Pbl Exam 7 Case 4

Front 1

1. Composition of the adrenal glands

Back 1

1. Adrenal medulla
-secretes epinephrine and norepinephrine

2. Adrenal cortex
-secretes corticosteroids

Front 2

2. Mineralocorticoids

Back 2

They specially affect the electrolytes (the "minerals") of the extracellular fluids; sodium and potassium, in particular.

Aldosterone: principal mineralcorticoid

Front 3

3. Glucocorticoids

Back 3

They exhibit important effects that increase blood glucose concentration.

They have additional effects on both protein and fat metabolism that are equally as important to body function as their effects on carbohydrate metabolism.

Cortisol: principal glucocorticoid

Front 4

4. Three layers of the adrenal cortex

Back 4

1. zona glomerulosa
2. zona fasciculata
3. zona reticularis

Front 5

5. Zona glomerulosa

Back 5

Outer layer:
Only layer with cells capable of secreting significant amts of aldosterone b/c they contain the enzyme aldosterone synthase.

Secretion is controlled by angiotensin II and potassium.

Front 6

6. Zona fasciculata

Back 6

Middle and widest layer:
Secretes glucocorticoids cortisol and corticosterone.

Controlled in large part by the HPA axis via ACTH

Front 7

7. Zona reticularis

Back 7

Deep layer:
Secretes the adrenal androgens DHEA and androstenedione.

Also regulated by ACTH, although other factors such as cortical androgen-stimulating hormone from the pituitary may be involved.

Front 8

8. Synthesis of adrenocortical hormones

Back 8

From cholesterol via de novo from small amounts of acetate, and 80% of the cholesterol used for steroid synthesis comes from LDL in the plasma

ACTH stimulates adrenal steroid synthesis but increasing the # of adrenocortical cell receptors for LDL

Once cholesterol enters the cells, it is delivered to the mitochondria where it is cleaved by cholesterol desmolase to form pregnenolone.

Front 9

9. Difference btwn cortisol and aldosterone

Back 9

Cortisol has a keto-oxygen on carbon 3 and is hydroxlated at carbon 11 and 21

Aldosterone has an oxygen atom bound at carbon 18

Front 10

10. Mineralocorticoids

(list them and describe their potencies)

Back 10

1. Aldosterone (very potent)
2. Desoxycorticosterone (1/30 as potent as aldosterone)
3. Corticosteone (slight mineralocorticoid activity)
4. 9α-Fluorocortisol (synthetic, slightly more potent than aldosterone)
5. Cortisol (very slight mineralocorticoid activity)
6. Cortisone (synthetic, slight mineralocorticoid activity)

Front 11

11. Glucocorticoids

(list them and their potency)

Back 11

1. Cortisol (very potent)
2. Corticosterone (way less potent than cortisol)
3. Cortisone (synthetic, almost as potent as cortisol)
4. Prednisone (synthetic, 5x as potent as cortisol
5. Dexamethasone (synthetic, 30x a potent as cortisol)

Front 12

12. Metabolization of adrenocortical hormones

Back 12

Degraded mainly in the liver and conjugated especially to glucuronic acid and to a lesser extent, sulfates.

About 25% are excreted in the bile and then in the feces.

Front 13

13. Functions of aldosterone (3)

Back 13

1. Increases renal tubular Excretion of potassium
2. Increases renal tubular Resorption of sodium and chloride
3. Maintenance of total extracellular fluid volume

*Major mineralocorticoid secreted by the adrenals

Front 14

14. Aldosterone and plasma sodium concentration

Back 14

Although it has a potent effect in decreasing the rate of sodium ion excretion by the kidneys, the concentration of sodium in the extracellular fluid often rises only a few milliequivalents.

This is b/c of the simultaneous osmotic resorption of water in the kidney tubules due to the increased sodium concentration. Also, small increases in sodium concentration stimulates thirst and increased water intake. Thus, the sodium concentration maintained

Front 15

15. Aldosterone and arterial pressure

Back 15

An aldosterone mediated increase in extracellular fluid volume lasting more than 1-2 days leads to an increase in arterial pressure which increases kidney excretion of salt and water, called "pressure natriuresis" and "pressure diuresis", respectively.

Front 16

16. Aldosterone escape

Back 16

The return to normal of salt and water excretion by the kidneys as a result of pressure natriuresis and diuresis.

Front 17

17. Excess aldosterone can cause what two things...?

Back 17

1. Hypokalemia
2. Muscle weakness

Front 18

18. Too little aldosterone can cause what two things...?

Back 18

1. Hyperkalemia
2. Cardiac toxicity

Front 19

19. Hypokalemia

Back 19

When the potassium ion concentration falls below about 2 mEq/L and causes muscle weakness due to the alteration of the electrical excitability of the nerve and muscle fiber membranes which prevents the transmission of normal action potentials.

Front 20

20. Excess aldosterone can also cause...?

Back 20

A mild degree of alkalosis due to the increase in tubular hydrogen ion secretion

Front 21

21. Effect of aldosterone on sweat and salivary glands

Back 21

Both glands form a primary secretion that contains sodium chloride but much of the sodium chloride, on passing thru the excretory ducts, is reabsorbed, while potassium and bicarbonate ions are secreted.

Its effect on the sweat glands is important to conserve body salt in hot environments and the effect on the salivary glands is to conserve salt when excessive quantities of saliva are lost.

Front 22

22. Sodium-potassium adenosine triphosphatase

(what stimulates the activity of this enzyme?)

Back 22

Aldosterone causes an increase in the enzyme sodium-potassium adenosine triphosphatase, which serves as the principal part of the pump for sodium and potassium exchange at the basolateral membranes of the tubular cells.

Front 23

23. Epithelial sodium channel proteins

Back 23

Inserted into the luminal membrane of th esame tubular cells that allows rapid diffusion of the sodium ions from the tubular lumen into the cell; then the sodium is pumped the rest of the way by the sodium-potassium pump.

Front 24

24. Evidence of nongenomic actions of aldosterone

Back 24

Aldosterone has been shown to increase formation of cAMP in vascular smooth muscle cells and in epithelial cells of the renal collecting tubules in less than two minutes.

This time period is far too short for gene transcription and translation of proteins.

Front 25

25. Four factors that play an important role in the regulation of aldosterone

Back 25

1. Increased potassium ion concentration in the extracellular fluid increases aldosterone secretion
2. Increased activity of the renin-angiotensin system also increases aldosterone secretion
3. Increased sodium ion concentration in the extracellular fluid very slightly decreases aldosterone secretion
4. ACTH from the anterior pituitary gland is necessary for aldosterone secretion but has little effect in controlling the rate of secretion

Front 26

26. Activation of the renin-angiotensin system

Back 26

Usually occurs in response to diminished blood flow to the kidneys or to sodium loss

Activation results in a severalfold increase in aldosterone secretion

Front 27

27. What happens when one blocks the formation of angiotensin II

Back 27

Markedly decreases plasma aldosterone concentration without significantly changing cortisol concentration.

This demonstrates the important role of Ang II in stimulating aldosterone secretion during sodium depletion

Front 28

28. Function of glucocorticoids

Back 28

Helps resist different types of physical or mental stress and minor illnesses.

At least 95% of the glucocorticoid activity of the adrenocortical secretions results from the secretion of cortisol, known also as hydocortisone.

Front 29

29. Effects of cortisol on carbohydrate metabolism (3)

Back 29

1. Stimulation of gluconeogenesis
2. Decreased glucose utilization by cells
3. Elevated blood glucose concentration

Front 30

30. How does cortisol stimulate gluconeogenesis? (2 ways)

Back 30

1. Cortisol increases the enzymes required to convert amino acids into glucose in the liver cells.
2. Cortisol causes mobilization of amino acids from the extrahepatic tissues mainly from muscle.

Front 31

31. How does cortisol decrease glucose utilization by cells?

Back 31

Most physiologist believe that glucocorticoids depress the oxidation of NADH to form NAD⁺.

Because NADH must be oxidized to allow glycolysis, the effect could account for the diminished utilization of glucose by the cells.

Front 32

32. How does cortisol cause elevated blood glucose concentration?

What is adrenal diabetes?

Back 32

The increased rate of gluconeogenesis and reduction in the rate of the utilization of glucose by the cells causes the blood glucose to rise.

Sometimes this rise is occasionally great enough that the condition is called adrenal diabetes.

-Insulin lowers the blood glucose concentration only a moderate amount in this case b/c the tissues are resistant to the effects of insulin (due to the glucocorticoids)

Front 33

33. What are three effects of cortisol on protein metabolism?

Back 33

1. Reduction in cellular protein
2. Increases liver and plasma proteins
3. Increased blood AAs, diminishes transport of AAs into extrahepatic cells, and enhances transport into hepatic cells

Front 34

34. What and where is the exception to the reduction in cellular protein with cortisol?

Back 34

In the liver, which may cause:

1. increased rate of deamination of AAs by the liver
2. increased protein synthesis in the liver
3. increased formation of plasma proteins by the liver
4. increased conversion of AAs to glucose (enhanced gluconeogenesis)

Front 35

35. What are two effects of cortisol on fat metabolism?

Back 35

1. Mobilization of fatty acids from adipose tissue and enhances the oxidation of fatty acids in the cells
2. Obesity is caused by excess cortisol

Essentially, the increased mobilization of fats helps shift the metabolic systems of cells to use fatty acids in times of starvation or other stresses instead of glucose

Front 36

36. How is cortisol important in resisting stress and inflammation?

Back 36

Any stress increases ACTH secretion by anterior pituitary gland which causes cortisol secretion.

The rapid mobilization of AAs and fats make them immediately available for energy and for synthesis of other compounds needed by different tissues of the body.

Front 37

37. What are the two main anti-inflammatory effects of cortisol?

Back 37

1. It can block the early stages of the inflammatory process before inflammation even begins

2. If inflammation has already begun, it causes rapid resolution of the inflammation and increased rapidity of healing.

Front 38

38. How does cortisol prevent inflammation?

5 ways...

Back 38

1. It stabilizes the lysosomal membranes which prevent lysosomes from rupturing
2. Decreases the permeability of the capillaries
3. Decreases both migration of white blood cells and phagocytosis
4. Suppresses the immune system, causing lymphocyte reproduction to decrease markedly
5. Attenuates fever mainly b/c it reduces the release of IL-1 from the white blood cells

Front 39

39. How does cortisol resolve inflammation?

Back 39

It blocks most of the factors that promote inflammation and enhances the rate of healing due to the mobilization of AAs and uses these to repair the damaged tissue.

