Pbl Exam 6 Case 1

Front 1

1. What does the maintenance of potassium balance in the extracellular fluid depend upon?

Back 1

Depends primarily on excretion by the kidneys b/c the amt excreted in the feces is only about 5-10% of the potassium intake.

Also, the control of potassium distribution between the extracellular and intracellular compartments also plays an important role in the balance. This redistribution between the intra and extracellular compartments provides a first line of defense against changes in extracellular fluid potassium concentration.

Front 2

2. What are four factors that shift potassium into cells (decrease extracellular concentrations)?

Back 2

1. Insulin
2. Aldosterone
3. β-adrenergic stimulation
4. Alkalosis

Front 3

3. What are 8 factors that shift potassium of of cells (increase extracellular concentrations)?

Back 3

1. Insulin deficiency (DM)
2. Aldosterone deficiency (Addisons)
3. β-adrenergic blockade
4. Acidosis
5. Cell lysis
6. Strenuous exercise
7. Increased ECF osmolarity
8. Acidosis

Front 4

4. How does insulin stimulate potassium uptake into cells?

Back 4

One of the most important factors that increase cell potassium uptake after a meal is insulin.

In people w/DM, the rise in plasma potassium concentration after eating is much greater that normal. Injections of insulin, however, can help to correct the hyperkalemia.

Front 5

5. How do variations in aldosterone affect potassium concentrations?

Back 5

Excess aldosterone secretion (Conn's syndrome) is almost invariably associated w/hypokalemia, due in part to movement of EC potassium into the cells.

Conversely, patients w/deficient aldosterone production (Addison's), often have clinically significant hyperkalemia due to accumulation of potassium in the EC space as well as to renal retention of potassium.

Front 6

6. How does β-adrenergic stimulation and blockade affect cellular uptake of potassium?

Back 6

Increased secretion of catecholamines, especially epinephrine, can cause movement of potassium from the EC to the IC fluid, mainly by activation of the β₂-adrenoceptors.

Treatment of hypertension w/β-blockers, such as propanolol, causes potassium to move out of the cells and creates a tendency toward hyperkalemia.

Front 7

7. How do acid-base abnormalities cause changes in potassium distribution?

Why?

Back 7

1. Metabolic acidosis increases EC potassium concentration b/c it causes a loss of potassium from the cells.

2. Metabolic alkalosis decreases EC fluid potassium concentration.

One effect of increased hydrogen ion concentration is to reduce the activity of the sodium-potassium ATPase pump. This in turn decreases cellular uptake of potassium and raises EC potassium concentration.

Front 8

8. Why does cell lysis cause increased EC potassium concentrations?

Back 8

As cells are destroyed, large amts of potassium contained in the cells are released into the EC compartment. This can cause significant hyperkalemia if large amts of tissue are destroyed as occurs w/severe muscle injury or w/RBC lysis.

Front 9

9. How can exercise affect potassium concentrations?

Back 9

Strenuous exercise can cause hyperkalemia by releasing potassium from skeletal muscle into the ECF.

Usually the hyperkalemia is mild, but it may be clinically significant after heavy exercise in patients treated w/β-blockers or those w/DM.

Front 10

10. How does increased ECF osmolarity affect potassium ion concentrations?

Back 10

Increased ECF osmolarity causes osmotic flow of water out of the cells.

The cellular dehydration increases intracellular potassium concentration, thereby promoting diffusion of potassium out of the cells and increasing ECF potassium concentration.

Decreased ECF osmolarity has the opposite effect.

Front 11

11. What three things determine renal potassium excretion?

What is the normal rate of potassium filtration per day?

Back 11

Determined by the sum of:
1. Rate of potassium filtration (GFR x plasma potassium concentration)
2. Rate of potassium re-absorption by the tubules
3. Rate of potassium secretion by the tubules

The normal rate of potassium filtration is about 756 mEq/day

Front 12

12. About how much of the filtered potassium is reabsorbed in the proximal tubules?

Loop of Henle?

Back 12

About 65% in the proximal

About 25-30% in the loop of Henle, esp in the TAL where potassium is actively co-transported along w/sodium and chloride.

Front 13

13. Most daily variations in potassium excretion is caused by what?

Back 13

Caused by changes in potassium secretion in distal and collecting tubules.

The most important sites of regulating potassium excretion are the principal cells of the late distal tubules and cortical collecting tubules. Here, potassium can either by reabsorbed or secreted, depending on the needs of the body.

Front 14

14. What are the cells in the late distal and cortical collecting tubules the secrete potassium called?

Back 14

Called "principal" cells, and make up about 90% of the epithelial cells in these regions.

Front 15

15. How does secretion of potassium from the blood into the tubular lumen occur?

Back 15

Secretion of potassium occurs via two steps:

1. Uptake of potassium from the interstium into the cell by the sodium-potassium ATPase pump in the basolateral membrane of the cell; this pump moves sodium out of the cell and moves potassium into the cell.

2. Passive diffusion of potassium from the interior of the cell into the tubular fluid. This is due to the high IC concentration of potassium caused by the ATPase pump. The luminal membrane of the principal cells is highly permeable to potassium due to the special channels that are specifically permeable to potassium ions.

Front 16

16. What are the three primary factors that control potassium secretion by principal cells?

Back 16

1. The activity of the Na-K ATPase pump
2. The electrochemical gradient for potassium secretion from the blood to the tubular lumen
3. The permeability of the luminal membrane for potassium

Front 17

17. What are the roles of intercalated cells?

Back 17

These cells can reabsorb potassium during potassium depletion.

This is believed to be a result of a H-K ATPase transport mechanism located in the luminal membrane. This transporter is necessary to allow potassium reabsorption during ECF potassium depletion, but under normal conditions it plays a small role in controlling the excretion of potassium.

Front 18

18. What are the three most important factors that stimulate potassium secretion by the principal cells?

What is one factor that decreases potassium secretion?

Back 18

1. Increased ECF potassium concentration
2. Increased aldosterone
3. Increased tubular flow rate

Acidosis decreases potassium secretion

Front 19

19. What are the three mechanisms by which increased ECF potassium concentration causes increased secretion?

Back 19

1. Increased ECF potassium stimulates the Na-K ATPase pump, thereby increases potassium uptake across the basolateral membrane which causes increased potassium to move into the tubule.
2. Increased ECF potassium concentration increases the potassium gradient from the renal interstitial fluid to the interior of the epithelial cell; this reduces backleakage of potassium ions form inside the cells thru the basolateral membrane.
3. Increased potassium concentration stimulates aldosterone secretion by the adrenal cortex, which further stimulates potassium secretion.

Front 20

20. How does aldosterone increase potassium secretion?

Back 20

Aldosterone stimulates active reabsorption of sodium ions by the principal cells of the late distal tubules and collecting ducts.

Also, aldosterone increases the permeability of the luminal membrane for potassium, further adding to the effectiveness of aldosterone in stimulating potassium secretion.

Front 21

21. What is the negative feedback system used to control ECF potassium ion concentration?

Back 21

1. An increase in plasma potassium concnetration stimulates aldosterone secretion and therefore increases the blood levels of aldosterone.
2. The increase in aldosterone causes a marked increase in potassium excretion by the kidneys
3. The increased potassium excretion then reduces the ECF potassium concentration back toward normal.

Front 22

22. What happens to potassium levels when the aldosterone feedback system is blocked?

Back 22

Any increases in potassium intake causes a much larger increase in potassium concentration.

This happens in Addison's disease.

Front 23

23. What effect does an increased distal tubular flow rate have on potassium secretion?

Why is this important?

Back 23

Increased distal tubular flow rate increases potassium secretion.

When potassium is secreted into the tubular fluid, the luminal concentration of potassium increases, thereby reducing the driving force for potassium diffusion across the luminal membrane. With increased tubular flow rate, the secreted potassium is continuously flushed down the tubule, so that the rise in tubular potassium concentration becomes minimized.

This is important b/c this preserves normal potassium excretion during changes in sodium intake. For instance, the high distal tubular flow rate that occurs w/a high sodium intake tends to increase potassium secretion.

Therefore the effects of high sodium intake, decreased aldosterone secretion and the high tubular flow rate, counterbalance each other, so that there is little change in potassium excretion.

Front 24

24. What effect does acute acidosis have on potassium secretion?

What about chronic acidosis?

Back 24

Acute acidosis reduces potassium secretion b/ the increases hydrogen ion concentration reduces the activity of the sodium-potassium ATPase pump.

Chronic acidosis can cause an increase in urinary potassium excretion. This is due in part to an effect of chronic acidosis to inhibit proximal tubular NaCl and water reabsorption, which increases distal volume delivery, thereby stimulating the secretion of potassium. This effect overrides the inhibitory effect of hydrogen ions on the sodium-potassium ATPase pump.

Front 25

25. What are the effects of hypocalcemia and hypercalcemia?

Back 25

Hypocalcemia causes the excitability of nerve and muscles cells to increase markedly and can result in tetany.

Hypercalcemia depresses neuromuscular excitability and can lead to cardiac arrhythmias.

Front 26

26. What happens to calcium binding to plasma proteins with acidosis and alkalosis?

Back 26

With acidosis, less calcium is bound. Conversely, in alkalosis, a greater amt of calcium is bound to the plasma proteins.

Thus, patients w/alkalosis are more susceptible to hypocalcemic tetany.

Front 27

27. What is the most important regulator of bone uptake and release of calcium?

What three main effects does it regulate?

Back 27

PTH.

PTH regulates plasma calcium concentration through three main effects:
1. Stimulating bone resorption
2. Stimulating activation of vitamin D, which then increases intestinal reabsorption of calcium
3. Directly increasing renal tubular calcium reabsorption.

Front 28

28. Where in the kidneys is filtered calcium secreted and reabsorbed?

Back 28

Only about 50% of the plasma calcium is ionized; therefore only about 50% of the plasma calcium can be filtered at the glomerulus.

Normally, about 99% of it is reabsorbed by the tubules, w/only 1% of the filtered calcium excreted.

About 65% of the filtered calcium is reabsorbed in the proximal tubule; 25-30% in the loop of Henle; and 4-9% in the distal and collecting tubules.

Front 29

29. What is one of the primary controllers of renal tubular calcium reabsorption?

Back 29

PTH. W/increased PTH, there is increased Ca reabsorption in the TAL of Henle and distal tubules, which reduces urinary excretion of calcium.

Conversely, reduction of PTH promotes calcium excretion by decreasing reabsorption in the loops of Henle and distal tubules.

Front 30

30. What happens to calcium reabsorption in the proximal tubules?

Back 30

It parallels sodium and water reabsorption. Thus, in EC volume expansion or increased arterial pressure (both of which decrease proximal sodium and water reabsorption) there is also reduction of calcium reabsorption and thus increased calcium excretion.

Front 31

31. What two other factors influence calcium reabsorption?

Back 31

1. Plasma concentration of phosphate. An increase in plasma phosphate stimulates PTH, which increases calcium reabsorption by the renal tubules.

2. Calcium reabsorption is also stimulated by metabolic acidosis and inhibited by metabolic alkalosis.

Front 32

32. How is renal phosphate excretion controlled?

Back 32

Controlled by an overflow mechanism and PTH.

PTH controls through two effects:
1. PTH promotes bone resorption, thereby dumping large amts of phosphate ions into the ECF for the bone salts
2. PTH decreases the transport maximum for phosphate by the renal tubules so that a greater proportion of the tubular phosphate is lost in the urine.

Thus, whenever plasma PTH is increased, tubular phosphate reabsorption is decreased and more phosphate is excreted.

Front 33

33. How is the regulation of magnesium excretion achieved?

Back 33

Via mainly by changing tubular reabsorption.

The proximal tubule usually reabsorbs about 25% of the filtered magnesium.

The primary site of reabsorption is the loop of Henle, where about 65% is reabsorbed.

Front 34

34. What three things lead to an increased magnesium excretion?

Back 34

1. Increased ECF magnesium concentration
2. ECF volume expansion
3. Increased ECF calcium concentration

Front 35

35. What mainly determines the ECF volume?

Back 35

The balance between intake and output of water and salt.

Front 36

36. Under steady-state conditions, how is sodium excretion controlled?

What two things are altered to control sodium excretion?

Back 36

Sodium excretion is precisely matched to intake under steady-state conditions.

Sodium excretion is controlled by (1) altering glomerular filtration or (2) tubular sodium reabsorption rates.

Front 37

37. If the kidneys become greatly vasodilated and the GFR increases, this raises NaCl delivery to the tubules...which in turn leads to what two compensations?

Back 37

1. Increased tubular reabsorption of much of the extra NaCl filtered, called glomerulotubular balance

2. Macula densa feedback, in which increased NaCl delivery to the distal tubular causes afferent arteriolar constriction and return of GFR toward normal.

Front 38

38. What happens to the effectiveness of pressure natriuresis with chronic increases in blood pressure?

Back 38

It becomes greatly enhanced b/c the increased bloop pressure also, after a short time delay, suppresses renin release and, therefore, decreases formation of angiotensin II and aldosterone.

Front 39

39. What are the two key components of a renal-body fluid feedback for regulating body fluid volumes and arterial pressure?

Back 39

Pressure natriuresis and diuresis

Front 40

40. Summary of renal-body fluid feedback system

Back 40

1. Increase in fluid intake above level of urine output causes increase of fluid in body.
2. Fluid accumulates in the blood and interstitial spaces, causing parallel increases in blood volume and ECF volume.
3. An increase in blood volume raises mean circulatory filling pressure
4. Increase in MCF pressure raises the pressure gradient for venous return
5. An increased pressure gradient for venous return elevates cardiac output
6. An increased cardiac output raises arterial pressure
7. An increased arterial pressure increases urine output via pressure diuresis
8. The increased fluid excretion balances the increased intake, and further accumulation of fluid is prevented.

Front 41

41. What are three reasons for why the blood volume remains constant?

Back 41

1. A slight change in blood volume causes marked change in cardiac output
2. A slight change in CO causes a large change in BP
3. A slight change in BP causes a large change in urine output.

