated disease in which active neutrophilic inflammation is not present, may appear virtually normal histologically. This does not preclude risk for dysplasia.

Front 196

196. What is a significant consequence of UC?

Back 196

The spectrum of epithelial changes signifying dysplasia and the progression to frank carcinoma. Nuclear atypia and loss of cytoplasmic differentiation may be present in inflamed or uninflamed colonic mucosa. Epithelial dysplasia is referred to as being low-grade or high-grade; cytologic features are the key to evaluating dysplasia.

Distinguishing between regenerative changes and dysplasia can be very difficult and sometimes impossible. Plaque-like dysplastic lesions, overt polypoid dysplasia (adenomas), or invasive carcinoma are the ultimate lesions arising from flat dysplasia. It should be noted that elderly patients with UC are also at risk for sporadic adenomas.

Distinction between IBD-associated dysplasia and a coexistent incidental adenoma may be difficult.

Front 197

197. What are the clinical features of UC?

Back 197

UC typically presents as a relapsing disorder marked by attacks of bloody mucoid diarrhea that may persist for days, weeks, or months and then subside, only to recur after an asymptomatic interval of months to years or even decades. If you're lucky, the first attack is your last.

At the other end, the explosive initial attack may lead to such serious bleeding and fluid and electrolyte imbalance as to constitute a medical emergency.

In most patients, bloody diarrhea containing stringy mucus, accompanied by lower abdominal pain and cramps usually relieved by defecation, is the first manifestation of the disease.

In a small number of paitnets, constipation may appear paradoxically due to disruption of normal peristalsis.

Front 198

198. What can cause UC to begin?

Back 198

Often the first attack is preceded by a stressful period in the patient's life. Spontaneously, or more often after appropriate therapy, these symptoms abate in the course of days to weeks.

Flare-ups, when they do occur, may be precipitated by emotional or physical stress and rarely by concurrent intraluminal growth of enterotoxin-forming C. difficile.

Sudden cessation of bowel function with toxic dilatation (toxic megacolon) rarely develops with severe acute attacks; perforation is a potentially lethal event.

Front 199

199. What two factors determine the prognosis of those w/UC?

Back 199

1. The severity of the active disease
2. Its duration

About 60% of patients have clinically mild disease. In these individuals, the bleeding and diarrhea are not severe, and systemic signs and symptoms are absent. However, almost all patients (97%) have at least one relapse during a 10-year period, and about 30% of patients require colectomy within the first 3 years of onset due to uncontrollable disease. On rare occasion, the disease runs a fulminant course; unless medically or surgically controlled, this toxic form of the disease can lead to death soon after onset.

Front 200

200. What is the most feared long-term complication of UC?

Back 200

Cancer.

There is a tendency for dysplasia to arise in multiple sites, and the underlying inflammatory disease may mask the symptoms and signs of carcinoma.

UC is characterized by DNA damage with microsatellite instability in mucosal cells. More recently, genomic instability was detected in non-dysplastic areas of patients with UC, suggesting that these patients have DNA repair deficiency and genomic instability throughout the intestinal tract.

The associated carcinomas are often infiltrative without obvious exophytic masses, further underscoring the importance of early diagnosis.

Front 201

201. What are the two situations in which hypersensitivity reactions may occur?

Back 201

1. Responses to foreign antigens may be dysregulated or uncontrolled, resulting in tissue injury

2. The immune responses may be directed against self antigens, as a result of the failure of self-tolerance

Front 202

202. What are type I hypersensitivity reactions?

Back 202

Immediate hypersenitivity, or type I, is a type of pathologic reaction that is caused by the release of mediators from mast cells. This reaction most commonly is triggered by the production of IgE antibody against environmental antigens and the binding of IgE to mast cells in various tissues.

Front 203

202. What are type II hypersensitivity reactions?

Back 203

Antibodies other than IgE may cause diseases in two ways:

Antibodies directed against cell or tissue antigens can damage these cells or tissues or impair their function. These diseases are said to be antibody mediated and represent type II hypersensitivity.

Front 204

203. What are type III hypersensitivity reactions?

Back 204

Sometimes, antibodies against soluble antigens may form complexes w/the antigens, and the immune complexes may deposit in blood vessels in various tissues, causing inflammation and tissue injury.

Such diseases are called type III hypersensitivity reactions.

Front 205

204. What are type IV hypersensitivity reactions?

Back 205

Some diseases result from the reactions of T lymphocytes, often against self antigens in tissues.

These T cell-mediated diseases represent type IV hypersensitivity.

Front 206

205. What is immediate hypersensitivity?

Back 206

Type I - This is a rapid, IgE antibody, and mast cell - mediated vascular and smooth muscle reaction, often followed by inflammation, that occurs in some individuals on encounter with certain foreign antigens to which they have been exposed previously.

These reactions are also called allergy, or atopy.

Front 207

206. What is the sequence of events in the development of immediate hypersensitivity?

Back 207

Consists of the production of IgE antibodies in response to an antigen, binding of IgE to Fc receptors of mast cells, cross-linking of the bound IgE by the antigen, and release of mass cell mediators.

Front 208

207. What is the late phase reaction?

Back 208

Some mast cell mediators cause a rapid increase in vascular permeability and smooth muscle contraction.

Other mast cell mediators are cytokines that recruit neutrophils and eosinophils to the site of the reaction over several hours. This inflammatory component is called the late phase reaction, and it is mainly responsible for the tissue injury that results from repeated bouts of immediate hypersensitivity.

Front 209

208. What causes the production of the IgE antibody?

Back 209

The individuals w/allergies encounter some antigens which results in the activation of TH2 cells and the production of IgE antibody.

Immediate hypersensitvity develops as a consequence of the activation of TH2 cells in response to protein antigens or chemicals that bind to proteins.

Front 210

209. What are the cytokines secreted by TH2 cells and what do they do?

Back 210

TH2 cells secrete interleukin IL-4 and IL-13, and these stimulate B lymphocytes specific for the foreign antigens to switch to IgE-producing plasma cells.

Front 211

210. How are mast cells activated in type I hypersensitivity reactions?

Back 211

IgE antibody produced in response to allergen binds to high-affinity Fc receptors specific for the ε heavy chain expressed on mast cells.

Mast cells are present in all connective tissues, and which of the body's mast cells are activated by cross-linking of allergen specific IgE often depends on the route of entry of the allergen.

Front 212

211. What is the FcεRI?

Back 212

The high-affinity Fcε receptor, called FcεRI, consists of three chains, one of which binds the Fc portion of the ε heavy chain very strongly. The other two chains of the receptor are signaling proteins.

The same FcεRI also is present on basophils, but the role of basophils in immediate hypersensitivity is not well established as the role of mast cells.

Front 213

212. What happens when mast cells sensitized by IgE are exposed to the allergen?

Back 213

The cells are activated to secrete their mediators; Mast cell activation results from binding of the allergen to two or more IgE antibodies on the mast cell.

When this happens, the IgE and the FcεRI molecules that are carrying the IgE are cross-linked, triggering biochemical signals from the signal transducing chains of FcεRI.