Front 40

40. What are four other effects of cortisol?

Back 40

1. Blocks the inflammatory response to allergic reactions
2. Decreases the number of eosinophils and lymphocytes in the blood
3. Large doses of cortisol causes atrophy of all the lymphoid tissue in the body
4. Increases red blood cell production

Front 41

41. What is ACTH?

Back 41

Controls secretion of cortisol.

Secreted by anterior pituitary gland

It is a large polypeptide w/a chain length of 39 AAs

Front 42

42. How is ACTH release controlled?

Back 42

The corticotropin-releasing factor (CRF) is secreted from the paraventricular nucleus of the hypothalamus and then carried to the anterior pituitary gland where it induces ACTH secretion.

Front 43

43. ACTH and second messengers

What is the rate limiting step for all the adrenocortical hormones?

Back 43

Principal effect of ACTH on adrenocortical cells is the activation of adenylyl cyclase which induces formation of cAMP

Also causes activation of the enzyme protein kinase A, which causes the initial conversion of cholesterol to pregnenolone*

*This is the rate limiting step for all the adrenocortical hormones

Front 44

44. Where does cortisol have negative feedback inhibition? (two places)

Back 44

1. Hypothalamus to decrease the formation of CRF

2. Anterior pituitary gland to decrease the formation of ACTH

*Stress can break through this negative feedback causing excessive cortisol secretion

Front 45

45. Addison's disease

Back 45

Results from a failure of the adrenal cortices to produce adrenocortical hormones and this in turn is most freq caused by primary atrophy of the adrenal cortices

It causes:
1. Mineralocorticoid deficiency
2. Glucocorticoid deficiency
3. Melanin pigmentation
4. Possible "addisonian crisis

Front 46

46. Symptoms of Addison's disease

Back 46

1. Progressive weakness and easy fatigability
2. GI disturbances
3. Loss of appetite
4. Weight loss
5. Hyperpigmentation of skin
6. Hyperkalemia
7. Hypernatremia
8. Volume depletion
9. Hypotension

Front 47

47. Treatment of Addison's disease

Back 47

An untreated person w/total adrenal destruction dies w/in a few days to a few weeks due to weakness and circulatory shock.

Person can live for years if small quantities of mineralocorticoids and glucocorticoids are administered daily

Front 48

48. What is an Addisonian crisis?

Back 48

In a person w/Addison's disease, the output of glucocorticoids does not increase during stress; this person is likely to have an acute need for excessive amounts of glucocorticoids to prevent death.

Front 49

49. What are four things that can cause Cushing's syndrome (hyperadenalism)?

Back 49

Hypersecretion by the adrenal cortex due to:
1. Adenomas of the anterior pituitary gland that secretes large amount of ACTH which causes adrenal hyperplasia
2. Abnormal function of the hypothalamus that causes high levels of CRF which stimulates ACTH release
3. Ectopic secretion of ACTH by a tumor elsewhere in the body
4. Adenomas of the adrenal cortex

Front 50

50. Characteristics of Cushing's syndrome

Back 50

1. *Central obesity (about trunk and upper back)
2. *Moon faces
3. Weakness and fatigability
4. *Hirsutism
5. *Hypertension
6. *Plethora
7. Glucose intolerance/diabetes
8. Osteoporosis
9. Neuropsychiatric abnormalities
10. Menstrual abnormalities
11. *Skin striae

Front 51

51. What is Pituitary Cushing syndrome?

Back 51

The most common form of Cushing's syndrome.

ACTH levels are elevated and cannot be suppressed by the administration of low dose dexamethasone but the pituitary then responds to higher doses of injected dexamethasone.

Front 52

52. Ectopic ACTH Cushing syndrome

Back 52

Results in an elevated ACTH but its secretion is completely insensitive to low or high doses of dexamethasone

Front 53

53. Adrenal tumor Cushing syndrome

Back 53

The ACTH level is quite low b/c of feedback inhibition of the pituitary.

Both low and high does dexamethasone fail to suppress cortisol excretion

Front 54

54. Cushing syndrome effects on carbohydrate and protein metabolism

Back 54

Abudance of cortisol can caused increased blood glucose concentration and high levels of glucocorticoids cause protein catabolism which results in severe weakenss.

Front 55

55. Treatment of Cushing syndrome

Back 55

Consists of removing an adrenal tumor if this is the cause or decreasing the secretion of ACTH if this is possible.

If ACTH secretion cannot easily be decreased, the only satisfactory treatment is usually bilateral partial or total adrenalectomy.

Front 56

56. What is Conn's syndrome (Primary Aldosteronism)?

Back 56

An autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system.

It results in:
1. Hypokalemia
2. Increase in extracellular fluid volume and blood volume
3. Almost always, hypertension
4. Occasional periods of paralysis caused by hypokalemia.

Front 57

57. What are three causes of primary aldosteronism?

Back 57

1. Adrenocortical neoplasm that produces large amounts of aldosterone
2. Primary adrenocortical hyperplasia
3. Glucocorticoid--remediable hyperaldosteronism which leads to a sustained production of hybrid steroids in addition to both cortisol and aldosterone.

Front 58

58. Dx criteria of primary aldosteronism

Back 58

Decreased plasma renin concentration

Front 59

59. Treatment of primary aldosteronism

Back 59

Surgical removal of the tumor or most of the adrenal tissue when hyperplasia is the cause.

Front 60

60. Androgenital syndrome

Back 60

Due to an excessive quantity of androgens that cause intense masculinizing effects throughout the body.

The excretion of 17-ketosteroids in the urine are 10 to 15x normal which is the useful in the diagnosis of this disease.

Front 61

61. What is the rate-limiting step in the synthesis of cortisol?

Back 61

The conversion of cholesterol to pregnenolone

Front 62

62. What oxidase enzyme catalyzes each step in the pathway of adrenocortical hormone synthesis?

Back 62

Mitochondrial cytochromes; similar to the liver P450 oxidase system.

Front 63

63. Why does the zona fasciculata synthesize cortisol, but not aldosterone or androgens?

Back 63

The enzymes required for cortisol synthesis, such as steroid 11β-hydroxylase, are expressed in the zona fasciculata, whereas enzymes required for aldosterone and androgen synthesis are not.

Front 64

64. What are the most important plasma proteins that binds cortisol?

Back 64

Corticosteroid-binding globulin (CBG) and albumin

CBG has a high affinity for cortisol but low overall capacity, whereas albumin has low cortisol affinity but high overall capacity

Front 65

65. Where are the two primary sites of peripheral cortisol metabolism?

Back 65

1. Liver
2. Kidneys

Front 66

66. What are type I vs. type II glucocorticoid receptors

Back 66

Mineralocorticoid receptors

Expressed in the organs of excretion (kidney, colon, salivary glands, sweat glands)

Type II receptors, on the other hand, have a broader tissue distribution

Front 67

67. Regulation of cortisol production

Back 67

1. Neurons from the hypothalamus secrete CRH
2. CRH binds to the G-protein receptors on the anterior pituitary gland
3. CRH binding stimulates production of proopiomelanocortin (POMC)
4. Cleavage of POMC yields ACTH and melanocyte stimulating hormone (MSH)
5. ACTH promotes synthesis of cortisol
6. High cortisol levels decrease synthesis and release of CRH and ACTH

Front 68

68. Why is tapering to a lower dosage of exogenous glucocorticoids necessary?

Back 68

If not tapered, can result in secondary adrenal insufficiency

Necessary to allow the HPA axis to regain full activity.

Exogenous glucocorticoids cause atrophy of the adrenal cortex

Front 69

69. Cortisol analogues (four of them)

Back 69

1. Prednisone
2. Prednisolone
3. Fludrocortison
4. Dexamethasone

Front 70

70. Glucocorticoid receptor agonists

Back 70

Mimic cortisol function by acting as agonists at the glucocorticoid receptor

1. Prednisone
2. Prednisolone
3. Methyprednisolone
4. Dexamethasone
5. Hydrocortisone
6. Fluticasone
7. Beclomethasone
8. Flunisolide
9. Triamcinolone
10. Budesonide

Front 71

71. Clinical application of glucocorticoid receptor agonists

(3)

Back 71

1. Inflammatory conditions in many different organs

2. Autoimmune diseases

3. Replacement therapy for primary and secondary adrenal insufficiency

Front 72

72. Adverse effects of glucocorticoid receptor agonists

Back 72

1. Immunosuppression
2. Hyperglycemia
3. Hypercortisolism
4. Impaired wound healing
5. Hypertension
6. Fluid retention
7. Inhaled oropharyngeal candidiasis

Front 73

73. 177. Contraindications of glucocorticoid receptor agonists

Back 73

Systemic fungal infection

Front 74

74. 178. Inhaled glucocorticoids

Back 74

1. Fluticasone
2. Beclomethasone
3. Flunisolide
4. Triamcinolone
5. Budesonide

*Inhaled formulations greatly reduce systemic adverse effects; do not switch abruptly from high-dose oral to inhaled glucocorticoids

Front 75

75. Glucocorticoid receptor antagonists

Back 75

Competitive antagonist of cortisol action at the glucocorticoid receptor

Mifepristone (RU-486)

Front 76

76. Clinical application of glucocorticoid receptor antagonists (Mifepristone)

Common adverse effects?

Back 76

Causes abortion (through day 49 of pregnancy)

Also, at high doses, it could potentially be useful in the treatment of ectopic ACTH syndrome

Can result in prolonged bleeding time, bacterial infections, sepsis, nausea, vomiting, diarrhea, cramps, vaginal bleeding, headache

Front 77

77. Contraindications of glucocorticoid receptor antagonists (Mifepristone)?

Back 77

1. Chronic adrenal failure
2. Ectopic pregnancy
3. Hemorrhagic disorders
4. Anticoagulation theraphy
5. Intrauterine devices

Front 78

78. Inhibitors of glucocorticoid synthesis

Back 78

Inhibits various steps in the glucocorticoid hormone biosynthesis

Includes:
1. Mitotane
2. Aminoglutethimide
3. Metyrapone
4. Trilostane
5. Ketoconazole

Front 79

79. Mitotane

Back 79

MOA: Structural analogue to DDT that is toxic to adrenocortical mitochondria

PURPOSE: Used in medical adrenalectomy in cases of severe Cushing syndrome or adrenocortical CA

ADVERSE: Can cause visual disturbances, and hemorrhagic cystitis Also can cause hypercholesterolemia

CONTRA: Live rotavirus vaccine

Front 80

80. Aminoglutethimide

Back 80

MOA: Inhibits side chain cleavage enzyme as well as aromatase, which is important for conversion of androgens to estrogens

PURPOSE: Used to treat Cushing's syndrome

ADVERSE: Cortisol insufficiency, agranulocytosis, leukopenia, neutropenia, pancytopenia, pruritus, hypotension.