Front 42

42. What are the four principal factors that can cause accumulation of fluid in the interstitial spaces?

Back 42

1. Increased capillary hydrostatic pressure
2. Decreased plasma colloid osmotic pressure
3. Increased permeability of the capillaries
4. Obstruction of lymphatic vessels

Front 43

43. Why does about almost all the additional fluid go into the interstitial spaces and not into the blood when the ECF volume rises more than 30-50% above normal?

Back 43

This occurs b/c once the interstitial fluid pressure rises from its negative value to become positive, the tissue interstitial spaces become compliant, and large amts of fluid then pour into the tissues w/o interstitial fluid pressure rising much more.

In other words, the safety factor against edema is lost once the tissues become highly compliant.

Front 44

44. When blood volume is reduced and the reflex activation of the sympathetic nervous system is activated, what three effects decrease sodium and water excretion?

Back 44

1. Constriction of the renal arterioles, with resultant decreased GFR
2. Increased tubular reabsorption of salt and water
3. Stimulation of renin release and increased angiotensin II and aldosterone formation, both of which further increase tubular reabsorption.

Front 45

45. What is one of the body's most powerful controllers of sodium excretion?

Back 45

Angiotensin II.

When sodium intake is elevated, renin secretion is decreased, causing decreased angiotensin II formation.

A reduced level of angiotensin II decreases tubular reabsorption of sodium and water, thus increasing the kidney's excretion of sodium and water.

Front 46

46. What happens when angiotensin II formation is blocked?

Back 46

It shifts pressure natriuresis to lower blood pressures.

Front 47

47. Why does excessive angiotensin II not cause large increases in ECF volume?

Back 47

Increased arterial pressure counterbalances angiotensin-mediated sodium retention.

With larger increases in angiotensin II levels, the high levels initially cause sodium and water retention by the kidneys and a small increase in ECF volume.

This also initiates a rise in BP that quickly increases kidney output of sodium and water, thereby overcoming the sodium- and water-retaining effects of the angiotensin II and re-establishing a balance between intake an output of sodium at a higher blood pressure.

Front 48

48. What is aldosterone's role in controlling renal excretion?

Back 48

Aldosterone increases sodium reabsorption, especially in the cortical collecting tubules. It also increases potassium excretion in the urine.

The function of aldosterone in regulating sodium is closely related to that of angiotensin II.

Front 49

49. During chronic oversecretion of aldosterone, what happens to the sodium retention as the arterial pressure rises?

Why?

Back 49

The kidneys "escape" from sodium retention as the pressure rises.

After 1-3 days of sodium and water retention, the ECF volume rises by about 10-15% and there is a simultaneous rise in BP. When the BP rises sufficiently, the kidneys escape from the sodium and water retention and thus excrete amts of sodium equal to the daily intake, despite continued presence of high levels of aldosterone.

This is mainly due to pressure natriuresis and diuresis.

Front 50

50. What happens to excess ADH secretion on sodium concentration?

Back 50

Excess ADH secretion usually causes only small increases in ECF volume but large decreases in sodium concentration.

Thus, high levels of ADH do not cause major increases of either body fluid volume or arterial pressures, although high ADH levels can cause severe reductions in EC sodium ion concentration. The reason for this is that increased water reabsorption by the kidneys dilutes the EC sodium, and at the same time, the small increase in blood pressure that does occur causes loss of sodium from the ECF in the urine through pressure natriuresis.

Front 51

51. What is the role of ANP in controlling renal excretion?

Back 51

ANP, released by the cardiac atrial muscle fibers is an important natriuretic hormone. Once released, ANP enters the circulation and acts on the kidneys to cause small increases in GFR and decreases in sodium reabsorption by the collecting ducts.

These combined actions of ANP leads to increased excretion of salt and water, which helps to compensate for the excess blood volume.

Front 52

52. Why does excessive production of ANP or even complete lack of ANP not cause major changes in blood volume?

Back 52

These effects can easily be overcome by small changes in blood pressure, acting through pressure natriuresis.

For example, infusions of large amts of ANP initially raise urine output of salt and water and cause slight decreases in blood volume. In less than 24 hours, this effect is overcome by a slight decrease in BP that returns urine output toward normal, despite continued excess of ANP.

Front 53

53. What triggers the various mechanism in the body to increase sodium excretion?

Back 53

High sodium intake leads to a slight increase in ECF volume. It is mainly this small increase in ECF volume that triggers these mechanisms.

Front 54

54. Explain increased blood volume with heart disease

Back 54

In congestive heart failures, the CO is reduced, and consequently, decreases arterial pressure. THis in turn activates multiple sodium retaining systems, especially the renin-angiotensin, aldosterone, and sympathetic nervous systems. In addition, the low BP itself causes the kidneys to retain salt and water.

Therefore, the kidneys retain volume in an attempt to return the arterial pressure and CO to normal.

If the heart is greatly weakened, however, arterial pressure will not be able to increase enough to restore urine output to normal. When this occurs, the person develops severe circulatory congestion and eventually dies of pulmonary edema.

Front 55

55. What is nephrotic syndrome?

Back 55

In nephrotic syndrome, the glomerular capillaries leak large amts of protein into the filtrate and the urine b/c of an increased permeability of the glomerulus. 30-50 g of plasma protein can be lost in the urine each day, sometimes causing the plasma protein concentration to fall. As a result, the plasma colloid osmotic pressure falls to low levels. This causes the capillaries all over the body to filter large amts of fluid into the various tissues, which in turn causes edema and decreases the plasma volume.

Front 56

56. Why does renal sodium retention occur in nephrotic syndrome?

Back 56

The leakage of protein and fluid from the plasma into the interstitial fluid activates the various sodium retaining systems.

The kidneys continue to retain sodium and water until plasma volume is restored nearly to normal. However, b/c of the large amt of sodium and water retention, the plasma protein concentration becomes further diluted, causing still more fluid to leak into the tissues of the body. The net result is massive fluid retention by the kidneys until tremendous EC edema occurs.

Front 57

57. What is cirrhosis and how does it affect sodium retention?

Back 57

In liver cirrhosis, the reduction in plasma protein concentration results from destruction of the liver cells, thus reducing the ability of the liver to synthesize enough plasma proteins.

Cirrhosis also impedes the flow of portal blood thru the liver which in turn raises capillary pressure throughout the portal vascular bed, which also causes ascites.

Once fluid and proteins are lost from the circulation, the renal responses are similar; sodium and water retention.

Front 58

58. What are three main implications of the anatomy of renal vessels?

Back 58

1. B/c the arteries are largely end-arteries, occlusion of any branch usually results in infarction of the specific area it supplies.
2. All tubular capillary beds are derived from the efferent arterioles and thus glomerular disease that interferes w/blood flow thru the glomerular capillaries has profound effects on the tubules
3. The peculiarities of the blood supply to the renal medulla render them especially vulnerable to ischemia; the medulla does not have its own arterial blood supply but is dependent on the blood emanating from the glomerular efferent arterioles. Thus, minor interference w/the blood supply of the medulla may result in medullary necrosis from ischemia.

Front 59

59. What are glomeruli and what are the major characteristics of their filtration?

Back 59

The glomerulus consists of an anastomosing network of capillaries lined by fenestrated endothelium invested by two layers of epithelium.

The major characteristics of normal glomerular filtration are an extraordinarily high permeability to water and small solutes, b/c of the highly fenestrated nature of the endothelium, and impermeability to proteins, such as molecules the size of albumin or larger.

Front 60

60. What is the glomerular barrier function?

Back 60

This function discriminates among various protein molecules depending on their size (the larger, the less permeable) and charge (the more cationic, the more permeable).

This size and charge dependent barrier function is accounted for by the complex structure of the capillary wall, the collagenous porous and charged structure of the BGM, and the many anionic moieties present within the wall, including the acidic proteoglycans of the GBM and the sialoglycoproteins of epithelial and epithelial cell coats.

The charge-dependent restriction is important in the virtually complete exclusion of albumin from the filtrate, b/c albumin in an anionic molecule of pI 4.5.

Front 61

61. What is the visceral epithelial cell AKA podocyte important for?

Back 61

The podocyte is important for the maintenance of glomerular barrier function; its slit diaphragm presents a size selective distal diffusion barrier to the filtration of proteins, and it is the cell type that is largely responsible for synthesis of GBM components.

Proteins located in the slit diaphragm control glomerular permeability.

Front 62

62. What are the important proteins have been identified in the slit diaphragm?

Back 62

Nephrin; a transmembrane protein w/a large EC portion made up of Ig like domains.

Nephrin then forms molecular connections w/podocin, CD2-associated protein, and ultimately the actin skeleton.

Mutations in the genes that encode for these proteins give rise to nephrotic syndrome.

Front 63

63. What is the structure and function of the tubules?

Back 63

The structure of the tubule is correlated with its function; for ex: the highly developed structure of the proximal tubular cells, with their abundant long microvilli, numerous mitochondria, apical canaliculi, and extensive intercellular interdigitations is correlated w/their major functions: reabsorption of 2/3's of filtered sodium and water as well as glucose, potassium, phosphate, AAs, and proteins.

The proximal tubule is particularly vulnerable to ischemic damage. Furthermore, toxins are freq reabsorbed by the proximal tubule, rendering it also susceptible to chemical injury.

Front 64

64. What is the juxtaglomerular apparatus?

Back 64

It lies against the glomerulus where the afferent arteriole enters it. It consists of:
1. The JG cells, modified granulated smooth muscle cells that contain renin
2. The macula densa
3. The lacis cells or nongranular cells.

The JG apparatus is a small endocrine organ, and the JG cells are the principal sources of renin production in the kidney.

Front 65

65. What are the four categories of renal diseases?

Back 65

Renal diseases are divided into four categories based on the four basic anatomic compartments affected:

1. Glomeruli
2. Tubules
3. Intersitium
4. Blood vessels

Whatever the origin, there is a tendency for all forms of chronic renal disease ultimately to destroy all four components of the kidney, culminating in chronic renal failure.

Front 66

66. What is azotemia?

Back 66

Azotemia is a biochemical abnormality that refers to an elevation of the blood urea nitrogen (BUN) and creatinine levels and is related largely to a decreased glomerular filtration rate (GFR).

Azotemia is produced by many renal disorders but also arises from extrarenal disorders.

Front 67

67. What is prerenal azotemia?

Back 67

This is encountered when there is hypoperfusion of the kidneys (e.g. in hemorrhage or shock) that impairs renal function in the absence of parenchymal damage.

Front 68

68. What is postrenal azotemia?

Back 68

This is seen whenever urine flow is obstructed below the level of the kidney. Relief of the obstruction is followed by correction of the azotemia.

Front 69

69. What is uremia?

Back 69

When azotemia becomes associated w/a constellation of clinical signs and symptoms and biochemical abnormalities, it is termed uremia.

Uremia is characterized no only by failure of renal excretory function but also by a host of metabolic and endocrine alterations resulting from renal damage. There is, in addition, secondary involvement of the GI system, peripheral nerves, and heart, which is usually necessary for the Dx of uremia.

Front 70

70. What is acute nephrotic syndrome?

Back 70

ANS is a glomerular syndrome dominated by the acute onset of usually grossly visible hematuria, mild to moderate proteinuria, and hypertension; it is the classic presentation of acute poststreptococcal glomerulonephritis.

Front 71

71. What is nephrotic syndrome?

Back 71

Nephrotic syndrome is characterized by heavy proteinuria, hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria (lipids in the urine)

Front 72

72. What is acute renal failure?

What is chronic renal failure?

Back 72

Acute renal failure is dominated by oliguria or anuria, with recent onset of azotemia. It can result from glomerular, interstitial, or vascular injury or tubular necrosis.

Chronic renal failure is characterized by prolonged symptoms and signs of uremia, and is the end result of all chronic renal parenchymal diseases.

Front 73

73. What are renal tubular defects?

Back 73

Renal tubular defects are dominated by polyuria, nocturia, and electrolyte disorders. They are the result of either diseases that directly affect tubular structure (e.g. medullary cystic disease) or defects in specific tubular functions. The latter can be inherited (e.g. familial nephrogenic diabetes, cystinuria, renal tubular acidosis) or acquired (e.g. lead nephropathy).

Front 74

74. What are the characteristics of UTIs?

Back 74

UTI is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may affect the kidney or the bladder.

Front 75

75. What are the four stages of chronic renal failure?

Back 75

1. Diminished renal reserve (GFR = 50% of normal)
2. Renal insufficiency (GFR = 20-50% of normal with azotemia, anemia, and hypertension)
3. Renal failure (GFR < 20-25% of normal; with edema, metabolic acidosis, and hypocelcemia)
4. End-stage renal disease (GFR < 5% of normal; this is the terminal stage of uremia)

Front 76

76. What is renal agenesis?

Back 76

Total bilateral agenesis of the kidney is incompatible w/life and is usually encountered in stillborn infants. It is often associated w/many other congenital disorders (e.g. limb defects, hypoplastic lungs) and leads to early death.

Unilateral agenesis is an uncommon anomaly that is compatible w/normal life if no other abnormalities exist. The opposite kidney is usually enlarged as a result of compensatory hypertrophy. Progressive glomerular sclerosis sometimes develops in the remaining kidney.

Front 77

77. What is renal hypoplasia?

Back 77

Refers to failure of the kidneys to develop to a normal size. This may occur bilaterally, resulting in renal failure in early childhood, but it is more commonly encountered as a unilateral defect.

True renal hypoplasia is extremely rare. ***A truly hypoplastic kidney shows no scars and has a reduced number of renal lobes and pyramids, usually 6 or less.

In one form of hypoplastic kidney, oligomeganephronia, the kidney is small but the nephrons are markedly hypertrophied.

Front 78

78. What is an ectopic kidney?

Back 78

Ectopic kidneys lie either just above the pelvic brim or sometimes within the pelvis.

Because of their abnormal position, kinking or tortuosity of the ureters may cause urinary obstruction, predisposing to bacterial infection.

Front 79

79. What are horseshoe kidneys?

Back 79

Fusion of the upper (10%) or lower (90%) poles produces a horseshoe-shaped structure continuous across the midline anterior to the aorta and inferior vena cava.

This anomaly is quite common and is found in about 1 in 500-1,000 autopsies.

Front 80

80. Why are cystic diseases of the kidney important?

Three reasons...