The signals lead to three types of responses in the mast cells: degranulation, synthesis and secretion of lipid mediators, and synthesis and secretion of cytokines.

Front 214

213. What are the most important mediators produced by mast cells?

Back 214

Vasoactive amines and proteases that are released from granules, products of arachidonic acid metabolism, and cytokines.

Front 215

214. What is the role of the cytokines produced by the mast cells?

Back 215

They stimulate the recruitment of leukocytes, which cause the late phase reaction.

The principal leukocytes involved int his reaction are eosinophils, neutrophils, and TH2 cells.

Mast cell-derived TNF and IL-4 promote neutrophil and eosinophil rich inflammation.

Chemokines produced by mast cells and by epithelial cells in the tissues also contribute to leukocyte recruitment.

Eosinophils and neutrophils liberate proteases, which cause tissue damage, and TH2 cells may make this worse by producing more cytokines.

Front 216

215. What activates eosinophils?

What does IL-13 do?

Back 216

Eosinophils are activated by the cytokine IL-5, which is produced by TH2 cells and mast cells.

The TH2 cytokine IL-13 acts on airway epithelial cells to stimulate the secretion of mucus.

Front 217

216. What are the different clinical syndromes of type I hypersensitivity reactions?

Back 217

1. Allergic rhinitis
2. Food allergies
3. Bronchial asthma
4. Anaphylaxis

Front 218

217. What is the aim of therapy for immediate hypersensitivity reactions?

Back 218

Aimed at inhibiting mast cell degranulation, antagonizing the effects of mast cell mediators, and reducing inflammation.

Corticosteroids are used to inhibit inflammation. Epinephrine inhibits further mast cell degranulation.

Front 219

218. What are type II hypersensitivity diseases?

Back 219

Antibodies (other than IgE) against cells or extracellular matrix components may deposit in any tissue that expresses the relevant target antigen.

Disease caused by such antibodies usually are specific for a particular tissue. Immune complexes tend to deposit in blood vessels at sites of turbulence or high pressure. Therefore, immune complex diseases tend to be systemic and often manifest as widespread vasculitis, arthritis, and nephritis.

Front 220

219. What is the etiology of antibody mediated disease?

Back 220

The antibodies that cause disease most often are autoantibodies against self antigens and less commonly are specific for foreign antigens.

The production of autoantibodies results from a failure of self tolerance.

Front 221

220. What are the two best examples of antibody mediated diseases that are late sequelae of streptococcal infections??

Back 221

Rhematic fever and poststroptococcal glomerulonephritis.

Some immune complex disease are cuased by the formation of complexes of antibodies against microbial antigens with the antigens. This may occur in patients with chronic infections with certain viruses, e.g. EBV, malaria.

Front 222

221. What are the mechanisms of antibody mediated disease?

Back 222

Antibodies specific for cell and tissue antigens may deposit in tissues and cause injury by inducing local inflammation, or they may interfere with normal cellular functions.

These antibodies induce inflammation by attracting and activating leukocytes. IgG antibodies of the IgG1 and IgG3 subclasses bind to neutrophil and macrophage Fc receptors and activate these leukocytes, resulting in inflammation.

The same antibodies,a s well as IgM, activate the complement system by the classical pathway, resulting in the production of complement byproducts that recruit leukocytes and induce inflammation.

Front 223

222. What is serum sickness?

Back 223

Serum sickness is induced by systemic administration of a protein antigen, which elicits an antibody response and leads to the formation of circulating immune complexes.

It usually occurs when a person receives injections of serum from other individuals or species.

Front 224

223. What is the Arthus reaction?

Back 224

The Arthus reaction is induced by subcutaneous administration of a protein antigen to a previously immunized animal; it results in the formation of immune complexes at the site of antigen injection, and a local vasculitis.

Front 225

224. What is the treatment in patients with an antibody specific for CD20, a surface protein of mature B cells, which results in depletion of B cells?

Back 225

There is interest in inhibiting the production of autoantibodies by treating patients with antagonists that block CD40 ligand and thus inhibit helper T cell dependent B cell activation.

Front 226

225. What is the etiology of T-cell mediated diseases?

Back 226

T-cell mediated hypersensitivity reactions are caused by autoimmunity and by responses to environmental antigens.

The autoimmune reactions usually are directed against cellular antigens w/restricted tissue distribution. Therefore, T cell-mediate autoimmune disease tend to be limited to a few organs and usually are not systemic.

Front 227

226. Tuberculosis, HBV, HCV, and poison ivy

Back 227

In tuberculosis, a T cell-mediated immune response is raised against M. tuberculosis, and the response becomes chronic b/c the infection is difficult to eradicate. The resultant granulomatous inflammation causes injury to normal tissues at the site of infection.

In the hepatitis virus infection, the virus itself may not be highly cytopathic, but the cytotoxic T lymphocyte response to infected hepatocytes may cause liver injury.

Front 228

227. What are superantigens?

Back 228

Excessive polycolonal T cell activation by certain microbial toxins produced by some bacteria and viruses can lead to production of large amts of inflammatory cytokines, causing a syndrome similar to septic shock.

These toxins are called superantigens b/c they stimulate large numbers of T cells.

Superantigens bind to invariant parts of T cell receptors on many different clones of T cells, regardless of antigen specificity, thereby activating these cells.

Front 229

228. What are the mechanisms of tissue injury in T cell-mediated diseases?

Back 229

Tissue injury is caused by a delayed type hypersensitivity reaction mediated by CD4+ T cells or by killing of host cells by CD8+ T cells.

Front 230

229. What are the cytokines involved in T-cell mediated diseases?

Back 230

CD4+ T cells may react against cell or tissue antigens and secrete cytokines that induce local inflammation and activate macrophages.

Different disease may be associated w/activation of TH1 and TH17 cells.

TH1 cells are the source of IFN-γ, the principal macrophage activating cytokine, and TH17 cells are thought to be responsible for recruitment of leukocytes, including neutrophils.

Front 231

230. What are the characteristics of T-cell mediated diseases?

Back 231

Many organ specific autoimmune diseases in humans are believed ot be caused by T cells.

These disorders are typically chronic and progressive, in part b/c T cell-macrophage interactions tend to amplify the reaction.

Also, tissue injury w/release and alteration of self proteins may result in reactions against these proteins, a phenomenon known as "epitope spreading" to indicate that the initial immune response against one or a few self antigen epitopes may expand to include responses against many more self antigens.

Front 232

231. What are the therapies for T-cell mediated diseases?

Back 232

Designed to reduce inflammation, using corticosteroids and antagonists against cytokines such as TNF, and to inhibit T cell responses with immunosuppressive drugs such as cyclosporine.

Antagonists of TNF have proved to be beneficial in patients w/RA and inflammatory bowel disease.

Front 233

233. What is a type I hypersensitivity reaction?

What is it mediated by?

Back 233

Type I hypersensitivity is a rapidly developing immunologic reaction occurring within minutes after the combination of an antigen w/antibody bound to mast cells in individuals previously sensitized to the antigen.