CONTRA: hypersensitivity to glutethimide or aminoglutethimide

Front 81

81. Metyrapone

Back 81

MOA: Inhibits 11β-hydroxylation, resulting in impaired cortisol synthesis

PURPOSE: Used for Dx evaluation of HPA axis and in Cushing's syndrome

ADVERSE: Can cause cortisol insufficiency and hypertension

CONTRA: Adrenal cortical insufficiency

Can also result in disinhibition of ACTH secretion

Front 82

82. Trilostane

Back 82

MOA: Reversible inhibitor of 3β-hydroxysteroid dehydrogenase, which reduces aldosterone and cortisol production in the adrenal cortex

PURPOSE: Used in Cushing's syndrome and aldosteronism

ADVERSE: Can cause an Addisonian crisis, postural hypotension, hypoglycemia

CONTRA: Adrenal cortical insufficiency, and renal or hepatic dysfunction

Front 83

83. Mineralocorticoid receptor agonists

Back 83

Agonist at the mineralocorticoid receptor

Fludrocortisone

Front 84

84. Fludrocortisone

Back 84

PURPOSE: Used in hypoaldosteronism

ADVERSE: Can cause hypertension, hypokalemia, heart failure, thrombophlebitis, secondary hypocortisolism, edema, rash, hyperglycemia

CONTRA: systemic fungal infection

NOTES: Adverse effects are related to its ability to mimic a state of mineralocorticoid excess

Front 85

85. Mineralocorticoid receptor antagonists

Back 85

Competetive antagonist of aldosterone action at the mineralocorticoid receptor

Includes:
1. Spironolactone
2. Eplerenone

Front 86

86. Adrenal sex steroid (DHEA)

Back 86

MOA: DHEA is a prohormone that is converted to testosterone in the periphery

PURPOSE: Used in hypoaldosteronism and in chronic fatigue syndrome

ADVERSE: Can cause acne, hepatitis, hirsutism, androgenization

CONTRA: Breast, ovarian or prostate CA

NOTES: May be used as replacement therapy for cases of Addison's disease w/documented DHEA deficiency.

Front 87

87. What is a key regulatory point in human sterol metabolism?

Back 87

Cholesterol absorption by intestinal cells b/c it ultimately determines what percentage of the 1,000 mg of biliary cholesterol produced by the liver each day and what percentage of the 300 mg of dietary cholesterol entering the gut per day is eventually absorbed into the blood.

In normal people, approx 55% of this intestinal pool enters the blood through the enterocyte each day.

Front 88

88. What is the mechanism that removes unwanted or excessive cholesterol and plant sterols from the enterocyte?

Back 88

The transport of sterols out of the enterocyte and into the gut lumen is related to the products of genes that code for the ATP binding cassette (ABC) protein family, ABC1, ABCG5, and AGCG8.

These proteins couple ATP hydrolysis to the transport of unwanted or excessive cholesterol and plant sterols from the enterocyte back into the gut lumen.

Front 89

89. How is cholesterol eliminated from the body?

Back 89

It cannot be metabolized to CO2 and water and is therefore eliminated from the body principally in the feces as unabsorbed sterols and bile acids.

Front 90

90. ABC proteins

Back 90

Their expression increases the amount of sterols present in the gut lumen, with the potential to increase elimination of the sterols into the feces.

Front 91

91. Phytosterolemia

Back 91

Rare autosomal disease AKA sitosterolemia

A defect in the function of either ABCG5 or ABCG8 occurs in the enterocytes, which leads to accumulation of cholesterol and phytosterols within these cells.

They eventually reach the bloodstream, markedly elevating the level of cholesterols in the blood.

This accounts for the increased cardiovascular morbidity in individuals with this disorder.

Front 92

92. Cholesterol structure

Back 92

It is an alicyclic compound whose basic structure includes the perhydrocyclopentanophenanthrene nucleus containing four fused rings.

In its free form, the cholesterol molecule contains 27 C's, a simple hydroxyl group at C3, a double bond between C5 and C6, an eight membered hydrocarbon chain attached to C17 in the D ring, a methyl group attached to C10, and a second methyl group (C18) attached to C13)

Front 93

93. About how much of the plasma cholesterol exists in the free or unesterified form?

Back 93

Approx 1/3 of the plasma cholesterol exists in the free or unesterified form

The reamining 2/3's exist as cholesterol esters.

Front 94

94. What can be inferred from cholesterol's structure?

Back 94

The structure suggests that its synthesis involves multimolecular interactions and significant reducing power.

All 27 C's are derived from one precursor, acetyl CoA.

Front 95

95. Where does the reducing power of cholesterol synthesis come from?

Back 95

NADPH provided by the G6PD of the hexose monophosphate shunt pathway.

Front 96

96. Where does cholesterol synthesis occur, and what does it require?

Back 96

Occurs in the cytosol

Requires hydrolysis of high energy thioester bonds of acetyl CoA and phosphoanhydride bonds of ATP.

Front 97

97. What are the four stages of cholesterol synthesis?

Back 97

1. Synthesis of mevalonate from acetyl CoA

2. Conversion of mevalonate to two activated isoprenes

3. Condensation of six activated 5-carbon isoprenes to form the 30-carbon squalene

4. Conversion of squalene to the four-ring steroid nucleus

Front 98

98. Stage 1 part 1 of cholesterol synthesis

What is significant about this stage?

Back 98

The synthesis of mevalonate is the committed, rate-limiting step in cholesterol formation.

Two molecuels of acetyle CoA condense, forming acetoacetyl CoA, which then condenses w/a third molecule of acetyl CoA to yield the 6-carbon β-hydroxy-β-methylglutaryl-CoA (HMG-CoA).

Front 99

99. Stage 1 part 2 of cholesterol synthesis

What is significant about this stage?

Back 99

The committed step and major point of regulation of cholesterol synthesis in stage 1 involves reduction of HMG-CoA to mevalonate, which is catalyzed by HMG-CoA reductase.

The reducing equivalents for this reaction are donated by two molecules of NADPH

Front 100

100. HMG-CoA reductase

Back 100

An enzyme that is embedded in the membrane of the ER

Contains eight membrane-spanning domains, and the amino-terminal domain, which faces the cytoplasm, contains the enzymatic activity.

Front 101

101. How is the rate of synthesis of HMG-CoA reductase mRNA controlled?

Back 101

The rate of synthesis of HMG-CoA reductase mRNA is controlled by one of the family of sterol-regulatory element binding proteins (SREBPs)

Front 102

102. SREBPs

Back 102

These transcription factors belong to the helix-loop-helix-leucine zipper family of transcripton factors.

They specifically enhance transcription of the HMG-CoA reductase gene by binding to the sterol-regulatory element (SRE) upstream of the gene, which increases the rate of transcription.

Front 103

103. SCAP and regulation of transcription of the reductase gene

Back 103

SREBPs, after synthesis, are integral proteins of the ER.

The SREBP is bound to SCAP (SREBP cleavage activating protein) in the ER membrane when cholesterol levels are high.

When cholesterol levels drop, the sterol leaves its SCAP binding site, and the SREBP:SCAP complex is transported to the golgi apparatus

When sterol levels rise, the sterols bind to SCAP and prevent translocation of the complex to the golgi, leading to a decrease in transcription of the reductase gene

Front 104

104. Proteolytic degradation of HMG-CoA reductase

Back 104

Rising levels of cholesterol and bile salts in the cells that synthesize these molecules also may cause a change in the oligomerization state of the membrane domain of HMG-CoA reductase, rendering the enzyme more susceptible to proteolysis which decreases its activity.

Front 105

105. How else is the activity of HMG-CoA regulated?

Five specific influences...

Back 105

Also regulated by phosphorylation and dephosphorylation

1. Elevated glucagon levels increase phosphorylation of the enzyme, thereby deactivating it.
2. Hyperinsulinemia increases the activity of the reductase by activating phophatases, which dephosphorylate the reductase.
3. Increased levels of intracellular sterols also may increase phosphorylation
4. Thyroid hormone increases enzyme activity
5. Glucocorticoids decrease its activity

Front 106

106. Cholesterol synthesis and ATP levels

Back 106

When ATP levels are low, cholesterol synthesis decreases

When ATP levels are high, it increases.

Front 107

107. Stage 2

What are the two main products formed at the end of this stage?

Back 107

Three phosphate groups are transferred from three moles of ATP to mevalonate.

The purpose of the phosphate transfers is to activate both C5 and the hydroxyl group on C3 for further reactions.

First product is an activated isoprene called ∆3-isopentyl pyrophosphate

Second activated isoprene product is formed when ∆3-isopentyl pyrophosphate is isomerized to dimethylallyl pyrophosphate

Front 108

108. Stage 3

What is the end product of this stage?

Back 108

Involves the head-to-tail condensation of isopentenylpyrophosphate and dimethylallyl pyrophosphate to produce geranyl pyrophosphate

This product then undergoes another head-to-tail condensation resulting in farnesyl pyrophosphate.

Afterwards, two moles of this farnesyl undergo a head to head fusion and then both pyrophosphate groups are removed to form squalene.

Front 109

109. Squalene

Back 109

End product of stage 3

Contains 30 carbons (24 in the main chain and 6 in the methyl group branches)

Front 110

110. Stage 4

Back 110

Enzyme squalene monooxygenase added a single oxygen atom from O2 to the end of the squalene molecule, forming an epoxide.

NADPH then reduces the other oxygen atom of O2 to H2O.

The epoxide undergoes cyclization to form lanosterol, a sterol w/the four ring structure.

Many subsequent reactions then lead to cholesterol from lanosterol.

Front 111

111. Where does most of the production of cholesterol occur?

Where else does it occur?

Back 111

Liver cells

Also occurs in the gut, adrenal cortex, and the gonads (as well as the placenta in pregnant women)

Front 112

112. The bulk of synthesized cholesterol is secreted from the hepatocyte as one of what three moieties?

Back 112

1. Cholesterol esters
2. Biliary cholesterol
3. Bile acids

Front 113

113. ACAT (acyl-CoA-cholesterol acyl transferase)

Back 113

Catalyzes cholesterol ester production in the liver.