Back 80

1. They are reasonably common and often represent diagnostic problems for clinicians, radiologists, and pathologists
2. Some forms, such as AKPD, are major causes of chronic renal failure
3. They can occasionally be confused w/malignant tumors.

Front 81

81. What are the classifications of renal cysts?

Back 81

1. Cystic renal dysplasia
2. Polycystic kidney disease
3. Medullary cystic disease
4. Acquired cystic disease
5. Simple renal cysts
6. Glomerulocytic disease
7. Extraparenchymal renal cysts
8. Renal cysts in hereditary malformation syndromes

Front 82

82. What is cystic renal dysplasia?

Back 82

Cystic renal dysplasia refers to sporadic, nonfamilial disease resulting from abnormal metanephric differentiation. It is frequently associated w/obstructive abnormalities of the ureter and lower urinary tract and may be uni- or bilateral.

Histologically, it is characterizedby the persistance in the kidney of abnormal structures- cartilage, undifferentiated mesenchyme, and immature collecting ductules, and by abnormal lobar organization.

Front 83

83. What are the gross and morphological characteristics of cystic renal dysplasia?

Back 83

Dysplasia can be unilateral or bilateral and is almost always cystic. In gross appearance, the kidney is usually enlarged, extremely irregular, and multicystic. The cysts vary in size from microscopic structures to some that are several cm in diameter.

On histologic exam, they are lined by flattened epithelium. Although normal nephrons are present, many have immature ducts.

*The characteristic histologic feature is the present of islands of undifferentiated mesenchyme, often w/cartilage, and immature collecting ducts.

Front 84

84. What are the clinical features of cystic renal dysplasia?

Back 84

When unilateral, the dysplasia is discovered by the appearance of a flank mass that leads to surgical exploration and nephrectomy.

The function of the opposite kidney is normal, and such patients have an excellent prognosis after surgical removal of the affected kidney. In bilateral renal dysplasia, renal failure may ultimately result.

Front 85

85. What is autosomal dominant adult polycystic kidney disease?

Back 85

ADPKD is a hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately destroy the renal parenchyma and cause renal failure.

It is a common condition affecting roughly 1/400 - 1,000 live births and accounting for about 5-10% of cases of chronic renal failure requiring transplantation or dialysis.

The disease is universally bilateral; reported unilateral cases probably represent multicystic dysplasia. The cysts initially involve only portions of the nephrons, so renal function is retained until the 4th or 5th decade of life.

Front 86

86. What are the genetic causes of ADPKD?

Back 86

ADPKD is autosomal dominant, with high penetrance. Family studies show that the disease is caused by mutations in genes located on chromosome 16p13.3 (PKD1) and 4q21 (PKD2).

Mutations of PKD1 account for about 85% of cases and are associated w/a more severe disease, ESRD or death occurring at an average of 53 years, compared to 69 years for PKD2.

Front 87

87. What is the role of the PKD1 gene?

Back 87

The PKD1 gene accounts for 85% of cases.

It encodes a large protein named polycystin1. Although the precise function is unknown, polycystin 1 normally localizes to tubular epithelial cells and has homology to proteins involved in cell-cell and cell-matrix interactions.

It also servers a suppressor function; its loss leads to hyperplasia of epithelial cells.

Front 88

88. What is the role of the PKD2 gene?

Back 88

The PKD2 gene product polycystin-2 is an integral membrane protein. Polycystin-2 may act as a calcium-permeable cation channel and that a basic defect in ADPKD is a disruption in the regulation of intracellular calcium levels.

Front 89

89. What is the general theory as to how these mutations cause the pathogenesis of ADPKD?

Back 89

*These mutations alter cell-cell and cell-matrix interactions that are important for tubular epithelial growth and differentiation.

Epithelial cells lining the cysts of ADPKD have a high proliferation rate. Cysts are freq detached from adjacent tubules and enlarge by active fluid secretion from the lining epithelial cells. In addition, the ECM produced by cyst-lining cells is abnormal. These findings have led to the scenario that cysts develop as a result of abnormality in cell differentiation, associated w/sustained cellular proliferation and some degree of apoptosis, transeptihelial fluid secretion, and remodeling of the ECM.

Front 90

90. What is the morphology of ADPKD?

1/2

Back 90

In gross appearance, the kidneys are usually bilaterally enlarged and may achieve enormous sizes. The external surface appears to be composed solely of a mass of cysts, up to 304 cm in diameter, w/no intervening parenchyma. However, microscopic exam reveals functioning nephrons dispersed between the cysts.

The cysts may be filled w/a clear, serous fluid or, more usually w/tubid, red to brown, sometimes hemorrhagic fluid.

Front 91

91. What is the morphology of ADPKD?

2/2

Back 91

As these cysts enlarge, they may encroach on the calyces and pelvis to produce pressure defects. The cysts arise from the tubules throughout the nephron and therefore have variable lining epithelia.

On occasion, papillary epithelial formations and polyps project into the lumen. Bowman capsules are occasionally involved in cyst formation, and glomerular tufts may be seen w/in the cystic space.

Front 92

92. What are the clinical features of ADPKD?

Back 92

Patients have flank pain from hemorrhage into cysts, hematuria, hypertension, proteinuria, progressive renal failure, and bilateral abdominal masses inducing a dragging sensation.

Progression is accentuated in the presence of hypertension, in blacks (w/sickle cell trait), and in males.

Patients w/PKD2 mutations tend to have an older age at onset and later development of renal failure.

Front 93

93. What are the extrarenal anomalies associated with ADPKD?

Back 93

1. About 40% have one to several cysts in the livers (polycystic liver disease) that are usually asymptomatic
2. Intracranial berry aneurysms, presumably from altered expression of polycystin in vascular smooth muscle, arise in the Circle of Willis, and subarachnoid hemorrhages from these account for death in about 4-10% of those with ADPKD
3. Mitral valve prolapse and other cardiac valvular anomalies occur in 20-25% of patients, but most are asymptomatic.

Front 94

94. What is autosomal-recessive (childhood) polycystic kidney disease?

Back 94

ARPKD is a rare developmental anomaly presenting from the perinatal through juvenile periods. Infants often succumb rapidly to renal failure.

Kidneys are enlarged by multiple, cylindrically dilated collecting ducts, oriented at right angels to the cortex and filling both the cortex and medulla.

Front 95

95. What are the genetic causes of ARPKD?

Back 95

The disease appears to be genetically homogenous, with a gene, PKHD1. The PKHD1 gene encodes a large novel protein, fibrocystin. This gene is highly expressed in adult and fetal kidney and also in liver and pancreas.

Fibrocystin is a protein that may function in cell surface receptors with a role in collecting-duct and biliary differentiation.

Front 96

96. What is the morphology of ARPKD?

Back 96

The kidneys are enlarged and have a smooth external appearance. On cut section, numerous small cysts in the cortex and medulla give the kidney a spongelike appearance.

Dilated elongated channels are present at right angles to the cortical surface, completely replacing the medulla and cortex.

On microscopic exam, there is cylindrical, or less commonly, saccular dilation of all collecting tubules. The cysts have a uniform lining of cuboidal cells, reflecting their origin from the collecting tubules.

The disease is bilateral; in almost all cases, the liver has cysts with portal fibrosis as well as proliferation of portal bile ducts.

Front 97

97. What is the clinical course in ARPKD?

Back 97

Patients who survive infancy may develop a peculiar type of hepatic fibrosis characterized by bland periportal fibrosis and proliferation of well-differentiated biliary ductules, a condition now termed congenital hepatic fibrosis. In older children, the hepatic picture in fact predominates.

Such patients may develop portal hypertension with splenomegaly.

Front 98

98. What is medullary sponge kidney?

Back 98

This disease should be restricted to lesions consisting of multiple cystic dilations of the collecting ducts in the medulla, usually presenting in adults.

Although it is typically an innocuous lesion discovered incidentally by radiographic studies, it can predispose to renal calculi, hematuria, infection, and dilated ducts.

On gross inspection, the papillary ducts in the medulla are dilated, and small cysts may be present. The cysts are lined by cuboidal epithelium or occasionally be transitional epithelium.

Front 99

99. What with nephronophthisis-medullary cystic disease complex?

Back 99

This complex is actually a family of progressive renal disorders, usually w/onset in childhood.

*The common characteristic is the presence of a variable number of cysts in the medulla, usually concentrated at the corticomedullary junction.

Although the presence of medullary cysts is important, the cortical tubulointerstitial damage is the cause of the eventual renal insufficiency.

Front 100

100. What are the four variants of nephronophthisis-medullary cystic disease complex?

Back 100

1. Sporadic; non-familial (20%)
2. *Familial juvenile nephronophthisis (50%)
3. *Renal-retinal dysplasia (15%)
4. **Adult onset medullary cystic disease (15%)

*Autosomal recessive
**Autosomal dominant

Front 101

101. What are the clinical features of nephronophthisis-medullary cystic disease complex?

Back 101

Affected children present first with polyuria and polydipsia, which reflect a marked defect in the concentrating ability of renal tubules. Sodium wasting and tubular acidosis are also prominent.

Some variants of juvenile nephronophthisis can have extrarenal associations, including ocular motor abnormalities, retinitis pigmentosa, liver fibrosis, and cerebellar abnormalities.

The expected course is progression to terminal renal failure in 5-10 years.

Front 102

102. What are the genes involved in the pathogenesis of nephronophthisis-medullary cystic disease complex?

Back 102

Thee genes, NPH1, NPH2, and NPH3, define the juvenile forms of the nephronophthisis and cause autosomal recessive disease.

The protein product of NPH1 is nephrocystin but its function is unknown.

Two genes (MCKD1 and MCKD2) with autosomal dominant transmission, have been identified as causing medullary cystic disease that is characterized by progression to endstage kidney disease in adult life.

Front 103

103. What is the morphology of nephronophthisis-medullary cystic disease complex?

Back 103

In gross appearance, the kidneys are small, have contracted granular surfaces, and show cysts in the medulla, most prominently at the corticomedullary junction. Small cysts are also seen in the cortex.

The cysts are lined by flattened or cuboidal epithelium and are usually surrounded by either inflammatory cells or fibrous tissues. In the cortex, there is widespread atrophy and thickening of the basement membranes of the proximal and distal tubules, together w/interstitial fibrosis.

Front 104

104. What is acquired (dialysis-associated) cystic disease?

Back 104

End-stage kidneys of patients undergoing dialysis can develop multiple cortical and medullary cysts.

They are often lined by atypical, hyperplastic epithelium that can undergo malignant transformation to renal cell carcinoma.

These cysts often contain calcium oxalate crystals.

Front 105

105. What are simple renal cysts?

How do they differ radiologically from renal tumors?

Back 105

These occur as multiple, single, usually cortical cystic spaces that vary widely. They are lined by low cuboidal epithelium and usually are 2-5 cm in diameter but can measure up to 10 cm. They have smooth walls and are filled w/clear serous fluid.

On occasion, they hemorrhage and calcification of the hemorrhage can cause flank pain and irregular contours, thus mimicking renal carcinoma.

Radiologic studies show that in contrast to renal tumors, renal cysts have smooth contours, are almost always avascular, and give fluid rather that solid signals on ultrasonography.

Front 106

106. What is acute interstitial nephritis?

Back 106

AIN is a syndrome that is characterized by an acute rise in serum creatinine w/fever, rash, eosinophilia, eosinphiluria, and histologically by interstitial edema w/cellular infiltrates.

AIN is an important cause of acute renal failure.

Front 107

107. What are the most common causes of AIN?

Back 107

Drugs:
1. Antimicrobial drugs
2. Penicillins (esp methicillin)
3. Rifampin
4. Sulfonamides
5. NSAIDs

Systemic infections:
1. Legionnaires' disease
2. Leptospirosis
3. Streptococcal infections
4. CMV
5. Infectious mononucleosis

Primary renal infections such as acute bacterial pyelonephritis

Immune disorders:
1. Acute allograft rejection
2. SLE
3. Sjogren's sydnrome

Front 108

108. What is acute pyelonephritis?

Back 108

It is classified histologically as a form of AIN, however; in contrast to the allergic form of AIN, acute pyelonephritis is associated w/direct bacterial invasion of the renal medulla.

The clinical manifestations are predominantly those of infection, fever, chills, and flank pain.

Front 109

109. How can a urinalysis provide important clues in the Dx of AIN?

Back 109

Hematuria, sterile pyuria, and leukocyte casts are common findings in AIN.

Eosinophilia is highly suggested of AIN. Mild to moderate proteinuria is present in a majority of patients

Front 110

110. How is the Dx of AIN made?

Back 110

1. Urinalysis findings
2. Electrolyte abnormalities include hyperkalemia, RTA, and renal sodium wasting
3. *Definitive Dx is made only by renal biopsy
4. A gallium scan can be helpful to differentiate AIN from acute tubular necrosis (ATN). (In AIN caused by intense inflammatory infiltrate, kidneys will light up, whereas in ATN, they do not.)

Front 111

111. What is the treatment for AIN?

Back 111

Discontinuing the use of the offending drug is the primary treatment of drug-induced AIN.

In most cases, this approach usually results in the restoration of renal function w/in several weeks.

A short course of high-dose corticosteroids (e.g. prednisone 1 mg/kg/day for 1-2 weeks) may accelerate recovery, but the added risk in patients with underlying infections must be weighed against possible benefits.

Front 112

112. What is chronic tubulotinerstitial nephropathy (CTN)?

Back 112

CTN is characterized clinically by slowly progressive renal insufficiency, non-nephrotic range proteinuria, and functional tubular defects.

Pathologically, CTN is characterized by interstitial fibrosis w/atrophy and loss of renal tubules.

Front 113

113. What are the clinical features of CTN?

Back 113

1. Mononuclear cell infiltrate along with fibrosis and tubular atrophy (these tubular defects are disproportionately severe in relation to the degree of renal failure
2. Most patients have no clinical evidence of active renal inflammation
3. The urinalysis may show modest pyuria and minimal hematuria and in some cases show WBC and granular casts. Proteinuria levels are usually less than 1g/day.