Immediate hypersensitivity is mediated by IgE antibodies directed against specific antigens (allergens).

Synthesis of IgE antibody requires the induction of CD4+ helper T cells of the TH2 type; these TH2 cells produce multiple cytokines that contribute to various aspects of this response.

Front 234

234. What cytokine is essential for IgE synthesis?

What is the first step in IgE synthesis?

Back 234

IL-4, produced by TH2 cells, is essential for IgE synthesis.

The first step in the synthesis of IgE is the presentation of the antigen to naive CD4+ helper T cells by dendritic cells that capture the antigen from its site of entry.

Front 235

235. What cytokines are responsible for promoting production and survival of eosinophils - important effector cells in type I hypersensitivity reactions?

Back 235

IL-3, IL-5, and granulocyte-macrophage colony stimulating factor (GM-CSF) promote production and survival of eosinophils.

Front 236

236. Where are IgE antibodies synthesized in response to prior exposure to allergens are normally bound to where?

Back 236

Mast cells and basophils via specific surface Fc receptors.

On re-exposure, allergen bind to and cross-links the IgE on mast cells and results in:
1. Degranulation of vesicles containing primary mediators
2. De novo synthesis and release of secondary mediators

Front 237

237. What six allergens can trigger mast cell and basophil degranulation?

Back 237

1. Complement fragments (C3a and C5a (anaphylatoxins)
2. Certain drugs i.e. codeine, morphine, adenosine
3. Mellitin (bee venom)
4. Sunlight
5. Trauma
6. Heat/cold

Front 238

238. What occurs in the initial phase of a type I hypersensitivity reaction?

Four things are released...

Back 238

Primary mast cell mediators that include the initial rapid response include:
1. Biogenic amines (e.g. histamine) which cause bronchial smooth muscle contraction, increased vascular permeability and dilation, and increased mucous gland secretions.
2. Chemotactic mediators (e.g. eosinophil chemotactic factors and neutrophil chemotactic factors)
3. Enzymes contained in granule matrix (e..g chymase, tryptase) that generate kinins and activated complement by acting on their precursor proteins.
4. Proteoglycans (e.g. heparin)

Front 239

239. What occurs in the second, delayed phase of a type I hypersensitivity reaction?

What drives this phase?

Back 239

This stage is characterized by an intense inflammatory cell infiltration with associated tissue damage. This late secondary phase is driven by lipid mediators and cytokines produced by the activated mast cells.

Front 240

240. What are the four lipid mediators produced by the mast cells in the delayed phase?

What is the role of each lipid mediator?

Back 240

1. Leukotriene B4 is highly chemcotactic for neutrophils, monocytes, and eosinophils
2. Leukotrienes C4, D4, and E4 are 1000x more potent than histamine in increasing vascular permeability and causing bronchial smooth muscle contraction. These also cause marked mucous gland secretion
3. Prostaglandin D2 causes intense bronchospasm, vasodilation, and mucous secretion
4. Platelet-activating factor causes platelet aggregation, histamine release, bronchoconstriction, vasodilation, and increased vascular permeability. It also has proinflammatory effects, such as chemoattraction and degranulation of neutrophils.

Front 241

241. In sum, what do the lipid mediators lead to?

Back 241

The lipid mediators are generated by sequential reactions in the mast-cell membranes that lead to activation of phospholipase A2, an enzyme that acts on the membrane phospholipids to yield arachidonic acid.

This is the parent compound from which leukotrienes and prostaglandins are derived by the 5-lipoxygenase and cyclooxygenase pathways.

Front 242

242. What are the important cytokine mediators in type I hypersensitivity reactions?

Back 242

The cytokines include TNF, IL-1, IL-3, IL-4, IL-5, IL-6, and GM-CSF, as well as chemokines, such as macrophage inflammatory protein (MIP)-1α and (MIP)-1β.

Mast cell derived TNF and chemokines are important mediators of the inflammatory response seen at the site of allergic inflammation. Inflammatory cells that accumulate at the sites of type I hypersensitivity reactions are additional sources of cytokines and of histamine-releasing factors that cause further mast-cell degranulation.

Front 243

243. What cytokines can epithelial cells produce?

Back 243

IL-6, IL-8 and GM-CSF

Front 244

244. What is the role of TNF-α in type I hypersensitivity reactions?

Back 244

TNF-α in particular is a powerful proinflammatory cytokine that recruits and activates many additional inflammatory cells.

Recruited inflammatory cells also release cytokines, and TNF-α-activated epithelial cells secrete chemokines (e.g. eotaxin and RANTES) that recruit eosinophils.

Front 245

245. What is the role of eosinophils in type I hypersensitivity reactions?

Back 245

Eosinophils are paritcularly important in late-phase responses; they cause tissue damage by releasing major basic protein and eosinophil cationic protein.

Front 246

246. What does atopy mean?

Back 246

Atopy refers to a predisposition to develop localized immediate hypersensitivity reactions to a variety of inhaled and ingested allergens.

Atopic individuals seem to have a higher serum IgE level, and more IL-4 producing TH2 cells, compared w/the general population.

Front 247

247. What are the genetic components of immediate hypersensitivity?

Back 247

A positive family history of allergy is found in 50% of atopic individuals.

Candidate genes have been mapped to 5q31 for asthma, where genes for the cytokines IL-3, 4, 5, 9, 13, and GM-CSF are located, consistent with the idea that these cytokines are involved in the reactions.

Linkage has also been noted to 6p, close to the HLA complex, suggesting that the inheritance of certain HLA alleles permits reactivity to certain allergens.

Another asthma associated locus is on chromosome 11q13, the location of the gene encoding the β chain of the high-affinity IgE receptor.

Front 248

248. What is systemic anaphylaxis?

Back 248

Systemic anaphylaxis typically follows parenteral or oral administration of an allergen. The severity reflects the level of sensitization, and even minuscule doses may induce anaphylactic shock in an appropriate host.

Pruritus, urticaria, and erythema occur minutes after exposure, followed by bronchoconstriction and laryngeal edema; this can escalate into laryngeal obstruction, hypotensive shock, and death within minutes to hours.

Front 249

249. What are local immediate hypersensitivity reactions?

Back 249

These reactions are exemplified by atopic allergies. There is a hereditary predisposition affecting 10% of the population (mapping to 5q31, where many of the TH2 type cytokines are located).

Affected individuals tend to develop local type I responses to common inhaled or ingested allergens.

Symptoms include urticaria, angioedema, rhinitis, and asthma.

Front 250

250. What is antibody-mediated (type II) hypersensitivity?

Back 250

Type II hypersensitivity is mediated by antibodies directed toward antigens present on cell surfaces or extracellular matrix.

The antigenic determinants may be intrinsic to the cell membrane or matrix, or they may take the form of an exogenous antigen such as a drug metabolite that is adsorbed on a cell surface or matrix.

In either case, the hypersensitivity reaction results from the binding of antibodies to normal or altered cell surface antigens. Most of these reactions involve the effector mechanisms that are used by antibodies, namely the complement system and phagocytes.