Catalyzes the transfer of a FA from CoA to the hydroxyl group on C3 of cholesterol.

Front 114

114. Low vs. high cholesterol diets and their effects on cholesterol synthesis in the liver

Back 114

Low: the liver synthesizes approx 800 mg cholesterol per day to replace bile salts and cholesterol lost in the feces

High: Suppresses the rate of hepatic cholesterol synthesis (feedback repression)

Front 115

115. Bile salt synthesis reactions

Back 115

Bile salts are synthesized in the liver from cholesterol by reactions that hydroxylate the steroid nucleus and cleave the side chain.

Front 116

116. Bile salt synthesis (First step)

What can inhibit this step?

Back 116

The first and rate-limiting reaction occurs when a α-hydroxyl group is added to C7.

The activity of the 7α-hydroxylase that catalyzes this step is decreased by an increase in bile salt concentration

Front 117

117. Bile salt synthesis (formation of two sets of bile salts)

Back 117

Two sets of compounds are produced;

One has α-hydroxyl groups at postions 3, 7, and 12 and produces the cholic acid series of bile salts

The other set has α-hydroxyl groups only at positions 3 and 7 and produces the chenocholic acid series.

Front 118

118. pKa of bile acids

Back 118

pKa = 6

In the intestinal lumen, which normally has a pH of 6, approx 50% of the molecules present are protonated and 50% are ionized, which form bile salts.

Front 119

119. Conjugation of bile salts

Back 119

The carboxyl group at the end of the side chain of the bile salts is activated by a reaction that requires ATP and CoA.

The CoA derivatives can react w/either glycine or taurine, forming amides that are known as conjugated bile salts.

Glycocholic acid and glycochenocholic acid are formed when salts conjugate w/glycine

Taurocholic acid and taurochenocholic acid are formed when salts conjugate w/glycine

Front 120

120. Glycine vs. taurine conjugation

How does this affect ionization?

Back 120

Glycocholic acid and glycochenocholic acid have a pKa of 4

Taurocholic acid and taurochenocholic acid have a pKa of 2

Therefore, compared w/glycoconjugates, an even greater percentage of the tauroconjugates are ionized in the lumen of the gut.

The lower the pKa, the better the detergent

Front 121

121. Breakdown of bile salts

Back 121

Intestinal bacteria deconjugate and dehydroxylate the bile salts, removing the glycine and taurine residues and the hydroxyl group at position 7.

These deconjugated and dehydroxylated bile salts are less soluble and therefore are less readily resorbed from the intestinal lumen.

Front 122

122. Secondary bile salts

Give an example of one...?

Back 122

Bile salts that lack a hydroxyl group at position 7 are called secondary bile salts.

Lithocholic acid is the least soluble bile salt; its major fate is excretion.

Front 123

123. Efficiency of enterohepatic circulation

Back 123

Less than 5% of the bile salts entering the gut are excreted in the feces each day.

Very efficient I would say...

Front 124

124. Three important functions of apoproteins...

Back 124

1. Add to the hydrophilicity and structural stability of the particle
2. Activate certain enzymes required for normal lipoprotein metabolism
3. Act as ligands on the surface of the lipoprotein that target specific receptors on peripheral tissues that require lipoprotein delivery for their innate cellular functions.

Front 125

125. Chylomicrons

Back 125

These are the largest of the lipoproteins and the least dense because of their rich TAG content.

They are synthesized from dietary lipids within the epithelial cells of the small intestine and then secreted into the lymphatics and bloodstream via the left subclavian vein.

Front 126

126. What are the major apoproteins of chylomicrons?

Back 126

1. ApoB-48
2. ApoC-II
3. ApoE

Front 127

127. ApoC-II

Back 127

Activates lipoprotein lipase which allows LPL to hydrolyze the chylomicrons, leading to the release of free FAs

Front 128

128. Chylomicron remnants

Back 128

The partially hydrolyzed chylomicrons remaining in the bloodstream, now partly depleted of their core TAGs, have lost their apoCII but still retain their ApoE and ApoB-48.

Receptors in the plasma membranes of the liver cells bind to ApoE on the surface of these remnants, allowing them to be taken up by the liver.

Front 129

129. Nascent VLDLs

Back 129

If dietary intake is in excess, the excess carbs are converted to TAGs, which, along w/free and esterified cholesterol, phospholipids, and ApoB-100 are packaged to form nascent VLDL

Front 130

130. Mature VLDLs

Back 130

The nascent VLDLs are secreted from the liver into the bloodstream, where they accept ApoCII and ApoE from circulating HDL particles

Front 131

131. VLDL remnants

Back 131

Approx 50% of these remnants are taken up from the blood by liver cells thru the binding of VLDL ApoE to the hepatocyte plasma membrane ApoE receptor, followed by endocytic internalization of the VLDL remnant.

Front 132

132. What happens to the other half of the VLDL remnants?

Back 132

The other half are into taken up by the liver but, instead, have additional core TAGs removed to form IDL.

Front 133

133. LDLs

Back 133

With the removal of addition TAGs from IDL thru hepatic TAG lipase within hepatic sinusoids, LDL is generated from IDL.

LDLs are rich in cholesterol and cholesterol esters.

Front 134

134. Transport of LDLs

Back 134

60% of the LDL is transported back to the liver, where its ApoB-100 binds to the liver cells.

The remaining 40% of LDLs are carried to extrahepatic tissues (i.e. adrenocortical and gonadal cells) that also have ApoB-100 receptors where they are internalized.

Front 135

135. What happens to excess LDLs in the blood?

Back 135

If the receptor mediated uptake system is saturated, the LDLs are now more readily available for non-specific uptake of LDL by macrophages (scavenger cells) present near the endothelial cells of artieries.

Possible explanation for the inflammatory response in atherosclerosis

Front 136

136. Synthesis of HDL (3 methods)

Back 136

1. Synthesis of nascent HDL by the liver and intestine
2. From budding of apoproteins from chylomicrons and VLDL particles as they are digested by LPL. The apoproteins and shells can then accumulate more lipid.
3. From free ApoAI, which may be shed from other circulating lipoproteins

Front 137

137. HDL composition

Back 137

Shells contains phospholipids, free cholesterol, and a variety of apoproteins, i.e. ApoAl, ApoAII, ApoCI, and ApoCII. Very low levels of TAGs or cholesterol esters are found in the hollow core.

Front 138

138. Maturation of nascent HDL

Back 138

Nacent HDL particles accumulate phospholipids and cholesterol from cells lining blood vessels.

As the central hollow core of nascent HDLs fills w/cholesterol esters, HDL takes on a more globular shape to eventually form the mature HDL particle

Does not require enzymatic activity.

Front 139

139. Reverse cholesterol transport

Back 139

HDL particles have the ability to remove cholesterol from cholesterol-laden cells and to return the cholesterol to the liver.

Requires a directional movement of cholesterol from the cell to the lipoprotein particles. This is done via ABC1

Front 140

140. ABC1

Back 140

Uses ATP hydrolysis to move cholesterol from inner leaflet of the membrane to the outer leaflet.

Once moved to the outer membrane, the HDL particle can accept it, but if the cholesterol is not modified within the HDL particle, the cholesterol can leave by the same route it entered.

Front 141

141. How is the cholesterol trapped/modified in the HDL particle?

Back 141

The HDL particle acquires the enzyme LCAT from the circulation

LCAT transfers a FA to form a cholesterol ester which migrates to the core of the HDL particle and is no longer free to return to the cell.

Front 142

142. Mutations in the ATP-binding cassette 1 protein

Back 142

Include familial HDL deficiency and Tangier disease.

Cholesterol depleted HDL cannot transport free cholesterol from cells that lack the ability to express this protein.

As a consequence, HDL is rapidly degraded.

Front 143

143. Clearance of HDL

Back 143

Can bind to hepatocytes but the primary means is thru its uptake by the scavenger receptor SR-B1.

Once bound to the receptor, its cholesterol and cholesterol esters are transferred into the cells.

Without the cholesterol and its esters, the HDL particle dissociates form the SR-B1 receptor and reenters circulation.

Front 144

144. What else does HDL do?

Back 144

Exchanges apoproteins and lipids w/other lipoproteins in the blood via CETP

Front 145

145. CEPT (cholesterol ester transfer protein)

Back 145

HDL can transport cholesterol esters and free cholesterol to circulating TAG rich lipoproteins such as VLDL and VLDL remnants.

In exchange, TAGs from the latter lipoproteins are transferred to HDL.

The greater the concentration of TAG rich lipoproteins in the blood, the greater will be the rate of these exchanges.

Front 146

146. How do lipoproteins enter cells?

Back 146

Via receptor mediated endocytosis

Front 147

147. Structure of the LDL receptor

What are the six regions?

Back 147

1. LDL binding domain
2. EGF like domain/Transducin-beta subunit-like domain
3. N-linked oligosaccharide domain
4. O-linked oligosaccharide domain
5. Transmembrane domain
6. Intracellular domain

Front 148

148. Four classes of mutations involving LDL receptors

Back 148

1. Null alleles that either direct the synthesis of no protein at all or a protein that cannot be precipitated by antibodies to the LDL receptor.
2. The alleles encode proteins, but they cannot be transported to the cell surface.
3. Encodes proteins that reach the cell surface but cannot bind LDL normally.
4. Encodes proteins that reach the surface and bind LDL but fail to cluster and internalize the LDL particles

End result is accumulation of LDL in the blood b/c cells cannot take up these particles at a normal rate.

Front 149

149. LDL receptor-related protein (LRP)

Back 149

Structurally related ot the LDL receptor but recognizes a broader spectrum of ligands.

In addition to lipoproteins, it binds the blood proteins alpha-2-macroglobulin and tPA and its inhibitors.

Also recognizes the ApoE of lipoproteins and binds remnants of produced by the digestion of teh triacylglycerols of chylomicrons and VLDL by LPL

Thus one of its functions is believed to be clearing these remnants from the blood.

Front 150

150. Locations of LRP

Back 150

Abundant in the cell membranes of the liver, brain, and placenta. In contrast to the LDL receptor, synthesis of the LRP receptor is not significantly affected by an increase in the intracellular concentration of cholesterol.

However, insulin causes the # of these receptors on the cell surface to increase.

Front 151

151. Macrophage scavenger receptor

Back 151

Variety of these receptors.