Front 114

114. How do the different causes of CTN damage different parts of the kidney?

Back 114

1. Conditions such as multiple myeloma or heavy metal toxicity, which affect proximal tubule structures, may exhibit proximal RTA, glycosuria, aminoaciduria, and uricosuria.
2. Distal RTA, salt wasting, and hyperkalemia are seen in patients w/isolated distal tubular damage, as may occur w/chronic obstruction of amyloidosis.
3. Patients w/analgesic nephropathy, sickle cell disease, or ADPKD may reveal polyuria that is caused by a urinary concentrating defect secondary to medullary involvement.

Front 115

115. What are the causes of CTN?

Back 115

1. Urinary tract obstruction drugs (analgesics, NSAIDs, cisplatin, nitrosourea, lithium)
2. Vascular diseases such as nephrosclerosis
3. Heavy metals
4. Metabolic disorders
5. Medullary cystic disease, ADPKD, sickle hemoglobinopathies
6. Malignancies and granulomatous diseases
7. Immunologic diseases

Front 116

116. What is analgesic nephropathy?

How is it Dx?

Back 116

Excessive consumption of certain analgesics such as phenacetin or acetaminophen usually in combo w/aspirin, may result in chronic interstitial nephritis.

Sloughed papilla into the urinary tract may be associated w/gross hematuria, flank pain, passage of tissue in the urine, and abrupt decline in renal function.

Demonstration of papillary necrosis in the absence of other common causes (e.g. DM, UT obstruction, infection) suggests Dx. *Plain CT is the Dx method of choice.

Front 117

117. What is the pathologic hallmark of benign nephrosclerosis?

Back 117

An arteriolopathy that is most pronounced in the interlobular and afferent arterioles.

Front 118

118. Lead nephropathy can lead to...?

What is the clinical triad?

Back 118

Lead accumulates in the tubule cells and causes a proximal tubular injury, which may lead to:
1. glycosuria
2. aminoaciduria
3. chronic interstitial disease

*Clinical triad of hypertension, gout, and renal insufficiency suggests the possibility of lead nephropathy.

Tx is ETDA

Front 119

119. What is the "myeloma kidney" (cast nephropathy)?

Back 119

Myeloma kidney is characterized by laminated refractile tubular casts (surrounded by inflammatory cells and multinucleated giant cells) and by tubular atrophy and interstitial fibrosis.

Cast nephropathy leads to renal failure rapidly.

Front 120

120. What are the most common functional abnormalities in the kidneys in Sjogren's syndrome?

Back 120

Renal involvement in Sjogren's syndrome is usually in the form of chronic interstitial nephritis.

The most common functional abnormalities are distal hypokalemic RTA and urinary concentrating defects.

Front 121

121. How is the Dx of polycystic kidney disease made?

Back 121

Made based on radiographic evidence of multiple cysts distributed throughout the renal parenchyma in association w/renal enlargement.

Renal ultrasound is helpful to demonstrate bilateral involvement. CT scan w/contrast medium occasionally reveals more cystic involvement.

Front 122

122. What is the treatment for polycystic kidney disease?

Back 122

Therapy is directed toward control of hypertension and toward prevention and early treatment of UTIs.

Cyst infections should be treated with trimethoprim-sulfamethoxazole, chloramphenicol, or cirpofloxacin, which penetrate cyst walls and attain therapeutic levels.

ESRD is managed either by dialysis or transplantation.

Front 123

123. How is the Dx of medullary sponge kidney made?

Back 123

The Dx is made on IV pyelography by the characteristic radial pattern "bouquet of flowers" or "bunch of grapes" of contrast filled medullary cysts.

Front 124

124. When are urinary tract obstructions thought to be a cause of renal failure?

Back 124

When any patient has renal failure of unknown origin, especially in the absence of proteinuria.

Renal sonography is the method of choice.

Front 125

125. What is postobstructive diuresis?

Back 125

Eliminating the urinary tract obstruction is occasionally associated with postobstructive diuresis, which is caused partially by a solute diuresis from salt and urea retained during obstruction and partially by the renal concentrating defect.

Front 126

126. What is nephrolithiasis?

Back 126

Nephrolithiasis is a common cause of morbidity in the US; the peak incidence in the age group of 20-45 years, w/a predilection for men.

Calcium stones are the most common (75%). Patients with nephrolithiasis usually have hematuria, and sudden onset of pain located in the flank and radiating to the groin on the same side. It can be associated with polyuria, dysuria, vomiting and ileus.

Front 127

127. How is the Dx of nephrolithiasis made?

Back 127

Urinalysis is helpful in determining the pH, identifying hematuria, ruling out infection, and most important, identifying the type of crystals.


Uric acid stones are easily identifiable b/c they are the only radiolucent stones; cystine stones are less radiopaque and may assume the calyceal shape. Additionally, triple phosphate stones have a staghorn appearance.

Most reliable way to ID stones is crystallographic study when the stone is obtained thru a strain of urine.

Front 128

128. What is the Tx for nephrolithiasis?

Back 128

The majority of stones (90%) are passed spontaneously. Lithotripsy treatment is more beneficial in patients with renal pelvic or upper ureteral stones. Ureteroscopy is more successful in patients w/lower ureteral stones.

Front 129

129. What is the recurrence of nephrolithiasis?

Back 129

40% of those w/a first episode have a second within 2-3 years

75% have a recurrence in 7-10 years.

After 20 years, less than 10% remain stone free.

Front 130

130. What are the recommendations for those with nephrolithiasis?

Back 130

1. Consume approx 3L of fluid per day and 8-10 ounces at night.
2. Restrict animal protein
3. Restrict salt intake
4. Metabolic work-up in 6-8 weeks

Front 131

131. What are the five risk factors for calcium oxalate and calcium phosphate stones?

What do they look like?

Back 131

1. Hypercalciuria
2. Hypocitraturia
3. Hyperuricosuria
4. Hyperoxaluria
5. Decreased urine volume

Appear opaque, round, with multiple calculi

Front 132

132. What are the four risk factors for magnesium ammonium phosphate stones (triple phosphate, struvite)?


What do they look like?

Back 132

1. Anatomic urologic abnormality
2. Infection w/urease-producing organism
3. Hypercalciuria
4. Hyperuricosuria

Appear opaque and staghorn

Front 133

133. What are the three risk factors for uric acid stones?

What do they look like?

Back 133

1. Hyperuricosuria
2. Urine pH < 5.0
3. Decreased urine volume

Appear radiolucent

Front 134

134. What are the two risk factors for cystine stones?

What do they look like?

Back 134

1. Hypercystinuria
2. Decreased urine volume

Appear radiopaque, may be staghorn.

Front 135

135. What are the characteristics of the blood flow through the liver from the portal vein and hepatic artery?

Back 135

The liver has high blood flow and low vascular resistance.

Front 136

136. What does cirrhosis of the liver do to the blood flow?

Back 136

Cirrhosis greatly increases resistance to blood flow.

This is b/c liver parenchymal cells are destroyed and they are replaced w/fibrous tissue that eventually contracts around the blood vessels and impedes the blood flow.

Front 137

137. Can the liver store blood?

Back 137

The liver is a large, expandable, venous organ capable of acting as a valuable blood reservoir in times of excess blood volume and capable of supplying extra blood in times of diminished blood volume.

Front 138

138. Does lymph flow through the liver?

Back 138

Yes, the liver has very high lymph flow. B/c the pores in the hepatic sinusoids are very permeable and allow ready passage of both fluid and proteins, the lymph draining from the liver usually has a protein concentration of about 6 g/dl, which is a little less than that of plasma.

Also, the extreme permeability of the liver sinusoid epithelium allows large quantities of lymph to form. Therefore, about half of all the lymph formed in the body under resting conditions arises in the liver.

Front 139

139. What is ascites?

Back 139

When the pressure in the hepatic veins rise about normal, excessive amts of fluid transude into the lymph and leak thru the outer surface of the liver capsule into the abdominal cavity.

At vena caval pressures of 10-15 mm Hg, hepatic lymph flow increases to as much as 20x normal and the sweating from the surface of the liver can be so great that it causes large amts of free fluid in the abdominal cavity, which is caused ascites.

Front 140

140. Can the liver regenerate?

Back 140

Yes, it has a remarkable ability to restore itself after significant hepatic tissue loss from either partial hepatectomy or acute liver injury, so long as the injury is uncomplicated by viral infection or inflammation.

Front 141

141. What factor is important in causing this regeneration?

What factor stops the regeneration?

Back 141

Hepatocyte growth factor (HGF) appears to be important in causing liver cell division and growth.

After the liver has returned to its original size, the process of hepatic cell division is terminated. This is done via transforming growth factor-beta, a cytokine secreted by hepatic cells.

Front 142

142. How is liver growth regulated?

Back 142

It is closely regulated by some unknown signal related to body size, so that an optimal liver-to-body weight ration is maintained for optimal metabolic function.

Front 143

143. What are Kupffer cells?

Back 143

These cells are large phagocytic macrophages that line the hepatic venous sinuses and eliminate colon bacilli.

Front 144

144. What are the four functions the liver performs in carbohydrate metabolism?

Back 144

1. Storage of large amounts of glycogen
2. Conversion of galactose and fructose to glucose
3. Gluconeogenesis
4. Formation of many chemical compounds from intermediate products of carb metabolism

Front 145

145. What is the glucose buffer function of the liver?

Back 145

Storage of glycogen by the liver allows the liver to remove excess glucose from the blood, store it, and then return it to the blood when the glucose concentration falls too low in the blood.

Gluconeogenesis in the liver is also important in maintaining a normal blood glucose concentration. In such a case, large amts of AAs and glycerol from TAGs are converted into glucose, thereby helping to maintain a relatively normal blood glucose concentration.

Front 146

146. What are three functions of the liver in fat metabolism?

Back 146

1. Oxidation of fatty acids to supply energy for other body functions
2. Synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins
3. Synthesis of fat from proteins and carbohydrates

Front 147

147. How does the liver derive energy from neutral fats?

Back 147

1. The fat is first split into glycerol and fatty acids.
2. The fatty acids are split via beta-oxidation into two carbon acetyl radicals that form acetyl coenzyme A.
3. Acetyl-CoA can enter the citric acid cycle and be oxidized to liberate large amts of ATP.

Front 148

148. Where does most of the beta oxidation take place in the body?

Back 148

Can take place in all cells of the body, but it occurs especially rapidly in the hepatic cells.

Front 149

149. Can the liver use all the acetyl-CoA that is formed?

Back 149

The liver itself cannot use all the acetyl-CoA that is formed; instead, it is converted by the condensation of two molecules of acetyl-CoA into acetoacetic acid. This is passed from the hepatic cells into the ECF and is then transported throughout the body to be absorbed by other tissues.

These tissues reconvert the acetoacetic acid into acetyl-CoA and then oxidize it in the usual manner.

Front 150

150. What about cholesterol and phospholipids in the liver?

Back 150

About 80% of the cholesterol synthesized in the liver is converted to bile salts, which are secreted into the bile; the remained is transported into lipoproteins and carried by the body to tissues.

Phospholipids are likewise synthesized in the liver and transported principally in the lipoproteins.

Front 151

151. What are the four important functions of the liver in protein metabolism?

Back 151

1. Deamination of AAs
2. Formation of urea for removal of ammonia from the body fluids
3. Formation of plasma proteins
4. Interconversions of the various AAs and synthesis of other compounds from AAs.

Front 152

152. What is the deamination process and where does it principally take place?

Back 152

Deamination of AAs is required before they can be used for energy or converted into carbs or fats.

Large amts of ammonia are formed via the deamination process.

A small amt of deamination can occur in the other tissues of the body, esp in the kidneys, but this is much less important than the deamination of AAs by the liver.

Front 153

153. What happens if the liver does not form urea?

Back 153

If the liver does not form urea, the plasma ammonia concentration rises rapidly and results in hepatic coma and death. Even greatly decreased blood flow through the liver can cause excessive ammonia in the blood.

Front 154

154. What plasma proteins are formed by the hepatic cells?

What happens to the hepatic cells when the plasma protein concentration is depleted?

Back 154

Essentially all the plasma proteins w/the exception of part of the gamma globulins, are formed by the hepatic cells. This accounts for about 90% of all the plasma proteins.

When the plasma protein concentration decreases, this causes rapid mitosis of the hepatic cells and growth of the liver to a larger size.

With chronic liver disease, plasma proteins may fall to very low levels, causing generalized edema and ascites.

Front 155

155. What vitamins does the liver store?

Back 155

The vitamin stored in greatest quantity in the liver is Vitamin A, but large quantities of vitamin D and B12 are normally stored as well.

Front 156

156. Where is iron stored in the body and how is the accomplished?

Back 156

Iron is stored in the greatest proportion in the liver in the form of ferritin. The hepatic cells contain large amts of protein called apoferritin, which is capable of combining with iron.

Thus, the apoferritin-ferritin system of the liver acts as a blood iron buffer, as well as an iron storage medium.

Front 157

157. What substances does the liver form that are used in coagulation?

Does the liver form vitamin K?

Back 157

1. Fibrinogen
2. Prothrombin
3. Accerator globulin
4. Factor 7


*The liver doesn't form vitamin K, instead, Vitamin K is required by the metabolic processes of the liver for the formation of prothrombin and factors 7, 9, and 10.

Front 158

158. What is bilirubin?

Back 158

This is a major end product of Hgb degradation. It also provides a valuable tool for diagnosing both hemolytic blood disease and various types of liver diseases.

Front 159

159. How is bilirubin formed?

Four main steps...

Back 159

1. When RBCs have become too fragile to last, their cell membranes rupture and the released Hgb is phagocytized by tissue macrophages (aka reticuloendothelial cells).
2. The Hgb is then split into globin and heme.
3. The heme ring is opened to give free iron and a straight chain of four pyrrole nuclei, which is the substrate from which bilirubin will be formed.
4. The first substance formed is biliverdin, but this is rapidly reduced to free bilirubin, which is gradually released from the macrophages into the plasma.

Front 160

160. What happens to the free bilirubin?

Back 160

It is absorbed through the hepatic cell membrane. In passing to the inside of the liver cells, it is released from the plasma albumin and soon thereafter conjugated about 80% with glucuronic acid to form bilirubin glucuronide, about 10% w/sulfate to form bilirubin sulfate, and about 10% with a multitude of other substances.