Front 251

251. What are the three major pathways in type II hypersensitivity reactions?

Back 251

1. Opsonization and complement- and Fc receptor-mediated phagocytosis

2. Complement- and Fc receptor-mediated inflammation

3. Antibody-mediated cellular dysfunction

Front 252

252. Opsonization and complement- and Fc receptor-mediated phagocytosis

Back 252

Cells can be directed lysed via the C5-C9 complement membrane attack complex (MAC) or they can be opsonized (enhanced phagocytosis) as a result of fixation of antibody or C3b fragments.

Low concentrations of bound antibody (IgG or IgE) can also cause cell lysis (w/o phagocytosis) by nonsensitized cells bearing Fc receptors (e.g. NK cells, so called antibody-dependent cell mediated cytotoxicity (ADCC).

Front 253

253. What is antibody-dependent cell mediated cytotoxicity (ADCC)?

Back 253

This form of antibody mediated cell injury does not involve fixation of complement but instead requires the cooperation of leukocytes.

Cells that are coated with low concentrations of IgG antibody are killed by a variety of effector cells, which bind to the target by their receptors for the Fc fragment of IgG, and cell lysis proceeds without phagocytosis.

Front 254

254. What mediates ADCC?

Back 254

ADCC may be mediated by monocytes, neutrophils, eosinophils, and NK cells.

Although, in most instances, IgG antibodies are involved in ADCC, in certain cases, e.g. eosinophil-mediated cytotoxicity against parasites), IgE antibodies are used.

Front 255

255. In what four situations does antibody-mediated cell destruction and phagocytosis occur?

Back 255

1. Transfusion reactions, in which cells from an incompatible donor react w/and are opsonized by preformed antibody in the host.
2. Erythroblastosis fetalis, in which there is an antigenic difference between the mother and the fetus, and antibodies (of the IgG class) from the mother cross the placenta and cause destruction of fetal red cells.
3. Autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia, in which individuals produce antibodies to their own blood cells, which are then destroyed.
4. Certain drug reactions, in which antibodies are produced that react w/the drug, which may be attached to the surface of erythrocytes or other cells.

Front 256

256. Complement- and Fc receptor-mediated inflammation

Back 256

The deposition of antibodies w/subsequent complement activation, e.g. C5a, in the extracellular matrix leads to the recruitment and activation of nonspecific inflammatory cells (neutrophils and macrophages).

These activated cells can release injurious proteases and reactive oxygen species that lead to tissue pathology.

Front 257

257. Antibody-mediated cellular destruction

What are some diseases that exemplify this mechanism?

Back 257

In some cases, antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation.

For example, in myasthenia gravis, antibodies reactive w/ACh receptors in the motor end-plates of skeletal muscles impair neuromuscular transmission and therefore cause muscle weakness.

In pemphigus vulgaris, antibodies against desmosomes disrupt intercellular junctions in epidermis, leading to the formation of skin vesicles.

The converse (i.e. antibody-mediated stimulation of cell function) is noted in Graves disease. In this disorder, antibodies against the TSH receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism.

Front 258

258. What is immune complex-mediate (type III) hypersensitivity?

Back 258

Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition.

The toxic reaction is initiated when antigen combines w/antibody within the circulation and these are deposited, typically in vessel walls, or the complexes are formed at extravascular sites where antigen may have been deposited previously (in situ immune complexes).

Front 259

259. What are the two general types of antigens that cause cell mediated injury?

Back 259

1. The antigen may be exogenous, such as a foreign protein, a bacterium, or a virus
2. Under some circumstances, the individual can produce antibody against self-components -endogenous antigens.

The latter can be circulating antigens present in the blood or, more commonly, antigenic components of one's own cells and tissues.

Front 260

260. What is systemic immune complex disease?

Back 260

Systemic immune complex disease is characterized by circulating immune complexes that are systemically deposited.

Acute serum sickness is the prototypical systemic immune complex disease. it is caused by administration of large amts of a foreign protein; after inoculation, newly synthesized antibodies complex w/the foreign antigen to form circulating immune complexes

Front 261

261. Do larger or smaller immune complexes circulate for longer periods of time?

Back 261

Smaller immune complexes circulate for longer periods of time b/c they bind w/low avidity to mononuclear phagocytes and are ineffectively cleared; these complexes are prone to deposit within a capillary or arteriolar walls, causing vasculitis.

With continued antibody production, large immune complexes eventually form; these are cleared by phagocytes, ending the disease process.

Front 262

262. What other factors enhance immune complex deposition?

Back 262

Immune complex deposition is enhanced by increased vascular permeability resulting from inflammatory cell activation by immune complex binding to Fc or C3b receptors.

The activated inflammatory cells release vasoactive mediators, including cytokines.

Front 263

263. Deposition of immune complexes causes...?

Back 263

Deposition of immune complexes activates the complement cascade and subsequent tissue injury derives largely from complement-mediated inflammation and cells bearing Fc receptors.

Front 264

264. C3b does...?

C5a does...?

Back 264

C3b enhances opsonization

C5a (chemotactic factor) release promotes neutrophil and monoctyte recruitment w/subsequent protease and reactive oxygen species elaboration.

Front 265

265. C3a and C5a do...?

Back 265

C3a and C5a release increases vascular permeability and causes smooth muscle contraction

Front 266

266. What is the relationship between immune complexes and platelet aggregation?

Back 266

Immune complexes also aggregate platelets (w/subsequent degranulation) and activate factor XII (Hageman factor).

Both of these reactions augment the inflammatory process and initiate the formation of microthrombi. The resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints, and so on.

The coagulation cascade and kinin systems are thus invovled as well.

Front 267

267. What is the pathogenesis of immune complex disorders?

Back 267

Complement-fixing antibodies (IgG and IgM) and antibodies that bind to leukocyte Fc receptors (some subclasses of IgG) induce pathologic lesions of immune complex disorders.

B/c IgA can activate complement by the alternative pathway, IgA-containing complexes may also induce tissue injury. The important role of complement in the pathogenesis of the tissue injury is supported by the observations that during the active phase of the disease, consumption of complement decreases the serum levels, and experimental depletion of complement greatly reduces the severity of the lesions.

Front 268

268. What is the morphology of immune complex injury?

Back 268

The morphologic consequences of immune complex injury are dominated by acute necrotizing vasculitis, with necrosis of the vessel wall and intense neutrophilic infiltration. The necrotic tissue and deposits of immune complexes, complement, and plasma protein produce a smudgy eosinophilic deposit that obscures the underlying cellular detain *an appearance termed fibrinoid necrosis.

When complexes are deposited in kidney glomeruli, the affected glomeruli are hypercellular b/c of swelling and proliferation of endothelial and mesangial cells, accompanied b neutrophilic and monocytic infiltration. The complexes can be seen on immunofluorescence microscopy as granular lumpy deposits of immunoglobulin and complement and on electron microscopy as electron-dense deposits along the glomerular basement membrane.