SR-B1 is used primarily for HDL binding, whereas the scavenger receptors expressed on macrophases are SR-A1 and SR-A2.

Modification of LDL freq involves oxidative damage, so these receptors allow the cells to take up damaged LDL long after intracellular cholesterol levels are elevated.

Front 152

152. Layers of the artery from the inside out (6 layers)

Back 152

1. Intima
2. Subintimal ECM
3. Tunica media
4. Internal elastic lamina
5. External elastic lamina
6. Adventitia

Front 153

153. Cholesterol is the precursor of what five classes of steroid hormones?

Back 153

1. Glucocorticoids
2. Mineralcorticoids
3. Androgens
4. Estrogens
5. Progestins

Front 154

154. Synthesis of cortisol vs. aldosterone vs. adrenal androgens vs. testosterone

Where does this take place?

Back 154

Cortisol: zona fasciculata

Aldosterone: zona glomerulosa

Adrenal androgens: zona reticulosum

Testosterone: Leydig cells in testes

Front 155

155. CAH

What are the three types?

Back 155

Most common deficiency is that of 21-α-hydroxylase, the activity of which is necessary to convert progesterone to 11-deoxycorticosterone and 17-α-hydroxy progesterone to 11-deoxycortisol. Reduces both cortisol and aldosterone production without affecting androgen production. If the enzyme deficiency is severe, it leads to an overabundance of androgens.

Can also involve deficiency in 11-β-hydroxylase, which results in the accumulation of 11-deoxycorticosterone. Causes hypertension May increase levels of adrenal androgens int eh blood.

Can also involve 17-α-hydroxylase deficiency which leads to an increase in aldosterone excess and hypertension but no virilization.

Front 156

156. DOC (Deoxycorticosterone)

Back 156

Although aldosterone is the major mineralocorticoid in humans, excessive production of a weaker mineralocorticoid, DOC, which occurs in patients w/a deficiency of the 11-hydroxylase may lead to clinical signs and symptoms of mineralocorticoid excess even though aldosterone secretion is suppressed in these patients.

Front 157

157. DHEAS

Back 157

The serum concentration of the stable metabolite of DHEA is used as a measure of adrenal androgen production in hyperadrogenic patients w/diffuse excessive growth of secondary sexual hair.

Front 158

158. Rickets

Back 158

A disorder of young children caused by a deficiency of vitamin D. Low levels of calcium and phosphorus in the blood are associated w/skeletal deformities in these children.

Front 159

159. Primary hypercholesterolemia

Back 159

Characterized by elevated levels of plasma cholesterol and LDL cholesterol, with normal levels of triglycerides.

Front 160

160. Causes of primary hypercholesterolemia (3)

Back 160

1. Familial hypercholesterolemia
2. Familial defective apoB100
3. Polygenic hypercholesterolemia

Front 161

161. Clinical features of familial hypercholesterolemia (heterozygous)

Back 161

1. High total plasma cholesterol concentrations
2. Tendon xanthomas
3. Arcus corneae (deposition of cholesterol in the cornea)

Front 162

162. Clinical features of familial hypercholesterolemia (homozygous)

Back 162

1. Very high total plasma cholesterol concentrations
2. Cardiovascular disease presents prior to age 20
3. Tendon xanthomas
4. Arcus corneae (deposition of cholesterol in the cornea)

Front 163

163. Inhibitors of cholesterol synthesis (statins)

How do they work?

Back 163

HMG CoA reductase inhibitors competetively inhibit the activity of HMG CoA reductase, the rate-limiting enzyme in cholesterol synthesis.

This decreases the cellular cholesterol concentration which activates a cellular signaling cascade culminating in the activation of SREBP2, which up-regulates the expression of the gene encoding the LDL receptor.

Increased LDL receptor expression causes increased uptake of plasma LDL and thus decreases plasma LDL cholesterol concentration.

Front 164

164. What are the four therapeutic benefits of statins?

AKA "pleiotropic effects of statins"

Back 164

1. Plaque stabilization
2. Improvement of coronary endothelial function via improved response to endothelial NO
3. Inhibition of platelet thrombus formation
4. Anti-inflammatory function

Front 165

165. What are statins used to treat?

Back 165

Effective in lowering plasma cholesterol levels in all types of hyperlipidemias, except homozygous familial hypercholesterolemia

Front 166

166. Fibrates

How do they work?

Back 166

Agonists of peroxisome proliferator-activated receptor α(PPARα).

PPARα functions as a ligand-activated transcription factor. Upon binding to its natural ligan or hypolipidemic drugs, PPARs are activated.

PPAR regulates the expression of genes encoding for proteins involved in lipoprotein structure and function.

Fibrate mediated gene expression leads to decreased TAGs by increasing the expression of LPL and decreasing ApoCII concentration.

Also increases the levels of HDL via increasing the expression of ApoAI and ApoAII.

Front 167

167. Thiazolidinediones (TZD)

Back 167

These drugs are a relatively new class of oral medication for Type II diabetes; the two currently available in the US is rosiglitazone and pioglitazone.

The TZDs do not affect insulin secretion, but rather enhance the action of insulin at target tissues.

Front 168

168. How do TZDs work?

Back 168

TZDs are agonists for nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ)

Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.

Hyperglycemia, hyperinsulinemia, hypertriacyglycerolemia and elevated HbA1c levels are improved.

Front 169

169. What is metformin?

Back 169

Used for Type 2 diabetes and Polycystic ovarian syndrome.

It increases glucose uptake and utilization by target tissues, which essentially reduces hepatic glucose output.

Like the sulfonylureas, metformin requires insulin for its action, but it differs from the sulfonylureas in that it does not promote insulin secretion.

Front 170

170. How does metformin work?

Back 170

Like TZDs, biguanides (Metformin) act by increasing insulin sensitivity.

The molecular target of the biguanides appears to be the AMP-dependent protein kinase (AMPPK).

Biguanides activate AMPPK to block the breakdown of fatty acids and to inhibit hepatic gluconeogenesis and glycogenolysis.

Secondary effects include increased insulin signaling as well as increased metabolic responsiveness by the liver and skeletal muscle to insulin.

Front 171

171. What are the three types of hyperadrenal clinical syndromes?

Back 171

1. Cushing syndrome, characterized by an excess of cortisol
2. Hyperaldosteronism
3. Adrenogenital or virilizing syndromes caused by a n excess of androgens

Front 172

172. What is the pathogenesis of Cushing syndrome?

Back 172

This disorder is caused by any condition that produces an elevation in glucocorticoid levels.

*In clinical practice, most causes of Cushing syndrome are the result of the administration of exogenous glucocorticoids.

Can also be caused by endogenous glucocorticoids.

Front 173

173. What are the three sources of hypercortisolism that can be categorized as endogenous Cushing syndrome?

Back 173

1. Primary hypothalamic-pituitary diseases associated w/hypersecreiton of ACTH
2. Hypersecretion of cortisol by an adrenal adenoma, carcinoma, or nodular hyperplasia
3. The secretion of ectopic ACTH by a nonendocrine neoplasm

Front 174

174. What accounts for 70-80% of cases of endogenous hypercortisolism?

Back 174

Primary hypersecretion of ACTH. This is AKA Cushing disease.

The disorder affects women about 5x more than men, and it occurs most freq during the 20's and 30's. In the vast majority of cases, the pituitary gland contains an ACTH-producing microadenoma that does not produce mass effects in the brain. In the remainder of cases, the anterior pituitary contains areas of corticotroph cell hyperplasia.

Front 175

175. What about primary adrenal neoplasms and primary cortical hyperplasia?

Back 175

Primary adrenal neoplasms, such as adrenal adenoma and carcinoma, and primary cortical hyperplasia are responsible for about 10-20% of cases of endogenous Cushing syndrome.

This form is AKA ACTH-independent Cushing syndrome or adrenal Cushing syndrome b/c the adrenals function autonomously.

*The diagnostic marker of adrenal Cushing syndrome is elevated serum levels of cortisol w/low levels of ACTH.

Front 176

176. In what populations are adenomas and CAs common?

What is the main difference btwn cortical carcinomas and adenomas or hyperplastic processes?

Back 176

They are about equally common in adults; in children, CAs predominate.

The cortical CAs tend to produce more marked hypercortisolism than the adenomas or hyperplastic processes.

Front 177

177. What causes a majority of hyperplastic adrenal processes?

What are the two types?

Back 177

Most arise from secondary influences, and primary cortical hyperplasia is uncommon. There are two types of primary bilateral adrenocortical hyperplasia:

1. Massive macronodular adrenocortical disease (MMAD)
2. Primary pigmented nodular adrenal disease (PPNAD)

Front 178

178. What is massive macronodular adrenocortical disease (MMAD)?

Back 178

In massive macronodular adrenocortical disease (MMAD), the nodules are usually greater than 3 mm in diameter. MMAD affects older adults, and there is no known genetic component.

Front 179

179. What is primary pigmented nodular adrenal disease (PPNAD)?

Back 179

The second variant of primary nodular hyperplasia, seen more often in children than in adults, is a familial condition known as primary pigmented nodular adrenal disease (PPNAD).

The adrenal glands in PPNAAD demonstrate diffuse bilateral micronodules (<3 mm in diameter) that are usually darkly pigmented (brown to black).

Front 180

180. What about secretion of ectopic ACTH by nonpituitary tumors as a cause of Cushing syndrome?

Back 180

Secretion of ectopic ACTH by nonpituitary tumors accounts for most of the remaining cases (~10%) of Cushing syndrome.

In many instances, the responsible tumor is a small cell CA of the lung, although other neoplasms, including carcinoid tumors, medullary CAs of the thyroid, and islet cell tumors of the pancreas have been associated w/the syndrome.

This variant of Cushing syndrome is more common in men and usually occurs in the forties and fifties.

Front 181

181. What is the morphology of the pituitary in Cushing syndrome?

Back 181

The pituitary in Cushing syndrome shows changes regarless of the cause. The msot common alteration, resulting form high levels of endo- or exogenous glucocorticoids, is termed *Crooke hyaline change.

In this condition, the normal granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary is replaced by homogeneous, lightly basophilic material. This alteration is the result of the accumulation of intermediate keratin filaments in the cytoplasm.