Front 161

161. What is the fate of the bilirubin in the intestines?

Back 161

Once in the intestines, about 1/2 of the conjugated bilirubin is converted by bacterial action into the substance urobilinogen, which is highly soluble.

Some of the urobilinogen is reabsorbed thru the intestinal mucosa back into the blood. Most of this is re-excreted by the liver back into the gut, but about 5% is excreted by the kidneys into the urine.

After exposure to air in the urine, the urobilinogen becomes oxidized to urobilin; alternatively in the feces, it becomes altered and oxidized to form stercobilin.

Front 162

162. What are the two most common causes of jaundice, and what are the type types of jaundice called?

Back 162

The most common causes:
1. Increased destruction of RBCs with rapid release of bilirubin into the blood
2. Obstruction of the bile ducts or damage to the liver cells so that even the usual amounts of bilirubin can not be excreted into the GI tract.

These two types are called hemolytic jaundice and obstructive jaundice, respectively.

Front 163

163. What causes hemolytic jaundice?

Back 163

Caused by hemolysis of RBCs.

In this condition, the excretory function of the liver is not impaired, but RBCs are hemolyzed so rapidly that the hepatic cells simply cannot excrete the bilirubin as quickly as it is formed. Therefore, the plasma concentration of free bilirubin rises to above normal levels. Likewise, the rate of formation of urobilinogen in the intestine is greatly increased, and much of this is absorbed into the blood and later excreted in the urine.

Front 164

164. What causes obstructive jaundice?

Is this the conjugated or free type?

Back 164

Caused by obstruction of bile ducts (gallstone or cancer blocks the common bile ducts) or liver disease (hepatitis).

In these conditions, the rate of bilirubin formation is normal, but the bilirubin formed cannot pass from the blood into the intestines. The free bilirubin still enters the liver cells and becomes conjugated in the usual way. This conjugated bilirubin is then returned to the blood via rupture of the congested bile canaliculi and direct emptying of the bile ino the lymph leaving hte liver.

*Thus, most of the bilirubin in the plasma becomes the conjugated type rather than the free type.

Front 165

165. What chemical test can differentiate between hemolytic and obstructive jaundice?

Back 165

In hemolytic jaundice, almost all the bilirubin is in the free form; in obstructive jaundice, it is in the conjugated form.

A test called the van den Berg reaction can be used to differentiate between the two.

Front 166

166. When there is total obstruction of bile flow, would urobilinogen show in the urine? What color would the stools be?

Back 166

In total obstructive jaundice, tests for urobilinogen in the urine are completely negative. Also, the stools become clay colored owing to a lack of stercobilin and other bile pigments.

Front 167

167. What is a major difference between free and conjugated bilirubin in severe obstructive jaundice?

Back 167

The kidneys can excrete small quantities of the highly soluble conjugated bilirubin but not the albumin bound free bilirubin.

Therefore, in severe obstructive jaundice, significant quantities of conjugated bilirubin appear int he urine. This can be demonstrated by simply shaking the urine and observing the foam, which turns an intense yellow.

Front 168

168. Where is the quadrate lobe of the liver located

Back 168

The quadrate lobe is visible on the upper part of the visceral surface of the liver and is bounded on the left by the fissure for ligamentum teres and on the right by the fossa for the gallbladder.

Functionally it is related to the left lobe of the liver.

Front 169

169. Where is the caudate lobe of the liver located?

Back 169

The caudate lobe is visible on the lower part of the visceral surface of the liver and is bounded on the left by the fissure for the ligamentum venosum and on the right by the groove for the inferior vena cava.

Functionally, it is separate from the right and the left lobes of the liver.

Front 170

170. What are the three parts of the gallbladder, and where are the located?

Back 170

1. A rounded end (fundus), which may project from the inferior border of the liver.
2. A major part in the fossa (body) which may be against the transverse colon and superior part of the duodenum.
3. A narrow part (neck) with mucosal folds forming the spiral fold.

Front 171

171. Where is the pancreas located?

Back 171

The pancreas lies mostly posterior to the stomach. It extends across the posterior abdominal wall from the duodenum, on the right, to the spleen, on the left.

The pancreas is retroperitoneal except for a small part of its tail and consists of a head, uncinate process, neck, body, and tail.

Front 172

172. Where is the head and uncinate process located?

Back 172

The head lies within the C shaped concavity of the duodenum

The uncinate process projects from the lower part of the head and passes posterior to the superior mesenteric vessels

Front 173

173. Where is the neck and tail located?

Back 173

The neck is anterior to the superior mesenteric vessels; posterior to the neck of the pancreas, the superior mesenteric and the splenic veins join to the form the portal vein.

The tail ends as it passes between layers of the splenorenal ligament.

Front 174

174. Where does the pancreatic duct follow?

What does it form with the bile duct?

Back 174

The pancreatic duct begins in the tail of the pancreas; it passes to the right thru the body of the pancreas, and then turns inferiorly after entering the head of the pancreas. In the lower part of the head of the pancreas, the pancreatic duct joins the bile ducts to form the hepatopancreatic ampulla.

Front 175

175. What is an annular pancreas?

Back 175

The pancreas develops from ventral and dorsal diverticula from the foregut. The dorsal bud forms most of the head, neck, and body of pancreas. The ventral bud rotates around the bile duct to form part of the head and the uncinate process.

If the ventral bud splits the two segments may encircle the duodenum. The duodenum is therefore constricted and may even undergo atresia. After birth, the child may fail to thrive and vomit due to poor gastric emptying.

Front 176

176. How can an annular pancreas be discovered in utero?

Back 176

Via ultrasound. The obstruction of the duodenum may also prevent the fetus from swallowing enough amniotic fluid causing polyhydraminos.

Front 177

177. Where is the spleen located?

Back 177

The spleen develops as part of the vascular system in the part of the dorsal mesentery that suspends the developing stomach from the body wall.

In the adult, the spleen lies against the diaphragm, in the area of rib 9 to rib 10. It is therefore in the left upper quadrant of the abdomen.

Front 178

178. What is Hartmann's pouch?

Back 178

From time to time, gallstones impact in the region of Hartmann's pouch, which is a bulbous region of the neck of the gallbladder.

When the gallstone lodges in this area, the gallbladder cannot empty normally and contractions of the gallbladder wall produce severe pain.

Front 179

179. To what areas are referred pain sent to in cholecystitis?

Back 179

If the inflammation involves the related parietal peritoneum of the diaphragm, pain may not only occur in the right upper quadrant, but may also be referred to the shoulder on the right side.

This referred pain is due to the innervation of the visceral peritoneum of the diaphragm by C3-C5.

Front 180

180. What is pre-hepatic jaundice?

Back 180

This is usually produced by conditions where there is an excessive breakdown of RBC (e.g. incompatible blood transfusion and hemolytic anemia).

Front 181

181. What is post-hepatic jaundice?

What are the two most common causes?

Back 181

Any obstruction of the biliary tree can produce jaundice, but the two most common causes are gallstones within the bile duct and an obstructing tumor at the head of the pancreas.

Front 182

182. Why is splenic rupture so common?

Back 182

The spleen has an extremely thin capsule and is susceptible to injury even when there is no damage to the surrounding structures.

When ruptured, it bleeds profusely into the peritoneal cavity.

Front 183

183. How are bacterial infections in UTIs acquired?

Back 183

Bacterial infection is usually acquired by the ascending route from the urethra to the bladder. The infection may then proceed to the kidney.

Front 184

184. In what two settings are UTIs most common in?

What is the most common cause of UTIs?

Back 184

1. Community-acquired (most common)
2. Hospital acquired (associated w/catheterizations)

Most common cause of UTIs is the gram-negative rod E. coli.

Front 185

185. What 5 other members of the Enterobacteriaceae are also implicated in causing UTIs?

Back 185

1. Proteeus mirabilis is often associated w/urinary stones b/c this organism produces a potent urease, which acts on urea to produce ammonia, rendering the urine alkaline.
2. Klebsiella*
3. Enterobacter*
4. Serratia*
5. Pseudomonas aeruginosa*

*Nosocomial

Front 186

186. What 3 gram positive species are associated w/UTIs?

Back 186

1. Staphyloccus saprophyticus is common in young sexually active women
2. Staphy. epidermidis*
3. Enterococcus*

*Nosocomial

Front 187

187. What 3 species can be found when there has been hematogeneous spread to the urinary tract?

Back 187

1. Salmonella typhi
2. Staph aureus
3. Mycobacterium tuberculosis

Front 188

188. Are viral causes of UTIs common?

What are they associated with?

Back 188

Viral causes of UTI are rare, although there are associations with hemorrhagic cystitis and other renal syndromes

Front 189

188. Which viruses lead to hemorrhagic cystitis?

Back 189

Human polyomaviruses, JC and BK, enter the body via the respiratory tract and infect eptiehlial cells in the kidney tubules and ureter. During normal pregnancy, the viruses may reactivate asymptomatically with the appearance of large amts of virus in the urine. Reactivation also occurs in immunocompromised patients and may lead to hemorrhagic cystitis.

In contrast to asymptomatic shedding, some serotypes of adenovirus have been implicated as a cause of hemorrhagic cystitis.

Front 190

189. What other viruses cause renal syndromes?

Back 190

High titers of CMV and rubella may be shed asymptyomatically in the urine of congenitally infected infants.

The rodent-borne hantavirus respsonsible for hemorrhagic fever, infects capillary blood vessels in the kidney and can cause a renal syndrome w/proteinuria.

Lastly, a number of other viruses can infect the kidneys, including mumps and HIV.

Front 191

190. Which parasites/fungi cause UTIs?

Back 191

1. Candidia spp. and Histoplasma capsulatum
2. Protozoan Trichomonas vaginalis (vaginitis)
3. Schistosoma haematobium, which results in inflammation of the bladder and commonly hematuria.

Front 192

191. How does Schistosoma haematobium cause problems?

Back 192

The eggs penetrate the bladder wall, and in severe infections large granulomatous reactions can occur and the eggs may become calcified.

Bladder cancer is associated w/chronic infections, although the mechanism is not known.

Obstruction of the ureter as a result of egg-induced inflammatory changes can also lead to hydronephrosis.

Front 193

192. What three mechanical factors predispose to UTIs?

Back 193

1. Anything that disrupts normal urine flow or complete emptying of the bladder or facilitates access of organisms to the bladder.
2. The shorter female urethra is shorter than the male urethra; sexual intercourse facilitates the movements of these organisms into the urethra.
3. In male infants, UTIs are more common in the uncircumcised and this is associated w/colonization of the inside of the prepuce and urethra w/fecal organisms.

Front 194

193. What are the five main causes of obstruction to complete bladder emptying?

Back 194

1. Pregnancy
2. BPH
3. Renal calculi
4. Tumors
5. Strictures

Front 195

194. Which neurologic conditions cause one to lose control of the bladder and sphincters and thus cause a functional obstruction in urine flow?

Back 195

Spina bifida, paraplegia, or MS cause a large residual volume of urine in the bladder and such patients are particularly prone to recurrent infections

Front 196

195. What about the vesicoureteral reflux in UTIs?

Back 196

This reflux is common in children w/anatomic abnormalities of the urinary tract and may predispose to ascending infection and kidney damage.

Front 197

196. Are people w/diabetes prone to UTIs?

Back 197

People w/DM may have more severe UTIs and if diabetic neuropathy interferes w/normal bladder function, persistent UTIs are common.

Front 198

197. How is catheterization a major predisposing factor for UTIs?

Back 198

Bacteria can be pushed into the bladder as the catheter is inserted and while it is in place, bacteria reach the bladder by tracking up between the outside of the catheter and the urethra.

Contamination of the drainage system by bacteria from other sources can also result in infection.

Regardless, the duration of catheterization is directly associated w/increased probability of infection (increases 3-5% per day)

Front 199

198. What serotypes of E. coli are specific to UTIs?

How are they different from those in GI tract infections?

Back 199

The ability to cause infection in the urinary tract is limited to certain serogroups of E. coli such as O serotypes and K serotypes.

These serotypes differ from those associated w/GI tract infection which leads them to be called UPEC (uropathogenic E coli).

The success of these strains is due to a variety of genes in chromosomal pathogenicity islands that cause it to colonize in the periurethral areas.

Front 200

199. What specific virulence factor allows UPEC to adhere?

Back 200

P. fimbriae (pyelonephritis associated pili (PAP) pili).

Front 201

200. What 3 virulence factors are present in E. coli that allow it to colonize and infect the urinary tract?

What about in Proteus spp.?

Back 201

1. P. fimbriae
2. Capsular acid polysaccharide (K) antigens are associated w/the ability to cause pyelonephritis and are known to enable E. coli strains to resist host defenses by inhibiting phagocytosis
3. Hemolysin production by E. coli is linked w/the capacity to cause kidney damage; many hemolysin act more generally as membrane-damaging toxins.

Proteus spp. infections are related to their ability to cause pyelonephritis and stones via their urease production.

Front 202

201. How is the healthy urinary tract resistant to bacterial colonization?

Back 202

With the exception of the urethral mucosa, the urinary tract is excellent at ridding infections. The pH, chemical content and flushing help dispose of them.

Although urine is a good culture medium for most bacteria, it is inhibitory to some, and anaerobes and other species (non-hemolytic streptococci, corynebacteria, and staphylococci), which comprise most of the normal urethral flora, do not readily multiply in urine.

Front 203

202. What antibodies are usually found in the urine after infection of the kidney?

What about in the lower urinary tract?

Back 203

Upper:
1. IgG
2. Secretory IgA

Lower:
Low or undetectable serologic response (this reflects the superficial nature of the infection; the bladder and urethral mucosa are rarely invaded in UTIs).

Front 204

203. What are the three symptoms of acute, lower UTIs?

Back 204

1. Dysuria
2. Urgency
3. Frequency of micturition

These symptoms in the elderly and those with indwelling catheters are usually asymptomatic.

Front 205

204. Pyruria in the absence of positive urine cultures can be due...?

Back 205

Chlamydiae or tuberculosis and is also seen in patients receiving antibacterial therapy for UTI.

Front 206

205. What are the symptoms of acute bacterial prostatitis?

How does it arise?

Back 206

Acute bacterial prostatitis causes systemic symptoms (fever) and local symptoms (perineal and low back pain, dysuria, and frequency).