Front 269

269. Disease progression in immune complex injury

Back 269

With time and clearance of the inciting antigen and immune complex, the lesions resolve.

In chronic serum sickness, resulting from recurrent or prolonged antigen exposures and ongoing immune complex deposition (e.g. systemic lupus erthematosus, SLE), there is intimal thickening and vascular and/or parenchymal scarring.

Front 270

270. What is the local immune complex disease (Arthus reaction)?

Back 270

The Arthus reaction is a localized are of tissue necrosis resutling from acute immune complex vasculitis, usually elicited in the skin. The reaction can be produced experimentally by intracutaneous injection of antigen in an immune animal having circulating antibodies against the antigen. As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally which precipitate in the vessel walls and trigger and inflammatory reaction.

In contrast to IgE mediated type I reactions, which appear immediately, the Arthus lesion develops over a few hours and reaches a peak 4-10 hours after injection.

Front 271

271. What is the morphology of local immune complex disease?

Back 271

It can be seen as an area of visible edema w/severe hemorrhage followed occasionally by ulceration.

Immunofluorescent stain reveal complement, immunoglobulins, and fibrinogen deposited in the vessel walls, usually the venules, and histologically the vessels show fibrinoid necrosis and inflammation. Thrombi are formed in the vessels, resulting in local ischemic injury.

Front 272

272. What is cell mediated (type IV) hypersensitivity?

Back 272

Cell mediated hypersensitivity is initiated by specifically sensitized T lymphocytes and includes delayed-type hypersensitivity mediated by CD4+ T cells, and T-cell mediated cytotoxicity, mediated by CD8+ T cells.

It is the principal pattern of immunologic response not only to a variety of intracellular microbiologic agents, such as Mycobacterium tuberculosis, but also to many viruses, fungi, protozoa, and parasites.

Front 273

272. What is delayed type hypersensitivity?

What drives it?

Back 273

This resposne is largely mediated by CD4+ TH1 cells that secrete specific cytokines after encounter w/processed antigen expressed by APCs.

The TH1 response is driven by IL-12 secreted by activated macrophages.

Front 274

273. What is the morphology of delayed type hypersensitivity?

1/2

Back 274

Morphologically, delayed type hypersensitivity is characterized by the accumulation of mononuclear cells around small veins and venules, producing a perivascular "cuffing".

There is an associated increased microvascular permeability caused by mechanisms similar to those in other forms of inflammation. Not unexpectedly, plasma proteins escape, giving rise to dermal edema and deposition of fibrin in the interstitium.

Front 275

274. What is the morphology of delayed type hypersensitivity?

2/2

Back 275

A classic example is the tuberculin reaction, which is produced by the intracutaneous injection of tuberculin, a protein LPS component of the tubercle bacillus.

With certain persistent or nondegradable antigens, such as tubercle bacilli colonizing the lungs or other tissues, the initial perivascular lymphatic infiltrate is replaced by macrophages over 2-3 weeks.

The accumulated macrophages often undergo a morphologic transformation into epithelium-like cells and are then referred to as eptheliod cells. A microscopic aggregation of epithleiod cells, usually surrounded by a collar of lymphocytes, is referred to as a granuloma. This pattern of inflammation is called granulomatous inflammation.

Front 276

275. What are the TH1 cytokines?

Back 276

TH1 cytokines include IFN-γ, IL-2, and TNF-α; these cytokines mediate injury by recruiting and activating antigen-nonspecific monocytes and macrophages.

Front 277

276. What is the importance of IL-12?

Back 277

IL-12, a cytokine produced by macrophages and dendritic cells, is critical for the induction of the TH1 response and hence delayed hypersensitivity. On initial encounter w/a microbe, the macrophages and dendritic cells that are presenting microbial antigens secrete IL-12, which drives the differentiation of naive CD4+ helper cells to TH1 cells.

These, in turn, produce other cytokines. IL-12 is also a potent inducer of IFN-γ secretion by T cells and NK cells. IFN-γ further augments the differentiation of TH1 cells.

Front 278

277. What is the importance of IFN-γ?

Back 278

IFN-γ has many effects and is the key mediator of delayed type hypersensitivity. Most importantly, it is a powerful activator of macrophages.

Activated macrophages are altered in several ways: their ability to phagocytose and kill microorganisms is markedly augmented; they express more class II molecules on the surface, thus facilitating further antigen presentation; they secrete several polypeptide growth factors, such as PDGF, which stimulate fibroblast proliferation and augment collagen synthesis; they secrete TNF, IL-1, and chemokines, which promote inflammation, and they produce more IL-12, thereby amplifying the TH1 response.

Front 279

278. What does IL-2 do?

Back 279

IL-2 causes autocrine and paracrine proliferation of T cells, which accumulates at sites of delayed hypersensitivity; included in this infiltrate are some antigen specific CD4+ TH1 cells and many more bystander T ells that are recruited to the site.

Front 280

279. What three things do TNF and lymphotoxin do to endothelial cells?

Back 280

1. Increased secretion of prostacyclin, which, in turn, favors increased blood flow causing local vasodilation
2. Increased expression of P-E selectins, adhesion molecules that promote attachment of the passing lymphocytes and monocytes
3. Induction and secretion of chemokines such as IL-8

Together, all these changes in the endothelium facilitate the extravasation of lymphocytes and monocytes at the site of the delayed hypersensitivity reaction.

Front 281

280. What is T cell-mediated cytotoxicity?

Back 281

Generation of cytotoxic T lymphocytes is the principal pattern of response to many viral infection and to tumor cells.

CTLs also contribute to allograft rejection. CTL-induced injury is mediated by perforin-granzyme and Fas-FasL pathways that ultimately induce apoptosis.

Front 282

281. What is perforin?

Back 282

Perforin can perforate the plasma membranes of the target cells that are under attack by CD8+ lymphocytes. At first, CD8+ T cells come in close contact w/the target cells; this is followed by polymerization of the released perforin molecules and their insertion into the target cell membranes, thus drilling holes into the membranes.

In addition, the perforin pores allow water to enter the cells, thus causing osmotic lysis.

Front 283

282. What are granzymes?

Back 283

The CTL granules contain proteases called granzymes, which are delivered into the target cells via the perforin-induced pores.

Once within the cells, granzymes activate caspases, which induce apoptosis of the target cells.

Front 284

283. What is the first step in catecholamine synthesis?

Back 284

The first step in catecholamine synthesis is the oxidation of tyrosine to dihydroxyphenylalanine (DOPA) by the enzyme tyrosine hydrolase, and is the rate limiting step.

Front 285

284. How is dopamine created?

How does this lead to norepinephrine?

Back 285

DOPA is converted to dopamine by a generic aromatic AA decarboxylase.

Dopamine can then be hydroxylated at the 9-position by dopamine-β-hydroxylase to yield norepinephrine.