Front 182

182. What is the morphology of the adrenal glands in Cushing syndrome?

Back 182

Depends on the cause of hypercortisolism. The adrenal have one of the following abnormalities:

1. Cortical atrophy
2. Diffuse hyperplasia
3. Nodular hyperplasia
4. An adenoma, rarely a carcinoma

Front 183

183. What is the morphology of cortical atrophy of the adrenal glands?

Back 183

In pts in whom the syndrome results from exogenous glucocorticoids, suppression of endogenous ACTH results in bilateral cortical atrophy, due to a lack of stimulation of the zona faciculata and the reticularis by ACTH.

The zona glomerulosa is of normal thickness in such cases b/c this portion of the cortex functions independently of ACTH.

Front 184

184. What is the morphology of diffuse hyperplasia of the adrenals?

Back 184

Diffuse hyperplasia is found in 60-70% of Cushing syndrome cases. Both glands are enlarged, either subtly or markedly, weighing up to 25-40gm. The adrenal cortex is diffusely thickened and yellow, owing to an increase in the size and number of lipid-rich cells in the zona-fasciculata and reticularis.

Most cases of hyperplasia are associated w/elevated serum levels of ACTH, whether of pituitary or ectopic origin.

Front 185

185. What is the morphology of nodular hyperplasia of the adrenals?

Back 185

Some degree of nodularity is common but is pronounced in nodular hyperplasia. This takes the form of bilateral, 0.5-2.0 cm yellow nodules scattered thru the cortex, separated by intervening areas of widened cortex.

The uninvolved cortex and nodules are composed of a mixture of lipid-laden clear cells and lipid-poor compact cells showing some variablility in cell and nuclear size w/occasional binucleate forms.

The combined adrenals may weigh up to 20-50 gm.

Front 186

186. What is the morphology of primary adrenocortical neoplasms?

Back 186

Primary adrenocortical neoplasms causing Cushing syndrome may be malignant or benign.

Adenomas or CAs of the adrenal cortex as the source of cortisol secretion are not macroscopically distinctive from nonfunctioning adrenal neoplasms.

Both the benign and the malignant lesions are more common in women in their 30's to 50's. They both results in suppression of endogenous ACTH by high cortisol levels.

Front 187

187. What is the morphology of adrenocortical adenomas?

Back 187

The adrenocortical adenomas are yellow tumors surrounded by thin or well-developed capsules, and most weigh less than 30 gm.

Microscopically, they are composed of cells that are similar to those encountered in the normal zona faciculata.

Their morphology is identical to that of nonfunctional adenomas and of adenomas associated w/hyperaldosteronisms.

Front 188

188. What is the morphology of the carcinomas associated w/Cushing syndrome?

Back 188

These tend to be larger than the adenomas. These tumors are unencapsulated masses frequently exceeding 200 to 300 gm in weight, having all the anaplastic characteristics of CA.

Again, there is suppression of endogenous ACTH by high cortisol levels.

Front 189

189. What is the clinical course of Cushing syndrome?

Back 189

1. Central obesity (about trunk and upper back)
2. Moon faces
3. Weakness and fatigability
4. Hirsutism
5. Hypertension
6. Plethora
7. Glucose intolerance/diabetes
8. Osteoporosis
9. Neuropsychiatric abnormalities
10. Menstrual abnormalities
11. Skin striae
12. Delayed wound healing/bruisability
13. Increased risk of infections

Front 190

190. How is Cushing syndrome diagnosed?

Back 190

1. The 24-hour urine free cortisol level, which is increased
2. Loss of normal diurnal pattern of cortisol secretion.

Front 191

191. What are the ACTH levels in pituitary Cushing syndrome?

Back 191

In pituitary Cushing syndrome, ACTH levels are elevated and cannot be suppressed by the administration of a low dose of dexamethasone. There is no reduction in urinary excretion fo 17-hydroxycorticosteroids.

After higher doses of injected dex, however, the pituitary responds by reducing ACTH secretion, which is reflected by suppression of urinary steroid secretion.

Front 192

192. What are the ACTH levels in ectopic and adrenal tumor Cushing syndrome?

Back 192

Ectopic ACTH secretion results in an elevated level of ACTH, but its secretion is completely insensitive to low or high doses or exogenous dexamethasone.

When Cushing sydnrome is caused by an adrenal tumor, the ACTH level is quite low b/c of feedback inhibition of the pituitary. As w/ectopic ACTH secretion , both low dose and high dose dex fail to suppress cortisol excretion.

Front 193

193. What is primary hyperaldosteronism?

Back 193

Primary hyperaldosteronism indicates an autonomous overproduction of aldosterone, w/resultant suppression of the renin-angiotensin system and decreased plasma renin activity.

It results in sodium retention and potassium excretion, with resultant hypertension and hypokalemia.

Front 194

194. What are the three ways in which primary hyperaldosteronism can be caused?

Back 194

1. Adrenocortical neoplasm (most commonly an aldosterone producing adrenocortical adenoma), or Conn syndrome (a solitary aldosterone secreting adenoma)
2. Primary adrenocortical hyperplasia (idiopathic hyperaldosoteronism)
3. Glucocorticoid-remediable hyperaldosteronism

Front 195

195. What is Conn syndrome?

Back 195

In approx 80% of the cases of adrenocortical adenoma, primary hyperaldosteronism is caused by a solitary aldosterone secreting adenoma, a condition called Conn syndrome.

This syndrome occurs most freq in adult middle life and is more common in women than men. Multiple adenomas may be present in the occasional pt.

Front 196

196. What is primary adrenocortical hyperplasia?

What is the genetic basis?

Back 196

Primary adrenocortical hyperplasia is characterized by bilateral nodular hyperplasia of the adrenal glands, highly reminiscent of those found in the nodular hyperplasia of Cushing syndrome.

The genetic basis is not clear, although it is possibly caused by an overactivity of the aldosterone synthase gene, CYP11B2.

Front 197

197. What is glucocorticoid-remediable hyperaldosteronism?

What is the genetic basis?

Back 197

Glucocorticoid-remediable hyperaldosteronism is an uncommon cause of primary hyperaldosteronism that is familial and genetic. In some families, it is caused by a chimeric gene resulting from fusion between CYP11B1 (the 11β-hydroxylase gene) and CYP11B2 (the aldosterone synthase gene).

This leads to a sustained production of hybrid steroids in addition to both cortisol and aldosterone. The activation of aldosterone secretion is under the influence of ACTH and hence is suppressible by exogenous administration of dexamethasone.

Front 198

198. What are the three cases in which secondary hyperaldosteronism occurs?

Back 198

It is characterized by increased levels of plasma renin and is encountered in conditions such as:

1. Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)
2. Arterial hypovolemia and edema (congestive heart failure, cirhosis, nephrotic syndrome)
3. Pregnancy (due to estrogen-induced increases in plasma renin substrate).

Front 199

199. What is the morphology of aldosterone producing adenomas?

Back 199

Aldosterone producing adenomas are almost always solitary, small (<2 cm in diameter), well circumscribed lesions, more often found on the left than on the right. They tend to occur in the 30's and 40's in women.

These lesions are often buried w/in the gland and do not produce visible enlargement. They are bright yellow and composed of lipid-laden cortical cells that more closely resemble fasciculata cells than glomerulosa cells (the normal source of aldosterone).

Front 200

200. What is a characteristic feature of aldosterone producing adenomas?

Back 200

The presence of eosinophilic, laminated cytoplasmic inclusions, known as spironolactone bodies, found after treatment with the antihypertensive drug spironolactone.

*These tumors do not usually suppress ACTH secretion. Therefore, the adrenal cortex is not atrophic.

Front 201

201. What is bilateral idiopathic hyperplasia?

Back 201

Bilateral idiopathic hyperplasia is marked by diffuse and focal hyperplasia of cells resembling those of the normal zona glomerulosa.

The hyperplasia is often wedge-shaped, extending from the periphery toward the center of the gland. Bilateral enlargement can be subtle in idiopathic hyperplasia, and as a rule, an adrenocortical adenoma should be carefully excluded as the cause of hyperaldosteronism.

Front 202

202. What is the clinical course of primary hyperaldosteronism?

Back 202

The clinical features include hypertension and hypokalemia.

Hypokalemia results from renal potassium wasting and can cause a variety of neuromuscular manifestations, including weakness, paresthesias, visual disturbances, and occasionally tetany.

Sodium retention increases the total body sodium and expands the ECF volume, resulting in hypertension.

Treatment is surgical excision or spironolactone.

Front 203

203. What is adenogenital syndrome?

Back 203

Disorders of sexual differentiation, such as virilization in the female and precocious puberty in the male, may be caused by primary gonadal or adrenal disorders.

Front 204

204. Adrenocortical neoplasms associated w/virilization are more likely to be...?

Back 204

Androgen-secreting adrenal carcinomas than adenomas.

Conversely, functioning adrenal cortical CAs are most often associated w/a virilization syndrome, usually in combo w/hypercortisolism.

Front 205

205. What is CAH?

Back 205

CAH represents a group of autosomal-recessive, inherited metabolic errors, each characterized by a deficiency of total lack of a particular enzyme involved in the biosynthesis of cortical steroids, particularly cortisol.

Steroidogenesis is then channeled into other pathways, leading to increased production of androgens, which accounts for virilization.

Also, the decrease in cortisol results in the increased secretion of ACTH, resulting in adrenal hyperplasia.

Front 206

206. What is 21-Hydroxylase deficiency?

What are the three distinctive syndromes associated w/this deficiency?

Back 206

Defective conversion of progesterone to 11-deoxycorticosterone by 21-hydroxylase (CYP21B) accounts for over 90% of cases of CAH.

May range from a total lack to a mild loss.

Associated with:
1. Salt-wasting (classic) adrenogenitalism
2. Simple virilizing adrenogenitalism
3. Nonclassic adrenogenitalism

Front 207

207. What is the mechanism of CYP21B gene inactivation?

Back 207

This involves recombination with a neighboring pseudogene on chromosome 6p21 called CYP21A (a pseudogene is an inactive homologous gene created by ancestral duplication).

In a majority of cases of CAH, portions of the CYP21A pseudogene replace all or part of the active CYP21B gene. The introduction of nonfunctional sequences from CYP21A into the CYP21B sequence has the same effect as inactivating mutations in CYP21B.

Front 208

208. What causes the salt-wasting syndrome?

Back 208

The salt-wasting syndrome results from an inability to convert progesterone into deoxycorticosterone b/c of a total lack of the hydroxylase.

Thus, there is virtually no synthesis of mineralocorticoids, and concomitantly, there is a block in the conversion of hydroxyprogesterone into deoxycortisol with deficient cortisol synthesis.