May arise from ascending or hematogeneous infection, and people lacking the antibacterial substances in their prostatic fluid are more susceptible.

Front 207

206. Patients with pyelonephritis present with...?

What organism is usually to blame?

Back 207

Lower urinary tract symptoms and usually have a fever.

Staphylococci are a common cause and renal abscesses are generally present.

Recurrent episodes of pyelonephritis result in loss of function of renal tissue -> hypertension

Front 208

207. Hematuria is a feature in...?

Pyuria is common in...?

Back 208

Hematuria is a feature of endocarditis and a manifestation of immune complex disease, as well as a result of infections of the kidney.

Pyuria is common in kidney infections by M. tuberculosis, which cannot be grown by normal urine culture methods and therefore the patient can appear to have a sterile pyuria.

Front 209

208. How are true infections distinguished from contaminated samples?

Back 209

Via quantitative culture methods.

Bacteriuria is defined as significant when a properly collected midstream sample is shown to contain over 10⁵ oganisms/mL.

Infected urine usually contains only a single bacterial species; contaminated urine usually has < 10⁴ organisms/mL and often contains more than one bacterial species.

These rules do not apply to samples collected via other means other than MSUs.

Front 210

209. Which two organisms require special urine samples?

Back 210

M. tuberculosis

Schistosoma haematobium

Front 211

210. Sterile pyruia is an important finding and may reflect...

Back 211

1. Concurrent antibiotic therapy
2. Other diseases such as neoplasms or urinary calculi
3. Infection w/organisms not detected by routine urine culture methods

Front 212

211. Which two agents are used only for lower UTIs?

Back 212

1. Nitrofurantoin
2. Nalidixic acid

This is because they do not achieve adequate serum and tissue concentrations to treat upper UTIs.

Front 213

213. What is the most common anomaly of the gallbladder?

Back 213

A folded fundus is the most common anomaly, creating the so-called phrygian cap (the fundus is folded inward).

Front 214

214. What is cholelithiasis?

Back 214

Bile secretion allows hepatic elimination of bilirubin, xenobiotics, and cholesterol. Detergent bile salts are necessary to disperse and hydrolyze dietary lipids and facilitate their intestinal absorption. Cholesterol is solubilized by bile salts and co-secreted lecithin; supersaturation of bile w/cholesterol or bilirubin salts promotes stone formation.

Besides cholesterol stones (>50% crystalline cholesterol), pigmented cholesterol stones may also form (predominantly bilirubin calcium salts).

Front 215

215. What are the risk factors for cholesterol gallstones?

Back 215

1. Native americans, adults in industrialized nations
2. Increasing age, w/a male-female ration of 1:2
3. Estrogenic influences, clofibrate, obesity or rapid weight loss
4. Gallbladder stasis, as in spinal cord injury or pregnancy
5. Hypercholesterolemic syndromes

Front 216

216. What are the risk factors for pigment gallstones?

Back 216

1. Asian mroe than Western, rural more than urban
2. Chronic hemolytic syndromes (sickle cell disease)
3. Biliary tract infection
4. Heal disease (resection or bypass)
5. Cystic fibrosis w/pancreatic insufficiency

Front 217

217. What is the pathogenesis of cholesterol stones?

Back 217

When cholesterol concentrations exceed the solubilizing capacity of bile, cholesterol can no longer remain dispersed and nucleates into solid cholesterol monohydrate crystals.

Front 218

218. What four simultaneous defects must occur for cholesterol stones to form?

Back 218

1. Bile must be supersaturated w/cholesterol
2. Gallbladder hypomotility promotes nucleation
3. Cholesterol nucleation in bile is accelerated
4. Mucus hypersecretion in the gallbladder traps the crystals, permitting their aggregation into stones.

Front 219

219. Which is the primary defect of the four? How is it mediated?

Back 219

Supersaturation of bile w/cholesterol is the result of hepatocellular hypersecretion of cholesterol. This is the primary defect, mediated by abnormal regulation of hepatic mechanisms for delivering cholesterol to bile.

This abundant free cholesterol is toxic to the gallbladder and penetrates the wall and exceeds the ability of the mucosa to detox. Gallbladder hypomotility ensues.

Front 220

220. What causes the gallbladder hypomotility?

Back 220

Muscular stasis appears to result from both intrinsic neuromuscular dysmotility and from diminished muscular responsiveness to CCK.

Front 221

221. What causes the accelerated nucleation of cholesterol crystals?

Back 221

The relative composition of trace proteins in bile may be altered, such that the balance of antinucleating and pronucleating proteins shifts in favor of acceleration nucleation of cholesterol crystals.

This is further promoted by the presence of microprecipitates such as calcium salts.

Front 222

222. How does gallbladder hypersecretion of mucus help form cholesterol stones?

Back 222

The cholesterol crystals become trapped in the mucus for sustained periods, enabling their growth in macroscopic concretions.

Front 223

223. What is the pathogenesis of pigmented stones?

Back 223

Pigmented stones are complex mixtures of abnormal insoluble calcium salts of unconjugated bilirubin along w/inorganic calcium salts.

Unconjugated bilirubin is normally a minor component of bile but increases when infection of the biliary tract leads to release of β-glucuronides. Thus, infection of the biliary tract, as w/E. coli or Ascaris lumbricoides or by the liver fluke Opisthorchis sinensis, increases the likelihood of pigment stone formation.

*Also, intravascular hemolysis leads to increased hepatic secretion of conjugated bilirubin, thus lending to pigment stone formation.

Front 224

224. What is the morphology of cholesterol stones?

Are they radio-lucent or radio-opaque?

Back 224

Arise exclusively in the gallbladder and are composed of cholesterol ranging from 100% to 50%. Pure cholesterol stones are pale yellow, round to ovoid, and have a finely granular hard external surface.

Single stones are ovoid; multiple stones may be faceted.

Stones composed largely of cholesterol are radiolucent; sufficient calcium carbonate is found in 10-20% of cholesterol stones to render them readio-opaque.

Front 225

225. What is the morphology of black pigment gallstones?

Where are they found?

Back 225

Pigment gallstones are classified as black and brown. In general, black stones are found in sterile gallbladder bile. They contain oxidized polymers of calcium salts of unconjugated bilirubin.

The black stones are rarely more than 1.5 cm in diameter, and are almost always present in great number, and may crumble to the touch.

Their contours are spiculated and molded. They are radio-opaque

Front 226

226. What is the morphology of brown pigment gallstones?

Where are they found?

Back 226

Brown stones are found in infected intrahepatic or extrahepatic ducts. They contain pure calcium salts of unconjugated bilirubin, mucin glycoprotein, a substantial cholesterol fraction, and calcium salts of palmitate and stearate.

Brown stones tend to be laminated and soft and may have a soaplike or greasy consistency. They are radio-lucent

Front 227

227. Which condition causes the "strawberry gallbladder" appearance?

Back 227

Cholesterol normally entering the gallbladder mucosa by free exchange w/the lumen may be esterified by acyl CoA:cholesterol acryltransferase. Cholesterol hypersecretion byt he liver promotes excessive accumulation of cholesterol esters within the lamina propria of the gallbladder. The mucosal surface is studded w/minute yellow flecks, producing the "strawberry gallbladder"

Front 228

228. What are the clinical features of gallstones?

Back 228

From 70-80% of gallstone patients remain asymptomatic throughout life. Asymptomatic patients become symptomatic at the rate of 1-3% per year, and risk diminishes w/time.

Symptoms include spasmodic, colicky pain, owing to obstruction of the bile ducts by passing stones. Gallbladder obstruction generates right upper abdominal pain.

Front 229

229. What are the complications of gallstones?

Are small or large stones more dangerous?

Back 229

Empyema, perforation, fistulae, inflammation of the biliary tree (cholangitis), and obstructive cholestasis or pancreatitis.

The larger the stone, the less likely they are to enter the cystic or common ducts to produce obstruction; it is the very small stones or "gravel" that are more dangerous.

Occasionally, however, a large stone may erode directly into an adjacent loop of small bowel, generating intestinal obstruction (gallstone ileus).

*Most notable is the increased risk for gallbladder CA.

Front 230

230. What is acute cholecystitis?

Back 230

Acute calculous cholecystitis is an acute inflammation of the gallbladder, precipitated 90% of the time by an obstruction of the neck or cystic duct.

*It is the primary complication of gallstones and the most common reason for emergency cholecystectomy.

Front 231

231. Does cholecystitis occur in the absence of gallstones?

Back 231

Yes, generally in the very ill patient. Most cases occur in these circumstances:
1. Postoperative state after major, nonbiliary surgery
2. Severe trauma
3. Severe burns
4. MSOF
5. Sepsis
6. Prolonged IV hyperalimentation
7. Postpartum state

Front 232

232. What is the pathogenesis of acute calculous cholecystitis?

1/2

Back 232

It results from chemical irritation and inflammation of the obstructed gallbladder.

The action of mucosal phospholipases hydrolyzes luminal lecithins to toxic lysolecithins. The normally protective glycoprotein mucus layer is disrupted, exposing the mucosal epithelium to the direct detergent action of bile salts.

Front 233

233. What is the pathogenesis of acute calculous cholecystitis?

2/2

Back 233

Prostaglandins released w/in the wall of the gallbladder contribute to mucosal and mural inflammation.

Gallbladder dysmotility develops; distention and increased intraluminal pressure compromise blood flow to the mucosa.

These events occur in the absence of bacterial infection; only later in the course may bacterial contamination develop.

Front 234

234. What is the pathogenesis of acute acalculous cholecystitis?

Back 234

Acute acalculous cholecystitis is thought to result from ischemia. The cystic artery is an end artery w/essentially no collateral circulation.

Contributing factors are:
1. Dehydration and multiple blood transfusions
2. Gallbladder stasis
3. Accumulation of microcrystals of cholesterol, viscous bile, and gallbladder mucus, causing cystic duct obstruction in the absence of stone formation
4. Inflammation and edema of the wall, compromising blood flow
5. Bacterial contamination and generation of lysolecithins

Front 235

235. What is the morphology of acute cholecystitis?

1/2

Back 235

The gallbladder is usually enlarged and tense, and it may assume a bright red or blotchy, violaceous to green-black discoloration, imparted by subserosal hemorrhages.

The serosal covering is freq layered by fibrin, and in severe cases, by a definite suppurative coagulated exudate.

In acalculous cholecystitis there is an absence of macroscopic stones. In the calculous form, the obstructing stone is usually present in the neck or the cystic duct.

Front 236

236. What is the morphology of acute cholecystitis?

2/2

Back 236

In addition to one or more stones, the gallblader lumen is filled w/a cloudy or turbid bile that may contain large amts of fibrin and frank pus, as well as hemorrhage.

Front 237

237. What is empyema of the gallbladder?

What is gangrenous cholecystitis?

Back 237

When the contained exudate is virtually pure pus, the condition is referred to as empyema of the gallbladder. In mild cases, the gallbladder wall is thickened, edematous, and hyperemic.

In more severe cases, it is transformed into a green-black necrotic organ, termed gangrenous cholecystitis.

Front 238

238. What are the clinical features of acute cholecystitis?

The calculous form?

Back 238

Symptoms include right upper quadrant or epigastric pain, mild fever, anorexia, tachycardia, diaphoresis, and nausea and vomiting. Jaundice suggests an obstruction of the common bile duct.

Acute calculous cholecystitis may appear w/remarkable suddenness and constitute an acute surgical emergency or may present w/mild symptoms that resolve without medical intervention.

Front 239

239. What are the clinical features of acute acalculous cholecystitis?

Back 239

The symptoms are more insidious; a high proportion of patients have no symptoms referable to the gallbladder. As a result of either delay in Dx or the disease itself, the incidence of gangrene and perforation is much higher than in the calculous form.

In rare instances, primary bacterial infection can give rise to acute acalculous cholecystitis including agents such as S. typhi and staph.

Front 240

240. What is chronic cholecystitis?

Back 240

Chronic cholecystitis may be a sequel to repeated bouts of mild to severe acute cholecystitis, but in many instances, it develops in the apparent absence of antecedent attacks. Although gallstones are usually present, they may not play a direct role in initiating inflammation. Rather, chronic supersaturation of bile w/cholesterol permits cholesterol stone formation and initiation of inflammation and gallbladder dysmotility.

Patient populations and symptoms are the same as for the acute form.

Microorganisms, usually E. coli and enterococci, can be cultured in about 1/3rd of cases.

Front 241

241. What is the morphology of chronic cholecystitis?

1/4

Back 241

The morphologic changes are variable and sometimes minimal. The serosa is usually smooth and glistening but may be dulled by subserosal fibrosis. Dense fibrous adhesions may remain as sequelae of prexistent acute inflammation.

Front 242

242. What is the morphology of chronic cholecystitis?

2/4

Back 242

On section, the wall is variably thickened, rarely to more than 3x normal.

**The wall has an opaque gray-white appearance and may be less flexible than normal. In the uncomplicated case, the lumen contains fairly clear, green-yellow mucoid bile and usually stones.

The mucosa itself is generally preserved.

Front 243

243. What is the morphology of chronic cholecystitis?

3/4

Back 243

On histologic exam, the degree of inflammation is variable. In the mildest cases, only scattered lymphocytes, plasma cells, and macrophages are found in the mucosa and in the subserosal fibrous tissue. In more developed cases, there is marked subepithelial and subserosal fibrosis, accompanied by mononuclear cell infiltration. Reactive proliferation of the mucosa and fusion of the mucosal folds may give rise to buried crypts of epithelium within the wall.

Front 244

244. What is the morphology of chronic cholecystitis? (What are Rokitansky-Aschoff sinuses?)

4/4

Back 244

Outpouchings of the mucosal epithelium through the wall (Rokitansky-Aschoff sinuses) may be quite prominent.

Superimposition of acute inflammatory changes imply acute exacerbation of a previously chronically injured gallbladder.

In rare instances, extensive dystrophic calcification within the gallbladder wall may yield a porcelain gallbladder, notable for a markedly increased incidence of cancer.

Front 245

245. What is xanthogranulomatous cholecystitis?

Back 245

A rare condition in which the gallbladder is shrunken, nodular, and chronically inflamed w/foci of necrosis and hemorrhage.