Front 286

285. How is epinephrine produced by tissues?

Back 286

In tissues that produce epinephrine, norepinephrine is then methylated on its amino group by phenylethanolamine-N-methyltransferase (PNMT)

Front 287

286. How is dopamine transported into synaptic vesicles?

Back 287

Dopamine is transported into synaptic vesicles by a 12-helix membrane-spanning proton antiporter called the vesicular monamine transporter (VMAT).

Dopamine inside the vesicle is converted to norepinephrine by dopamine-β-hydroxylase.

Front 288

287. What are hexamethonium and mecamylamine?

Back 288

Ganglionic blockers such as hexamethonium and mecamylamine block the ganglionic nicotinic ACh receptor, without significant effects on skeletal muscle ACh receptors.

Front 289

288. What mediates reuptake of catecholamine into the neuronal cytoplasm?

Back 289

Reuptake of catecholamine into the neuronal cytoplasm is mediated by a selective catecholamine transported (e.g. norepinephrine transporter or NET).

This symporter uses the inward sodium gradient to concentrate catecholamines in the cytoplasm of sympathetic nerve endings, thus limiting the postsynaptic response and allowing neurons to recycle the transmitter for subsequent release.

Front 290

289. What is MAO and catechol-O-methyltransferase (COMT)?

Back 290

MAO is a mitochondrial enzyme that is expressed in most neurons. It exists in two isoforms, MAO-A and MAO-B.

The two isoforms have some degree of ligand specificity; MAO-A preferentially degrades serotonin, norepinephrine, and dopamine, while MAO-B degrades dopamine more rapidly than serotonin and norepinephrine.

COMT is a cytosolic enzyme that is expressed primarily in the liver.

Front 291

290. What are adrenergic receptors?

Back 291

AKA adrenoceptors; they are selective for norepinephrine and epinephrine.

These receptors are divided into two main classes, termed α & β

Front 292

291. What are PDZ proteins?

Back 292

Members of the PDZ family mediate regulatory functions, including receptor internalization and coupling to adaptor proteins such as Grb2 or guanine-nucleotide exchange factors that regulate small monomeric G proteins.

Front 293

292. What is G protein receptor kinase (GRK)?

What is β-arrestin?

Back 293

The accumulation of the βγ subunits in the membrane recruits a G protein receptor kinase (GRK), which phosphorylates the receptor at residues in the C-terminus that are important targets for inactivator proteins.

The phosphorylated state of a G protein can bind to another protein called β-arrestin that sterically inhibits the receptor-G protein interaction, effectively silencing receptor signaling.

Front 294

293. What are the epinephrine receptors?

Back 294

Epinephrine is an agonist at both α & β adrenoceptors.

At low concentrations, epinephrine has predominantly β₁ and β₂ effects, while at high concentrations, its α₁ effects predominate.

Front 295

294. What are the norepinephrine receptors?

Back 295

Norepinephrine is an agonist at α₁ and β₁ receptors, but has relatively little effect at β₂ receptors.

Front 296

295. What are the inhibitors of catecholamine synthesis, and what are they used for?

Back 296

Inhibitors of catecholamine synthesis have limited clinical utility b/c such agents nonspecifically inhibit the formation of all catecholamines.

α-Methyltyrosine is a structural analogue of tyrosine that is transported into nerve terminals, where it inhibits tyrosine hydroxylase, the first enzyme int he catecholamine biosynthesis pathway.

This agent is used occasionally in the treatment of hypertension associated with pheochromocytoma.

Front 297

296. α-Methyltyrosine

Back 297

MOA: Inhibits tyrosine hydroxylase.

PURPOSE: pheochromocytoma associated hypertension

ADVERSE: Orthostatic hypertension and sedation

CONTRA: Hypersensitivity to α-Methyltyrosine

NOTES: *Used rarely.

Front 298

297. What are inhibitors of catecholamine storage?

Back 298

MOA: These agents inhibit catecholamine storage in vesicles, resulting short term increase in release of catecholamines from the synaptic terminal ("sympathomimetic") but long-term depletion of available pool of catecholamines ("sympatholytic").

Includes:
1. Reserpine
2. Guanethidine
3. Guanadrel
4. Amphetamine
5. Methylphenidate
6. Pseudoephedrine

Front 299

298. Reserpine

Back 299

MOA: Reserpine binds tightly to the vesicular antiporter VMAT. The drug irreversibly damages VMAT, resulting in vesicles that lose their ability to concentrate and store norepinephrine and dopamine.

PURPOSE: Hypertension

ADVERSE: cardiac arrhythmia, GI hemorrhage, thrombocytopenia, dream anxiety disorder, impotence, psychotic depression, dizziness, and nasal congestion.

CONTRA: Active GI disease, depression, electroshock therapy, and renal failure

NOTES: Used experimentally to assess whether effect of drug requires its concentration in presynaptic terminals. Rarely used as a therapeutic agent due to its irreversible action and its association with psychotic depression.

Front 300

299. Tyramine

Back 300

Tyramine is a dietary amine that is ordinarily metabolized in the GI tract and liver by MAO. In patients taking MAO inhibitors, tyramine is absorbed in the gut, transported through the blood, and taken up by sympathetic neurosn, where it is transproted into synaptic vesciles by VMAT.

By this mechanism, an acute challenge with large amts of tyramine can cause acute displacement of vesicular NE and massive non-vesicular release of NE from the nerve terminal.

Front 301

300. Octopamine

Back 301

Although tyramine itself is poorly retained in synaptic vesicles, its hydroxylated metabolite octopamine can be stored at high concentrations in the vesicles.

B/c octopamine has little agonist activity at most mammalian adrenoceptors, postsynaptic response to sympathetic stimulation may gradually be diminished, leading ultimately to postural hypertension.

Front 302

301. Guanethidine

Back 302

MOA: Like tyramine, guanethidine concentrates in transmitter vesicles and displaces NE, leading to gradual depletion of NE.

PURPOSE: Hypertension

ADVERSE: Kidney disease, apnea, orthostatic hypotension, fluid retention, dizziness, blurred vision, impotence.

CONTRA: MAOI therapy, heart failure and pheochromocytoma.

NOTES: Inhibition of cardiac sympathetic nerves leads to reduced cardiac output; inhibition of sympathetic response leads to symptomatic hypotension following exercise.

Front 303

302. Guanadrel

Back 303

Guanadrel has similar MOA as guanethidine. Guanadrel also acts as a false neurotransmitter.

As with guanethidine, this agent can be used in the treatment of hypertension, but it is no longer a first line agent.

Adverse effects similar to guanethidine.

Front 304

303. Amphetamine

Back 304

MOA: (1) it displaces endogenous catecholamines from storage vesicles; (2) it is a weak inhibitor of MAO; (3) it blocks catecholamine reuptake mediated by NET and DAT.

PURPOSE: ADHD and narcolepsy

ADVERSE: hyperension, tachyarrhythmia, Tourette's syndrome, seizure, psychotic disorder w/prolonged use, restlessness, dysphoric mood, rebound fatigue, addiction potential, loss of appetite, irratibility, erectile dysfunction

CONTRA: advanced cardiovascular disease, glaucoma, hyperthyroidism, MAOI therapy, and severe hypertension.