Front 209

209. What are the features of the salt-wasting syndrome?

Back 209

There is salt wasting, hyponatremia, and hyperkalemia, which induce acidosis, hypotension, cardiovascular collapse, and possibly death.

Front 210

210. Male vs. female differences in virilization in salt-wasting adrenogenitalism

Back 210

Females have a range of mild clitoral enlargement to complete labioscrotal fusion to marked clitoral enlargement enclosing the urethra, thus producing a phalloid organ

Males with this disorder are generally unrecognized at birth but come to clinical attention 5 to 15 days later b/c of some salt losing crisis.

Front 211

211. What is simple virilizing adrenogenital syndrome w/o salt wasting?

Back 211

Simple virilizing adrenogenital syndrome w/o salt wasting (presenting as genital ambiguity) may occur in individuals w/a less than total 21-hydroxylase defect b/c w/less severe deficiencies the level of mineralocorticoid, although reduced, is sufficient for salt reabsorption, but the lowered glucocorticoid level fails to cause feedback inhibition of ACTH secretion.

Thus, the level of aldosterone is mildly reduced, testosterone is increase, and ACTH is elevated, w/resultant adrenal hyperplasia.

Front 212

212. What is the nonclassic or late-onset adrenal virilism?

Back 212

This type is more common than the classic patterns. Pts w/this syndrome may be virtually asymptomatic or have mild manifestations, such as hirsutism.

The Dx can only be made via demonstration of biosynthetic defects in steroidogeneis and by genetic studies.

Front 213

213. What is the morphology of the adrenals in CAH?

Back 213

In all cases of CAH, the adrenals are bilaterally hyperplastic, sometimes expanding to 10-15x their normal weights b/c of the sustained elevation in ACTH.

The adrenal cortex is thickened and nodular, and on cut section, the widened cortex appears brown, owing to total depletion of all lipid.

The proliferating cells are mostly compact, eosinophilic, lipid-depleted cells, intermixed w/lipid-laden clear cells.

Hyperplasia of corticotroph (ACTH-producing) cells is present in the anterior pituitary in most CAH pts.

Front 214

214. What is the clinical course of CAH?

Back 214

The features are determined by the specific enzyme deficiency and include abnormalities related to androgen excess.

CAH should be suspected in any neonate w/ambiguous genitalia; severe enzyme deficiency in infancy can be a life-threatening condition w/vomiting, dehydration and salt wasting.

In the milder variants, women may present w/delayed menarche, oligomenorrhea, or hirsutism.

Front 215

215. What is the treatment for CAH?

Back 215

Pts w/CAH are treated w/exogenous glucocorticoids.

Mineralocorticoid supplementation is required in the salt-wasting variants of CAH.

Front 216

216. What is adrenomedullary dysplasia?

Back 216

In pts w/severe salt-wasting 21-hydroxylase deficiency, a combo of low cortisol levels and developmental defects of the medulla (adrenomedullary dysplasia) profoundly affects catecholamine secretion, further predisposing these individuals to hypotension and circulatory collapse.

Front 217

217. What are the three patterns of adrenal insufficiency?

Back 217

May be caused by either primary adrenal disease (primary hypoadrenalism) or decreased stimulation of the adrenals owing to a deficiency of ACTH (secondary hypoadrenalism).

1. Primary acute adrenocortical insufficiency (adrenal crisis)
2. Primary chronic adrenocortical insufficiency (Addison disease)
3. Secondary adrenocortical insufficiency

Front 218

218. In what three settings does primary acute adrenocortical insufficiency occur?

Back 218

1. As a crisis in pts w/chronic adrenocortical insufficiency precipitated by any form of stress
2. In pts maintained on exogenous corticosteroids, in whom rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress
3. As a results of massive adrenal hemorrhage, which destroys the adrenal cortex sufficiency to cause acute adrenocortical insufficiency.

Front 219

219. What is Waterhouse-Friderichsen syndrome?

What are the four characteristics of this syndrome?

Back 219

1. Overwhelming bacterial infection (classically associated w/N. meningitidis septicemia)
2. Rapidly progressive hypotension leading to shock
3. Disseminated intravascular coagulation w/widespread purpura
4. Rapidly developing adrenocortical insufficiency associate w/massive bilateral adrenal hemorrhage

***The adrenals are converted to sacs of clotted blood virtually obscuring all underlying detail***

Front 220

220. What is primary chronic adrenocortical insufficiency (Addison disease)?

Back 220

This is an uncommon disorder that results from progressive destruction of the adrenal cortex.

In general, clinical manifestations of adrenal cortical insufficiency do not appear until at least 90% of the adrenal cortex has been compromised.

Front 221

221. What are the four most common causes of primary adrenal insufficiency?

Back 221

1. Autoimmune adrenalitis
2. Tuberculosis
3. AIDS
4. Metastatic cancers

Front 222

222. What is autoimmune adrenalitis?

Back 222

Autoimmune adrenalitis accounts for 60-70% of cases, and it is by far the most common cause of primary adrenal insufficiency in developed countries.

There is autoimmune destruction of steroidogenic cells, and autoantibodies to several key steroidogenic enzymes (21-hydroxylase, 17-hydroxylase) have been detected in these pts.

Front 223

223. What are the three clinical settings in which autoimmune adrenalitis can occur?

Back 223

1. Autoimmune polyendocrine syndrome type 1 (APS1) AKA autoimmune polyendocrinopathy
2. Autoimmune polyendocrine syndrome type 2 (APS2)
3. Isolated autoimmune Addison disease

Front 224

224. What is autoimmune polyendocrine syndrome type 1 (APS1) AKA autoimmune polyendocrinopathy?

Back 224

APS1 is caused by mutations in the autoimmune regulator-1 (AIRE1) gene on chromosome 21q22, and is characterized by chronic mucocutaneous candidiasis and abnormalities of skin, dental enamel, and nails

It often occurrs in association with a combo of organ-specific autoimmune disorders (autoimmune adrenalitis, autoimmune hypoparathyroidism, idiopathic hypogonadism, pernicious anemia).

Front 225

225. What is the function of the AIRE protein?

Back 225

The expression is primarily in the thymus, where it appears to function as a transcription factor that promotes the expression of many self-antigens, leading to negative selection (death) of self-reactive T cells.

Front 226

226. What is APS2?

Back 226

Autoimmune polyendocrine syndrome type 2 (APS2) usually starts in early adulthood and presents as a combo of adrenal insufficiency w/autoimmune thyroididits or type 1 DM.

Unlike in APS1, mucocutaneous candidiasis, ectodermal dysplasia, and autoimmune hypoparathyroidism do not occur. APS2, unlike APS1, is not a monogenic disorder, although some studies have suggested a possible association w/polymorphisms in teh HLA loci.

Front 227

227. What is isolated autoimmune Addison disease?

Back 227

Isolated autoimmune Addison disease presents with autoimmune destruction restricted to the adrenal glands.

However, in terms of age at presentation and linage to HLA and other susceptibility loci, isolated autoimmune adrenalitis overlaps w/APS2, suggesting that the former may be a variant of the latter.

Front 228

228. What infections can cause primary chronic adrenocortical insufficiency?

Back 228

Particularly *tuberculosis* and those caused by fungi such as Histoplasma capsulatum and Coccidioides immitis, may destroy the adrenals.

Pts w/AIDS are at risk for developing adrenal insufficiency from complications of their disease (CMV, mycobacterium avium-intracellulare, Kapose sarcoma).

Front 229

229. What about metastatic neoplasms and the adrenals?

Back 229

Metastatic neoplasms are an uncommon cause of adrenal insufficiency. However, the adrenals are a fairly common site for metastases in pts with disseminated CAs.

Common primary tumors include carcinomas of the lung and breast.

Front 230

230. What are the genetic disorders of adrenal insufficiency?

Back 230

These include adrenal hypoplasia congenital (AHC) and adrenoleukodystrophy.

Technically, these disorders are also associated w/chronic adrenal insufficiency, though they are not commonly including in the causes of Addison disease.

Front 231

231. What is the morphology of the adrenals in autoimmune adrenalitis?

Back 231

Primary autoimmune adrenalitis is characterized by irregularly shrunken glands, which may be difficult to identify w/in the suprarenal adipose tissue.

Histologically, the cortex contains only scattered residual cortical cells in a collapsed network of connective tissue. A variable lymphoid infiltrate is present in the cortex and may extend into the subjacent medulla, although the medulla is otherwise preserved.

Front 232

232. What is the morphology of adrenal insufficiency caused by tuberculous and fungal diseases, as well as that caused by metastatic CA?

Back 232

In cases of tuberculous and fungal disease, the adrenal architecture is effaced by a granulomatous inflammatory reaction identical to that encountered in other sites of infection.

When hypoadrenalism is caused by metastatic CA, the adrenals are enlarged, and their normal architecture is obscured by the infiltrating neoplasm.

Front 233

233. What is the clinical course of Addison disease?

Back 233

Features of Addison disease include weakness, fatigue, anorexia, hypotension, nausea, vomiting, and cutaneous hyperpigmentation.

Lab values show elevated levels of corticotropin, hyperkalemia, and low sodium (hyponatremia) associated w/volume depletion and hypotension.

Front 234

234. What is secondary adrenocortical insufficiency?

Back 234

Any disorder of the hypothalamus and pituitary that reduces the output of ACTH leads to a syndrome of hypodrenalism that has many similarities to Addison disease.

Prolonged administration of exogenous glucocorticoids suppresses the output of ACTH and adrenal function.

**With secondary disease, the hyperpigmentation of primary Addison disease is lacking because melanotropic hormone levels are low

Also, the adrenals may be moderately to markedly reduced in size.

Front 235

235. What is the morphology of secondary adrenocortical insufficiency?

Back 235

In cases of hypoadrenalism secondary to hypothalamic or pituitary disease, depending on the extent of ACTH lack, the adrenals may be moderately to markedly reduced in size.

They are reduced to small, flattened structures that usually retain their yellow color owing to a small amt of residual lipid.

The cortex may be reduced to a thin ribbon composed largely of zona glomerulosa. The medulla is unaffected.

Front 236

236. What is the morphology of adrenocortical adenomas?

Back 236

Most adrenocortical adenomas are clinically silent and are usually encountered incidentally. There are two types; functional and non-functional;
Functional are associated w/atrophy of the adjacent cortex

The typical cortical adenoma is a well-circumscribed, nodular lesion up to 2.5 cm in diameter that expands the adrenal. In contrast to functional adenomas, which are associated with atrophy of the adjacent cortex, cortex adjacent to nonfunctional adenomas is of normal thickness.