Abundant macrophages packed w/lipids are admixed w/an exuberant fibrous tissue response, resulting in a massively thickened wall.

Gallstones are usually present.

Front 246

246. What is hydrops of the gallbladder?

Back 246

An atrophic, chronically obstructed gallbladder may contain only clear secretion.

Front 247

247. What are the clinical features of chronic cholecystitis?

Back 247

Usually characterized by recurrent attacks of either steady or colicky epigastric or right upper quadrant pain.

Nausea, vomiting, and intolerance for fatty foods are freq accompaniments.

Front 248

248. What is choledococholithiasis?

What is the prevalence?

Back 248

Choledocholithiasis is defined as the presence of stones within the bile ducts of the biliary tree, as opposed to cholethithiasis (stones in the gallbladder).

In western nations, almost all biliary tract stones are derived from the gallbladder, although both cholesterol and pigmented stones can form anywhere in teh biliary tree. In Asia, there is a much higher incidence of primary stone formation within the biliary tree, usually pigmented as a result of the biliary tract infections.

Front 249

249. What are the symptoms of choledococholithiasis?

Back 249

May be asymptomatic or may cause:
1. Obstruction
2. Pancreatitis
3. Cholangitis
4. Hepatic abscess
5. Secondary biliary cirrhosis
6. Acute calculous cholecystitis

Front 250

250. What is cholangitis?

What causes it?

Back 250

Cholangitis is the term used for bacterial infection of the bile ducts.

It can result from any lesion that creates obstruction to bile flow, most commonly choledocholithiasis. Uncommon causes include indwelling stents or catheters, tumors, acute pancreatitis, benign strictures, etc..

Front 251

251. Where does bacteria enter into the biliary tract in cholangitis?

Back 251

Bacteria most likely enter the biliary tract thru the sphincter of Oddi; infection of intrahepatic biliary radicals is termed ascending cholangitis.

Front 252

252. What are the symptoms of cholangitis?

Back 252

Cholangitis usually presents with fever, chills, abdominal pain, and jaundice, accompanied by acute inflammation of the wall of the bile ducts w/entry of neutrophils into the luminal space.

Intermittence of symptoms suggests bouts of partial obstruction.

Front 253

253. What is the most severe form of cholangitis?

Back 253

Suppurative cholangitis, in which purulent bile fills and distends bile ducts.

Front 254

254. What is biliary atresia?

Back 254

Extrahepatic biliary atresia is complete obstruction of the lumen of the extrahepative biliary tree within the first 3 months of life.

It is the single most frequent cause of death from liver disease in early childhood and accounts for 50-60% of children referred for liver transplantation, owing to the rapidly progressing secondary biliary cirrhosis.

Front 255

255. What are the two major forms of biliary atresia?

Back 255

They are based on the timing of luminal obliteration:
1. Fetal form (20%)
2. Perinatal form (more common)

Front 256

256. What is the fetal form of biliary atresia?

What is the presumed cause?

Back 256

This form accounts fo up to 20% of cases and is commonly associated w/other anomalies resulting from ineffective establishment of laterality of thoracic and abdominal organ development. These include malrotation of abdominal viscera, interrupted inferior vena cava, polysplenia, and congenital heart disease.

*The presumed cause is aberrant intrauterine development of the extrahepatic biliary tree.

Front 257

257. What is the perinatal form of biliary atresia?

What is the cause?

Back 257

More common is the perinatal form, in which a presumed normally developed biliary tree is destroyed following birth.

Although the cause is not known, viral infection has long been implicated, particularly reovirus and rotavirus. Genetic inheritance is also under scrutiny, given reports of biliary atresia occurring in twins and in families.

Regardless, a "multihit" process is proposed in which viral or toxic insult to the biliary epithelium leads to destruction of the biliary tree.

Front 258

258. What is the morphology of biliary atresia?

1/3

Back 258

The salient features include inflammation and fibrosing stricture of the hepatic or common bile ducts, periductular inflammation of intrahepatic bile ducts, and progressive destruction of the intrahepatic biliary tree.

Front 259

259. What is the morphology of biliary atresia?

2/3

Back 259

On liver biopsy, florid features of extrahepatic biliary obstruction are evident via marked bile ductular proliferation, portal tract edema and fibrosis, and parenchymal cholestasis.

In the remainder, inflammatory destruction of intrahepatic ducts leads to paucity of bile ducts and absence of edema or bile ductular proliferation on liver biopsy.

If unrecognized or uncorrected, cirrhosis develops within 3-6 mos of birth.

Front 260

260. What are the three anatomic types of biliary atresia?

Back 260

When the disease is limited to the common (type I) or hepatic bile ducts (type II) with patent proximal branches, the diseases is surgically correctable.

Unfortunately, 90% of patients have type III biliary atresia, in which there is also obstruction of bile ducts at or above the portahepatis. Theses cases are noncorrectable, since there are no patent bile ducts amenable to surgical anastomosis.

Front 261

261. What are the clinical features of biliary atresia?

Back 261

Infants w/biliary atresia present w/neonatal cholestasis, exhibit normal birth weight and postnatal weight gain, and the progression of initially normal stools to acholic stools.

At the time of presentation, serum bilirubin values are usually in the 6-12 mg/dL range, w/only moderately elevated ALT and AST and ALKPHOS levels.

Liver transplantation w/accompanying donor bile ducts remains the primary hope for salvage of these young patients.

Front 262

262. What are choledochal cysts?

Back 262

Choledochal cysts are congenital dilation of the common bile duct, presenting most often in children before age 10 w/the nonspecific symptoms of jaundice, and or recurrent abdominal pain that are typical of biliary colic.

Front 263

263. Where do choledocal cysts form and what are the complications?

Back 263

These uncommon cysts may take the form of segmental or cylindrical dilation of the common bile duct, diverticuli of the extrahepatic ducts, or choledochoceles, which are cystic lesions that protrude into the duodenal lumen.

Choledocal cysts predispose to stone formation, stenosis and stricture, pancreatitis, and obstructive biliary complications within the liver. In the older patient, the risk of bile duct CA is elevated.

Front 264

264. Where do neoplasms of primary clinical importance derive from in the biliary tract?

How are adenomas classified?

Back 264

Those of clinical importance derive from the epithelium lining the biliary tree.

Adenomas are benign epithelial tumors, and are classified as tubular, papillary, and tubulopapillary and are similar to adenomas found elsewhere in the alimentary tract.

Front 265

265. What are inflammatory polyps in the biliary tract?

What is adenomyosis of the gallbladder?

Back 265

Inflammatory polyps are sessile mucosal projections w/a surface stroma infiltrated with chronic inflammatory cells and lipid laden macrophages. These lesions may be difficult to differentiate from neoplasms on imaging studies.

Adenomyosis of the gallbladder is characterized by hyperplasia of the muscularis, containing intramural hyperplastic glands.

Front 266

266. What is carcinoma of the gallbladder?

Back 266

CA of the gallbladder is the 5th most common cancer of the digestive tract. It is slightly more common in women, typically presenting over the age of 60. Gallstones coexist in 60-90% of cases.

Presumably, gallbladders containing stones or infectious agents develop cancer as a result of irritative trauma and chronic inflammation.

Front 267

267. What are the two patterns of growth in gallbladder CA?

Back 267

1. Infiltrating
-more common and usually appears as a poorly defined area of diffuse thickening and induration of the gallbladder wall that may cover several square cm or may involve the entire gallbladder. *These tumors are scirrhous and have a very firm consistency.

2. Exophytic
-this pattern grows into the lumen as an irregular, cauliflower mass but at the same time invades the underlying wall. The luminal portion may be necrotic, hemorrhagic, and ulcerated. *The most common sites of involvement are the fundus and the neck.

Front 268

268. What type of CA are most common in the gallbladder?

Back 268

Adenocarcinomas are the most common. Some are papillary in architecture and are well to moderately differentiated; others are infiltrative and poorly differentiated to undifferentiated.

About 5% are squamous. A minority may exhibit carcinoid features.

**By the time these neoplasms are discovered, most have invaded the liver centrifugally, and may have extended to the cystic duct and adjacent bile ducts.

Front 269

269. What are the clinical features of gallbladder CA?

Back 269

Presenting symptoms are insidious and typically indistinguishable from those with cholelithiasis: abdominal pain, jaundice, anorexia, and nausea and vomiting.

Front 270

270. What are carcinomas of the extrahepatic biliary tree?

Back 270

These are uncommon but insidious tumors and generally produce painless, progressively deepening jaundice. They occur in older individuals and unlike cancers of the gallbladder, occur slightly more freq in men.

Gallstones are present in about 1/3 of cases.

Risk is increased in patients w/primary sclerosing cholangitic, UC, and cystic liver diseases, and from biliary tree fluke infections.

Front 271

271. What are periampullary carcinomas?

Back 271

A subgroup of biliary tree CAs are those arising in the immediate vicinity of the ampulla of Vater. Tumors of this regions also include adenomas of the duodenal mucosa and pancreatic CA.

Collectively, these tumors are referred to as periampullary tumors.

Front 272

272. What is the morphology of extrahepatic bile duct CA?

Back 272

Most tumors are firm, gray nodules within the bile duct wall; some may be diffusely infiltrative lesions; other are papillary, polypoid lesions.

Most bile duct tumors are adenocarcinomas that may or not be mucin-secreting.

An abundant fibrous stroma accompanies the epithelial proliferation.

Front 273

273. What are Klatskin tumors?

Back 273

Tumors arising from the part of the common bile duct between the cystic duct junction and the confluence of the right and left hepatic ducts at the liver hilus are called Klatskin tumors.

These tumors are notable for their slow-growing behavior, marked sclerosing characteristics, and the infrequent occurrence of distal metastases.

Front 274

274. What are the clinical features of extrahepatic bile duct CA?

Back 274

Jaundice, often preceded by decolorization of the stools, nausea, and vomiting and weight loss.

Hepatomegaly is present in about 50% and a palpable gallbladder is present in 25%.

Associated changes are elevated levels of serum ALKPHOS and aminotransferases and bile-stained urine.

Mean survival times range from 6-18 mos.

Front 275

275. What is a common concern following laparoscopic cholecystectomy?

Back 275

Biliary stricture most commonly follows operative trauma, involving iatrogenic injury to the biliary tree or the feeding vasculature.

Structures of the common hepatic duct proximal to the cystic ducts are usually malignant.

Front 276

276. What is the composition of gram-positive bacteria?

Back 276

In Gram-positive bacteria, the cell wall is composed of a thick layer of murein, through which nutrients, waste products, and antibiotics can diffuse. Lipoteichoic acids in the outer leaflet of the cytopasmic membrane intercalate thru the cell wall to the outer surface of Gram-positive bacteria.

The hydrophilic side chains of these molecules are involved in bacterial adherence, feeding, and evasion of the host immune system.

These bacteria appear purple.

Front 277

277. What is the composition of gram-negative bacteria?

Back 277

In gram-negative bacteria, the murein layer is thinner and is surrounded by a second, outer lipid bilayer membrane. Hydrophilic molecules cross this outer membrane through channels, which are formed by a cylindrical arrangement of porins.

Gram-negative bacterial also have LPS in the outer membrane, which is a major antigen for the immune response to Gram-negative organisms.

These bacteria appear pink.

Front 278

278. What is the main difference between Gram-negative bacteria and mycobacteria?

Back 278

Both mycobacteria and Gram-negative bacteria are encolsed by an inner membrane, a murein layer, and an outer membrane.

The main structural different is that in mycobacteria, the two leaflets of the outer membrane are asymmetric in size and composition; the inner leaflet of the outer membrane is composed of arabinogalactan and mycolic acids, whereas the outer leaflet is composed of extractable phospholipids.

Front 279

279. What are the four inhibitors of murein monomer synthesis?

Back 279

1. Fosfomycin
2. Fosmidomycin
3. Cycloserine
4. Bacitracin

Front 280

280. Fosfomycin

Back 280

MOA: Inhibits murein monomers. It is a PEP analogue that inhibits bacterial enol pyruvate transferase by covalent modification of the enzyme's active site. It enters the cells via G-6-P that are normally used by bacteria

Purpose: Gram-negative urinary tract infections: E. coli, Klebsiella, Serratia, Clostridia. ***It is excreted unchanged in the urine***

ADVERSE: Headache, diarrhea, nausea

CONTRA: Hypersensitivity

Front 281

281. Therapeutic considerations for fosfomycin

Back 281

1. Synergistic with beta-lactams, aminoglycosides, and fluoroquinolones
2. Decreased absorption when coadministered with antacids or motility agents such as metoclopramide
3. Less effective against Gram-positive bacteria b/c these bacteria generally lack selective glycerophosphate and G6P transporters.

Front 282

282. Fosmidomycin

Back 282

Fosmidomycin, another PEP analogue, acts by the same mechanism as fosfomycin, and resistance typically arises via mutations in glycerophosphate or G6P transports.

Fosmidomycin also has activity against malaria, but the drug has a different MOA and is not currently in clinical use for that organism.

Front 283

283. Cycloserine

Back 283

MOA: Cycloserine is a structural analogue of D-Ala; it irreversibly inhibits both the alanine racemase and the synthetase that joins together two D-Ala molecules.

PURPOSE: Multidrug resistant tuberculosis infection and M. avium complex

ADVERSE: Seizures, somnolence, peripheral neuropathy, psychosis

CONTRA: Epilepsy, depression, anxiety, psychosis, severe renal insufficiency, alcohol abuse

Front 284

284. Cycloserine therapeutic considerations

Back 284

1. Alcohol, isoniazid, and eithionamide potentiate cycloserine toxicity
2. Pyridoxine may prevent cycloserine-induced peripheral neuropathy
3. Cycloserine inhibits hepatic metabolism of phenytoin

Front 285

285. Bacitracin

Back 285

MOA: Peptide antibiotic that inhibits dephosphorylation by forming a complex with bactoprenol pyrophosphate, rendering this lipid carrier useless for further rounds of murein monomer translocation.

PURPOSE: Cutaneous and eye infections (topical), GI decontamination of C. difficile or VRE (oral)

ADVERSE: If systemic absorption occurs: nephrotoxicity, neurotoxicity, bone marrow suppression; With topical: contact dermatitis, blurred vision, red eye

CONTRA: Coadministration with nephrotoxic agents or neuromuscular blocking agents.