Front 305

304. Methylphenidate

Back 305

Methylphenidate is a structural analogue of amphetamine, and is widely used in psychiatry to treat ADHD in children; its major effect is though to be related to enhanced attention.

Front 306

305. Pseudoephedrine

Back 306

MAO: Structurally related agents with actions less marked than those of amphetamine

PURPOSE: Allergic rhinitis and nasal congestion

ADVERSE: atrial fibrillation, ventricular premature beats, myocardial ischemia, hypertension, tachyarrhythmia, rebound congestion, insomnia

CONTRA: advanced cardiovascular disease, MAOI therapy and severe hypertension

NOTES: Used as an OTC decongestant; often found in cold remedies and appetite suppressants. Ephedrine and phenylpropanolamine have been restricted in the US.

Front 307

306. How do inhibitors of catecholamine reuptake work, and what are they?

Back 307

These agents inhibit NE transporter (NET) mediated reuptake of catecholamine, potentiating catecholamine action.

In other words, they prolong the time that released neurotransmitter remains in the synaptic cleft.

Includes:
1. Cocaine
2. Imipramine
3. Amitriptyline

Front 308

307. Cocaine

Back 308

Cocaine is a potent inhibitor of NET; unlike other uptake inhibitors, cocaine essentially eliminates catecholamine transport.

Cocaine is a controlled substance with high abuse potential. It is used occasionally as a local anesthetic but its most important role is as an agent of abuse.

Front 309

308. TCAs such as imipramine and amitriptyline

Back 309

MOA: These agents inhibit NET-mediated reuptake of NE into presynatic terminals, and thus allow accumulation NE in the synaptic cleft. The TCAs also inhibit serotonin as well as NE reuptake into presynaptic terminals and blocking serotonergic, α-adrenergic, histaminergic, and muscarinic receptors at therapeutic doses.

PURPOSE: Depression

ADVERSE: Postural hypotension (through α-adrenergic blockage), sinus tachycardia (through potentiation of NE action on cardiac sympathetic nerves), and arrhythmia

NOTES: Although these drugs begin inhibiting NE and serotonin reuptake immediately, there is a latency period of several weeks before improvement in symptoms is seen.

Front 310

309. What are MAOIs?

Back 310

MAOIs prevent secondary deamination following reuptake of catecholamines into presynaptic terminals by inhibiting MAO.

Therefore, more catecholamine accumulates in presynaptic vesicles for release during each action potential.

Front 311

310. What are the non-selective MAOIs (Agents that inhibit both MAO-A and MAO-B)?

Back 311

Agents that inhibit both MAO-A and MAO-B:

1. Phenelzine
2. Iproniazid
3. Tranylcypromine

Front 312

311. What are the selective MAOIs?

Back 312

Clorgyline is selective for MAO-A

Selegiline is selective for MAO-B

Front 313

312. What are the newer, reversible inhibitors of MAO-A?

Back 313

1. Brofaromine
2. Befloxatone
3. Moclobemide

Front 314

313. Purpose of MAOIs

What about Selegiline?

Back 314

MAOIs are used to treat depression.

Selegiline is also approved for the treatment of Parkinson's disease; its mechanism fo action may include both potentiation of dopamine in the remaining nigrostriatal neurons and decreased formation of neurotoxic intermediates.

Front 315

314. MAOI contraindications

Back 315

Patients taking MAOIs should avoid eating certain fermented food containing large amounts of tyramine and other monoamines, b/c MAOIs block oxidative deamination of these monoamines int eh GI tract and liver, causing a hypertensive crisis.

Concomitant use of MAOIs and SSRIs is also contraindicated b/c it may lead to the serotonin syndrome, characterized by restlessness, tremors, seizures, and possibly coma and death.

Front 316

315. What are α₁-adrenergic agonists?

What are the names of the α₁-adrenergic agonists?

Back 316

The α₁-selective adrenergic agonists increase peripheral vascular resistance and thereby maintain or elevate blood pressure.

These drugs may also cause sinus bradycardia through activation of reflex vagal responses.

These include:
1. Methoxamine
2. Phenylephrine
3. Oxymetazoline
4. Tetrahydrazoline

Front 317

316. Methoxamine

Back 317

MOA: Selectively activates α₁-adrenergic receptors to increase peripheral vascular resistance

PURPOSE: Hypotension, shock

ADVERSE: Bradycardia (vagal reflex), ventricular ectopic beat, hypertension, vasoconstriction, nausea, headache, and anxiety.

CONTRA: Severe hypertension

NOTES: very limited clinical use in the treatment of shock

Front 318

317. Phenylephrine, oxymetazoline, and tetrahydrazoline

Back 318

PURPOSE: Opthalmic hyperemia, nasal congestion, hypotension (phenylephrine only)

ADVERSE: Cardiac arrhythmia, hypertension, headache, insomnia, nervousness, rebound nasal congestion

CONTRA: narrow angle glaucoma, severe hypertension or tachycardia (for IV form of phenylephrine)

NOTES: Used in the OTC remedies Afrin and Visine for relief of nasal congestion and ophthalmic hyperemia; rebound of symptoms often accompanies use of these drugs. Phenylephrine is also used intravenously in the treatment of shock.

Front 319

318. What are α₂-adrenergic agonists?

What drug is the best characterized α₂-agonist?

What are the names of the α₂-agonists?

Back 319

MOA: These agents selectively activate central α₂-adrenergic receptors, and thereby inhibit sympathetic outflow from CNS.

Clonidine is the best characterized α₂-agonist.

Includes:
1. Clonidine
2. Guanabenz
3. Guanfacine
4. Methyldopa

Front 320

319. Clonidine

Back 320

MOA: Selectively activates central α₂-adrenergic receptors, and thereby inhibit sympathetic outflow from CNS.

PURPOSE: Hypertension, opioid withdrawal, cancer pain

ADVERSE: Bradycardia, heart failure, hypotension, constipation, xerostomia, sedation, dizziness

NOTES: Clonidine is used for treatment of hypertension and symptoms associated with opioid withdrawal.

Front 321

320. Guanabenz, guanfacine, and methyldopa

Back 321

MOA: Selectively activates central α₂-adrenergic receptors, and thereby inhibit sympathetic outflow from CNS.

PURPOSE: Hypertension

ADVERSE: Bradycardia, hepatotoxcity (methyldopa), autoimmune hemolytic anemia (methyldopa), hypotension, constipation, xerostomia, sedation, dizziness.

CONTRA: MAOI therapy and active liver disease (contraindications for use of methyldopa)

NOTES: Methyldopa is drug of choice for treatment of hypertension during pregnancy

Front 322

321. What are β-adrenergic agonists?

Back 322

Stimulation of β₁-adrenergic receptors causes an increase in heart rate and the force of contraction, resulting in increased cardiac output, while stimulation of β₂-adrenergic receptors causes relaxation of vascular, bronchial, and GI smooth muscle.

Front 323

322. Isoproterenol

Back 323

MOA: A nonselective β-agonist; it lowers peripheral vascular resistance and diastolic BP (a β₂ effect), while systolic BP remains unchanged or slightly increased (a β₁ effect). It increases cardiac contractility and cardiac output.

PURPOSE: Bronchoconstriction in asthma, arrhythmia, bradycardia (atropine resistant)

ADVERSE: Stokes-Adams seizures, arrhythmias, cardiac arrest, bronchospasm, hypotension, nervousness, tachycardia, angina, nausea

CONTRA: Angina, cardiovascular disease, hyperthyroidism, DM, tachycardia

NOTES: Causes less hyperglycemia than does epinephrine, because the former agent stimulates β-adrenergic activation of insulin secretion. This drug has been mostly supplanted by newer β₂-selective agonists.

Front 324

323. Dobutamine isomers

Back 324

MOA: The (-) isomer acts as both an α₁-agonist and a weak β₁-agonist, whereas the (+) isomer acts as both an α₁-antagonist and a potent β₁-agonist. The α₁-agonist and α₁-antagonist effectively cancer each other out when the racemic mixture is administered, and the observed clinical result is that of a selective β₁-agonist.

Front 325

324. What is dobutamine used for?

Back 325

This agent has more prominent inotropic than chronotropic effects, resulting in increased contractility and cardiac output.

Dobutamine is used clinically in the acute management of heart failure.

Front 326

325. What are the other β-adrenergic agonists?

Back 326

Metaproterenol is the prototype β₂ selective agonist. This drug is used to treat obstructive airway disease and acute bronchospasm.

Terbutaline and albuterol are two other agents in this class that have similar efficacy and duration of action.

Salmeterol is a long acting β₂-agonist -its effects last for about 12 hours.

Front 327

326. What are α-adrenergic antagonists?

Back 327

α-adrenergic antagonists block endogenous catecholamines from binding to α₁ and α₂ adrenoceptors. These agents cause vasodilation, decreased BP, and decreased peripheral resistance.

The baroreceptor reflex usually attempts to compensate for the fall in BP, resulting in reflex increases in HR and CO.

Front 328

327. Phenoxybenzamine

Back 328

MOA: Blocks both α₁ and α₂ receptors irreversibly.

PURPOSE: Pheochromocytoma associated hypertension and sweating

ADVERSE: Seizure, postural hypotension, tachycardia, palpitations, xerostomia, sedation, miosis, absence of ejaculation

CONTRA: Severe hypotension

NOTES: Used only in preoperative management of pheochromocytoma

Front 329

328. Phentolamine

Back 329

MOA: Phentolamine is a reversible, nonselective α-adrenoceptor antagonist.

This drug can also be used in the preoperative management of pheochromocytoma.

ADVERSE: same as phenoxybenzamine

CONTRA: Severe hypotension and coronary artery disease

Front 330

329. Prazosin

Back 330

MOA: Selective blocker of α₁-receptors in arterioles and veins; results in decreased peripheral vascular resistance and dilation of the venous vessels. Has little tendency to increase cardiac output and HR.

PURPOSE: Hypertension, BPH

ADVERSE: Pancreatitis, hepatotoxicity, SLE, marked first dose hypotension, palpitations, dyspepsia, dizziness, sedation, increased urinary freq, nasal congestion

NOTES: TCAs may increase postural hypotension. Due to potential severe postural hypotension, the dose is generally prescribed for small quantities around bed time.

Front 331

330. Terazosin and doxazosin

Back 331

These agents are similar to prazosin but have longer half-life, allowing less frequent dosing.

Front 332

331. Tamsulosin

Back 332

MOA: Specific antagonist of α₁ₐ-receptors.

PURPOSE: BPH

ADVERSE: same as prazosin, except less postural hypotension

CONTRA: hypersensitivity to tamsulosin

NOTES: Tamsulin has more specificity for genitourinary smooth muscle, thus it has lower incidence of orthostatic hypotension.

Front 333

332. Yohimbe

Back 333

MOA: Selective blockage of α₂-autoreceptors leads to increased release of NE with subsequent stimulation of cardiac β₁-receptors and peripheral vasculature α₁-receptors.

PURPOSE: organic and psychogenic impotence

ADVERSE: Bronchospasm, nervousness, tremor, anxiety, agitation, increased BP, antidiuresis

CONTRA: Chronic inflammation of sexual organs or prostate, concurrent use with mood altering drugs, gastric and duodenal ulcers, pregnancy, psychiatric patients, renal and liver disease.

NOTES: Also leads to increased insulin release due to blockage of α₂-receptors in pancreatic islets.

Front 334

333. Propanolol, nadolol, and timolol

Back 334

MOA: Propanolol, nadolol, and timolol interact with β₁ and β₂ receptors equally and do not block α receptors.

PURPOSE: Hypertension, angina, heart failure, pheochromocytoma, glaucoma

ADVERSE: Bronchospasm, AV block, bradyarrhythmia, sedation, decreased libido, mask symptoms of hypoglycemia, depression, dyspnea, wheezing.

CONTRA: Bronchial asthma or COPD, cardiogenic shock, uncompensated cardiac failure, 2nd and 3rd degree AV block, severe sinus bradycardia

NOTES: Propanolol is extremely lipophilic, its concentration is sufficiently high that sedation and decreased libido may result. An ocular formulation of timolol is used for the treatment of glaucoma.

Front 335

334. Labetalol and carvedilol

Back 335

MOA: Labetalol and carvedilol block α₁, β₁, and β₂ receptors (labetalol also acts as a weak partial agonist at β₂ receptors but has a 5-10x greater effect as a β blocker). These drugs decrease blood pressure.

PURPOSE: Hypertension and angina

ADVERSE: Same as propanolol, additionally, labetalol can cause hepatotoxicity - liver enzymes must be monitored

Front 336

335. Pindolol

Back 336

MOA: Pindolol is a partial agonist at β₁ and β₂ receptors. The drug blocks the action of endogenous norepinephrine at β₁ receptors and is useful in treating hypertension.

As a partial agonist, pindolol also causes partial stimulation of β₁ receptors, leading to overall smaller decreases in resting heart rate and BP than those caused by pure β atagonists.

***Therefore, the drug may be preferable in hypertensive patients who have bradycardia or decreased cardiac reserve.

Front 337

336. Acebutolol

Back 337

Acebutolol is a partial agonist at β₁ adrenoceptors but has no effect at β₂ receptors.

This drug is also used to treat hypertension.

Front 338

337. Esmolol, metoprolol, and atenolol

Back 338

MOA: Esmolol, metoprolol, and atenolol are β₁-selective adrenergic antagonists. The elimination half life is the main feature that distinguishes these agents. Esmolol has the shortest (3-4 min), metoprolol and antenolol have intermediate (4-9 hrs).

PURPOSE: B/c of its short half-life, esmolol is used for emergency β-blockade as in thyroid storm. Also used in hypertension, angina, and heart failure.

Front 339

338. Celiprolol

Back 339

Celiprolol is a β₁-selective antagonist and β₂-selective agonist.

Also used in treating hypertension, angina, and heart failure.