NOTE: Drugs that act as metal chelators could interfere with the activity of bacitracin.

Front 286

286. What are the two inhibitors of murein polymer synthesis?

How do they work?

Back 286

Vancomycin and teicoplanin are glycopeptides with bactericidal activity against Gram-positive rods and cocci.

These agents interrupt cell wall syntehsis by binding tightly to the D-Ala D-Ala terminus of the murein monomer unit, inhibiting transglycosidase and thereby blocking the addition of murein units.

Front 287

287. Vancomycin and teicoplanin

Back 287

MOA: Interrupts cell wall syntehsis by binding tightly to the D-Ala D-Ala terminus of the murein monomer unit, inhibiting transglycosidase and thereby blocking the addition of murein units.

PURPOSE: MRSA (IV), and C. difficile enterocolitis (oral)

ADVERSE: Neurtropenia, ototoxicity, nephrotoxicity, anaphylaxis, *Red man syndrome*

CONTRA: Solutions containing dextrose in patients with known corn allergy

Front 288

288. Vancomycin and teicoplanin therapeutic considerations

Back 288

1. Increased nephrotoxicity w/aminoglycosides
2. Red man syndrome can be avoided by slowing infusion rate or pre-administering antihistamines
3. Resistance occurs thru acquisition of DNA encoding enzymes that catalyze formation of D-Ala D-lactate
4. Teicoplanin is not used clinically in the US.

Front 289

289. What is the "red man syndrome"?

Back 289

Skin flushing or rash caused by fast infusion rates of vancomycin.

Other adverse effects of vancomycin are drug fever, hypersensitivity rash, and anaphylaxis.

These can be prevented by slowing the rate of infusion and by giving antihistamines prophylactically.

Front 290

290. What are the four families of β-lactam agents?

Back 290

1. Penicillins
2. Cephalosporins
3. Monobactams
4. Carbapenems

Front 291

291. What are the two factors that determine a β-lactam's spectrum of action?

Back 291

1. The degree to which it can penetrate the outer membrane and cell wall
2. Its ability to bind to specific transpeptidases once in the periplasmic space.

Front 292

292. What are the broad spectrum β-lactams?

Back 292

Hydrophilic agents such as ampicillin, amoxicillin, and especially, piperacillin, ticarcillin, carbenicillin, and mezolocillin tend to have broader spectrum of action.

Front 293

293. What are the narrow spectrum β-lactams?

Back 293

Hydrophobic agents such as oxacillin, cloxacillin, dicloxacillin, nafcillin, methicillin, and penicillin G tend to have narrow spectrum of action.

Front 294

294. Penicillin G and V

Back 294

MOA: β-lactams inhibit transpeptidase by forming a covalent dead-end acyle enzyme intermediate (Suicide substrate inhibition). Penicillins have a 5-membered accessory ring attached to the β-lactam ring.

PURPOSE: Penicllin-sensitive S. aureus and S. pyogenes, rogal anaerobes, N. meningitidis, Clostridia species; Syphilis, Yaws, Leptospirosis. Prophylaxis of rheumatic fever (penicillin V)

ADVERSE: Seizures, pseudomembranous enterocolitis, drug-induced eosinophilia, hemolytic anemia, acute interstitial nephritis, anaphylaxis, rash, fever, injection site reaction, Jarisch Herxheimer reaction when used to treat syphilis.

CONTRA: Hypersensitivity to penicillins

Front 295

295. Penicillin G and V notes

Back 295

1. Penicillin G is the IV preparation; Penicillin V is the oral preparation
2. Anticoagulant effects of warfarin may be potentiated by concomitant penicillin administration
3. IV penicillin G is preferred to oral penicillin V in hospital settings
4. *β-lactamase sensitive

Front 296

296. What are the common uses for penicillin V?

Back 296

Used mostly to treat mixed aerobic-anaerobic infections of the head and neck, such as dental abscesses.

Additionally, it is used to prevent recurrent rheumatic fever and recurrent streptococcal cellulitis in patients with lymphedema.

Front 297

297. What are the five antistaphylococcal penicillins?

Back 297

1. Oxacillin
2. Cloxacillin
3. Dicloxacillin
4. Nafcillin
5. Methicillin

Front 298

298. Oxacillin, Cloxacillin, Dicloxacillin, Nafcillin, Methicillin

Back 298

MOA: β-lactams inhibit transpeptidase by forming a covalent dead-end acyle enzyme intermediate (Suicide substrate inhibition). Penicillins have a 5-membered accessory ring attached to the β-lactam ring.

PURPOSE: Skin and soft-tissue infections or systemic infection with β-lactamase producing MRSA

ADVERSE: Diarrhea, nausea, vomiting, pseudomembranous colitis (cloxacilling, dicloxacillin), Hepatitis (oxacilling) interstitial nephritis, phlebitis (nafcillin)

CONTRA: Hypersensitivity

NOTES: *β-lactamase resistant! These agents are narrow spectrum.

Front 299

299. What are the names of the four amino penicillins?

Back 299

1. Ampicillin
2. Amoxicillin
3. Amoxicillin/clavulanic acid
4. Ampicillin/sulbactam

These agents have a positively charged amino group on the side chain which enhances diffusion through porin channels but does not confer resistance to β-lactamases.

Front 300

300. What are the uses for IV ampicillin?

Back 300

Invasive enterococcal infections and Listeria meningitis

Front 301

301. What are the uses for oral amoxicillin?

Back 301

Uncomplicated ear nose and throat infections, endocarditis prevention, dental surgery prophylaxis, and component of combination therapy for H pylori infection.

Front 302

302. Adverse, contra, and notes for the amino penicillins

Back 302

ADVERSE: Rash, anusea, vomiting, diarrhea

CONTRA: Hypersensitivity

NOTES:
1. Broad spectrum anti-bacteria activity
2. Ampicillin and amoxicillin are beta-lactamase sensitive as single agents; clavulanic acid and sulbactam are beta-lactamase inhibitors
3. Positively charged amino group on side chain enhances diffusion thru porin channels of Gram-negative bacteria

Front 303

303. What are the two carboxy penicillins?

Back 303

1. Carbenicillin
2. Ticarcillin

These agents are broad spectrum antibiotics that have a side chain carboxyl group that provides a negative charge which confers some resistance to some β-lactamases

Front 304

304. What are the two ureido penicillins?

Back 304

1. Piperacillin
2. Mezlocillin

These drugs have both positive and negative charges on their side chains and are generally more potent than the carboxy penicillins.

Their spectrum of action is similar to that of carboxy penicillins; in addition, they have activity against Klebsiella and enterococci

Front 305

305. Carbenicillin, ticarcillin, piperacillin, mezlocillin

Back 305

PURPOSE: Primarily used as treatment or prophylaxis against P. aeruginosa infection; Hospital acquired pneumonia due to resistant Gram-negative organisms

ADVERSE: Rash, nausea, vomiting, diarrhea

CONTRA: Hypersensitivity to penicillins

NOTES: Broad spectrum activity but primarily used against P. aeruginosa. Generally beta-lactamase sensitive except for carbenicillin and ticarcillin

Front 306

306. What are the cepholsporins?

Back 306

Cephalosporins differ structurally from penicillins by having a six-membered ring rather than a five membered ring attached to the β-lactam ring.

Front 307

307. First generation cephalosporins:

Cefazolin & cephalexin

Back 307

MOA: β-lactams inhibit transpeptidase by forming a dead-end acyl enzyme intermediate; relatively good Gram-positive coverage; sensitive to many β-lactamases

PURPOSE: Proteus mirabilis, E. coli, Klebsiella pneumoniae, Skin and soft tissue infections, surgical prophylaxis

ADVERSE: Psuedomembranous enterocolitis, leukopenia, thrombocytopenia, hepatotoxicity, nausea, vomiting, rash, diarrhea

CONTRA: Hypersensitivity to cephalosporins (rarely cross-react w/penicillins)

Front 308

308. Second generation cephalosporins:

Cefuroxime, cefotetan, cefoxitin

Back 308

MOA: β-lactams inhibit transpeptidase by forming a dead-end acyl enzyme intermediate; relatively broader Gram-negative coverage than first gen; more resistant to β-lactamases than first gen

PURPOSE: H. influenzae (cefuroxime), Enterobacter spp., Neisseria spp., P. mirabilis, E. coli, K. pneumoniae (cefotetan and cefoxitin)

ADVERSE: Psuedomembranous enterocolitis, leukopenia, thrombocytopenia, hepatotoxicity, nausea, vomiting, rash, diarrhea, **Cefotetan may produce disulfiram-like reaction w/alcohol ingestion and block synthesis of vitamin K-dependent coagulation factors

CONTRA: Hypersensitivity to cephalosporins (rarely cross-react w/penicillins)

Front 309

309. Common uses for cefuroxime, cefotetan and cefoxitin?

Back 309

Cefuroxime is primarily used in community acquired pneumonia

Cefotetan and cefoxitin are primarily used in intra-abdominal and pelvic infections.

Front 310

310. Third generation cephalosporins:

Cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime

Back 310

MOA: β-lactams inhibit transpeptidase by forming a dead-end acyl enzyme intermediate; *Highest CNS penetration of the cephalosporins.

PURPOSE: N. gonorrhoeae, Borrelia burgdorferi, H. influenza, most Enterobacteriaceae (ceftriaxone), H. influenzae (cefotaxime), P. aeruginosa (ceftazidime).

ADVERSE: Psuedomembranous enterocolitis, leukopenia, thrombocytopenia, hepatotoxicity, nausea, vomiting, rash, diarrhea, **Ceftriaxone may cause cholestatic hepatitis, and cefoperazone may produce disulfiram-like reaction w/alcohol ingestion and block synthesis of vitamin K-dependent coagulation factors

CONTRA: Hypersensitivity to cephalosporins (rarely cross-react w/penicillins)

NOTE: Resistant to many β-lactamases; highly active against Enterobacteriaceae, but less active against Gram-positive organisms than are first gen cephalosporins

Front 311

311. Fourth generation cephalosporin:

Cefepime

Back 311

MOA: β-lactams inhibit transpeptidase by forming a dead-end acyl enzyme intermediate; *resistant to many beta-lactamases

PURPOSE: Enterobacteriaceae, Neisseria, H. influenzae, P. aeruginosa, Gram-positive organisms

ADVERSE: Psuedomembranous enterocolitis, leukopenia, thrombocytopenia, hepatotoxicity, nausea, vomiting, rash, diarrhea, **Cefepime may produce erythrocyte autoantibodies w/o significant hemolysis

CONTRA: Hypersensitivity to cephalosporins (rarely cross-react w/penicillins)

Front 312

312. What are the inhibitors of polymer crosslinking?

Back 312

1. Aztreonam
2. Imipenem/cilastatin
3. Meropenem
4. Ertapenem

Front 313

313. Aztreonam

Back 313

MOA: A monobactam that inhibits transpeptidase by forming a dead-end acyl enzyme intermediate

PURPOSE: Gram-negative bacteria; *used in penicillin allergic patients*

ADVERSE: Same as penicillins

NOTES: No Gram-positive coverage

Front 314

314. Imipenem/cilastatin, Meropenem, Ertapenem

Back 314

MOA: A carbapenem that inhibits transpeptidase by forming a dead-end acyl enzyme intermediate

PURPOSE: Gram-positive and Gram-negative bacteria except MRSA, VRE, and Legionella

ADVERSE: same as penicillins, except *High plasma levels of imipenem and meropenem may cause seizures

Front 315

315. Carbapenem notes

Back 315

NOTES:
1. Cilastin inhibits renal dehydropeptidase I, which would otherwise inactivate imipenem
2. Probenecid may increase meropenem levels
3. All three agents decrease valproate levels
4. Ertapenem can be give one-daily.

Front 316

316. What are the three antimicrobial agents?

Back 316

1. Ethambutol
2. Pyrazinamide
3. Isoniazid (INH)

Front 317

317. Ethambutol

Back 317

MOA: Inhibits the arabinosyl transferase that adds arabinose units to the growing arabinogalactan chain and thus decreases arabinogalactan synthesis.

PURPOSE: Mycobacteriostatic, and used in combo with other antimycobacterials, including rifampin and streptomycin

ADVERSE: Optic neuritis, blindness, peripheral neuropathy, neutropenia, thrombocytopenia, hyperuricemia, mania, nausea, vomiting

CONTRA: Known optic neuritis, patients unable to report visual changes such as young children, *Coadministration with antacids

Front 318

318. Pyrazinamide

Back 318

MOA: Pyrazinamide is a prodrug that must be converted to its active form pyrazinoic acid, which inhibits fatty acid synthestase 1 (FAS1) and thus inhibits mycolic acid synthesis.

PURPOSE: Mycobacterium species; used in combo w/rifampin and streptomycin

ADVERSE: Anemia, hepatotoxicity, arthralgias, hyperuricemia (usually asymptomatic)

CONTRA: Acute gout, severe hepatic dysfunction

Front 319

319. Isoniazid and ethionamide

Back 319

MOA: Targets the FAS2 complex and thus inhibits mycolic acid synthesis.

PURPOSE: Mycobacterium species, and is used in combo with other antimycobacterials

ADVERSE: Hepatitis, *neurotoxicity (paresthesias, peripheral neuropathy, ataxia), SLE, seizure, hematologic abnormalities

CONTRA: Acute liver disease

NOTES: Can inhibit or induce p450 enzymes and thus interacts w/other drugs such as rifampin, antiseizure meds, antifungals, and alcohol; *INH neurotoxicity can be prevented by pyridoxine supplementation

Front 320

320. How does resistance to INH occur?

Back 320

Resistance to INH results from an inactivating mutation in the mycobacterial enzyme catalase-peroxidase, which converts INH to ints antimycobacterial form. Mutations in the INHA gene, which is required for mycolic acid synthesis, also confer resistance to INH.

Front 321

321. How does resistance to ethambutol occur?

Back 321

Results from mutations in the arabinosyl transferase gene, some of which cause overexpression of the target enzyme

Front 322

322. How does resistance to pyrazinamide occur?

Back 322

Due to mutations in the pyrazinamidase gene, which result in the inability to convert the prodrug into its active form.