On cut surface, the adenomas are usually yellow to yellowish born. Nuclei in cells are small, and the cytoplasm in the neoplastic cells ranges from eosinophilic to vacuolated, depending on lipid content.

Front 237

237. What are adrenocortical carcinomas?

Back 237

Adrenocortical CAs are rare neoplasms that can occur at any age, including childhood. *More likely to be functional than adenomas are, and carcinomas are therefore often associated w/virilism or hyperadrenalism.

Invasion of contiguous structions, including the adrenal vein and IVC, is common.

May be difficult to differentiate from carcinoma that metastatized to the adrenals.

Front 238

238. What is the morphology of adrenocortical CAs?

Back 238

In most cases, they are large, invasive lesions, many exceeding 20 cm in diameter, that efface the native adrenal gland.

On cut surface, they are poorly demarcated lesions containing areas of necrosis, hemorrhage, and cystic change.

Microscopically, they may be composed of well-differentiated cells resembling those seen in cortical adenomas or bizarre, monstrous giant cells.

Front 239

239. Which CA may metastasize to the adrenals and be difficult to differentiate from primary cortical CAs?

Back 239

CAs of bronchogenic origin.

Front 240

240. What are two rare inherited causes of adrenal cortical CAs?

Back 240

1. Li-Fraumeni syndrome
2. Beckwith-Wiedemann syndrome

Front 241

241. What are adrenal cysts?

Back 241

Relatively uncommon lesions.

They may produce an abdominal mass and flank pain.

Both cortical and medullary neoplasms may undergo necrosis and cystic degeneration and may present as "non-functional" cysts.

Front 242

242. What are adrenal myelolipomas

Back 242

Adrenal myelolipomas are unusual benign lesions composed of mature fat and hematopoietic cells. They may reach massive proportions.

Mature adipocytes are admixed w/aggregates of hematopoietic cells belonging to all three lineages.

May be seen in cortical tumors and in adrenals with cortical hyperplasia.

Front 243

243. What is an adrenal incidentaloma?

Back 243

The term adrenal incidentaloma refers to the incidental discovery of adrenal masses in asymptomatic individuals or in individuals in whom the presenting complain is not directly related to the adrenal gland.

*The vast majority of adrenal incidentalomas are nonsecreting cortical adenomas.

Front 244

244. What is pheochromocytoma?

Back 244

Pheochromocytomas are relatively uncommon neoplasms composed of chromaffin cells, which synthesize and release catechoamines and produce hypertension.

The hypertension can be fatal when the pehochromocytoma goes unrecognized.

Front 245

245. What are the five "rule of 10's" for pheochromocytomas?

Back 245

1. 10% of pheochromocytomas arise in association with several familial syndromes (MEN-2A and MEN-2B, NF1, vHL syndrome, and Sturge-Weber)
2. 10% of pheochromocytomas are extra-adrenal, occurring in sites such as the organ of Zuckerkandl and the carotid body
3. 10% of nonfamilial adrenal pheochromocytomas are bilateral
4. 10% of adrenal pheochromocytomas are biologically malignant
5. 10% of adrenal pheochromocytomas arise in childhood, usually the familial subtypes, w/a strong male predominance. Nonfamilial pheochromocytoma most commonly occur in the 40's and 50's.

Front 246

246. What are the components of MEN-2A

Back 246

1. Medullary thyroid CAs and C-cell hyperplasia
2. pheochromocytomas and adrenal medullary hyperplasia
3. Parathyroid hyperplasia

Front 247

247. What are the components of MEN-2B?

Back 247

1. Medullary thyroid CAs and C-cell hyperplasia
2. Pheochromocytomas and adrenal medullary hyperplasia
3. Mucosal neuromas
4. Marfanoid features

Front 248

248. What are the components of von Hippel-Lindau syndrome?

Back 248

1. Renal, hepatic, pancreatic, and epididymal cysts
2. Renal cell CAs
3. Pheochromocytomas
4. Angiomatosis
5. Cerebellar hemangioblastomas

Front 249

249. What are the components of von Recklinghausen syndrome?

Back 249

1. Neurofibromatosis
2. Cafe au lait skin spots
3. Schwannomas, meningiomas, gliomas
4. Pheochromocytomas

Front 250

250. What are the components of Sturge-Weber syndrome?

Back 250

1. Cavernous hemangiomas of fifth cranial nerve distribution
2. Pheochromocytomas

Front 251

251. What is the morphology of pheochromocytomas?

1/2

Back 251

Pheochromocytomas range from small, circumscribed lesions confined to the adrenal to large hemorrhagic masses weighing kgs. The avg weight is 100 gm, but some can be 4kg.

The larger tumors are well demarcated by either CT or compressed cortical or medullary tissue.

On section, the cut surfaces of smaller pheochromocytomas are yellow-tan. Larger lesions tend to be hemorrhagic, necrotic, and cystic, and typically efface the adrenal gland. Incubation of fresh tissue w/a potassium dichromate solution turns the tumor a dark brown color, owing to oxidation of stored catecholamines.

Front 252

252. What is the morphology of pheochromocytomas?

2/2

Back 252

The histologic pattern is variable.

***The tumors are composed of polygonal to spindle-shaped chromaffin cells or chief cells, clustered w/the sustentacular cells into small nests or alveoli (zellballen) by a rich vascular network.***

The cytoplasm has a finely granular appearance, best demonstrated with silver stains. The nuclei are usually round to ovoid, with a stippled "salt-and pepper" chromatin that is characteristic of most neuroendocrine tumors.

Front 253

253. How can one test for the immunoreactivity of pheochromocytomas?

Back 253

Immunoreactivity for neuroendocrine markers (chromogranin and synaptophysin) is present in the chief cells, while the peripheral sustentacular cells label with S-100, a calcium-binding protein expressed by a variety of mesenchymal cell types.

Front 254

254. What is the criteria for determining malignancy in pheochromocytomas?

Back 254

*There is no single histologic feature that can reliably predict clinical behavior in pheochromocytomas.

Cellular and nuclear pleomorphism, including the presence of giant cells, and mitotic figures are often seen in benign pheochromocytomas, while cellular monotony is paradoxically associated w/an aggressive behavior.

***The definitive Dx of malignancy is pheochromocytomas is based exclusively on the presence of metastases.***

Front 255

255. What is the clinical course of pheochromocytomas?

Back 255

THe dominant clinincal feature in pts w/pheochromocytoma is hypertension. Classically, this feature is described as an abrupt, precipitous elevation in BP associated w/tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension.

Paroxysmal release of catecholamines may also be associated w/episodic headache, anxiety, sweating, tremor, visual disturbances, abdominal pain, and nausea.

Front 256

256. What are the complications of pheochromocytoma-associated hypertension?

What is catecholamine cardiomyopathy?

Back 256

May rpoduce other organ dysfunction, including congestive heart failure, MI, cardiac arrhythmia, and cerebral hemorrhage.

Cardiac complications are due to ischemic myocardial damage secondary to catecholamine induced vasoconstriction (catecholamine cardiomyopathy).

Front 257

257. What are paragangliomas?

What are chemodectomas?

What are carotid body tumors?

Back 257

Pheochromocytomas that develop in paraganglia other than the adrenal medulla are called paragangliomas.

Tumors arising in the carotid body are designated carotid body tumors, whereas those originating in the jugulotypanic body are sometimes referred to as chemodectomas.

The cartoid body tumor forms a palpable mass in the neck enveloping the carotid vessels.

Front 258

258. What is a neuroblastoma?

Back 258

Neuroblastoma is the most common extracranial solid tumor of childhood. They occur most commonly during the first 5 years of life and may arise during infancy.

They may occur anywhere in the sympathetic NS, and occasionally w/in the brain, but they are most common in the abdomen. Most cases arise in either the adrenal medulla or the retroperitoneal sympathetic ganglia.

Front 259

260. What are five distinct features of the tumors arising in the context of MEN syndromes that separate them from their sporadic counterparts?

Back 259

1. These tumors occur at a younger age than sporadic CAs
2. They arise in MEN organs, either synchronously or metachronously (at different times)
3. Even in one organ, the tumors are often multifocal
4. The tumors are usually preceded by an asymptomatic stage of endocrine hyperplasia involving the cell of origin of the tumor.
5. These tumors are usually more aggressive and recur in a higher proportion of cases than do similar endocrine tumors that occur sporadically.

Front 260

261. What is MEN-1, or Wermer syndrome?

Back 260

MEN-1, or Wermer syndrome, is a rare heritable disorder w/a prevalence of about 2 per 100,000. It is characterized by abnormalities involving the PTH, pancreas, and pituitary glands (the 3Ps)

Front 261

262. What are the 3P's of MEN-1?

Back 261

1. Parathyroid: Primary hyperparathyroidism is the most common manifestation of MEN-1 and is the initial manifestation of the disorder in most pts.
2. Pancreas: Endocrine tumors of the pancreas are a leading cause of morbidity and mortality in MEN-1 pts. (Zollinger-Ellison syndrome and insulinomas are the most common subtypes).
3. Pituitary: The most frequent anterior pituitary tumor encountered in MEN-1 is a prolactinoma; some pts develop acromegaly from somatotrophin-secreting tumors.

Front 262

263. What causes MEN-1 syndrome?

Back 262

MEN-1 is caused by germ-line mutations in the MEN1 gene.

MEN1 is a classic tumor suppressor gene in that both alleles are inactivated in the MEN-1 associated tumors.

Front 263

264. What are the clinical manifestations of MEN-1?

Back 263

The dominant clinical manifestations of MEN-1 are usually defined by the peptide hormones and include such abnormalities are recurrent hypoglycemia in insulinomas and recurrent peptic ulcers in pts w/gastrin-secreting neoplasms (Zollinger-Ellison syndrome).

Front 264

265. What is MEN-2A?

What are the genetic alterations associated w/MEN-2A?

Back 264

MEN-2A, AKA Sipple syndrome, is characterized by pheochromocytoma, medullary CA, and PTH hyperplasia.

MEN-2A is clinically and genetically distinct from MEN-1 and has been linked to germ-line mutations in the RET protooncogene.

***In MEN-2A, germ line mutations constitutively activate the RET receptor, resulting in a gain of function***

Front 265

266. What is MEN-2B?

Back 265

MEN-2B has overlap with MEN-2A. Pts develop medullary thyroid CAs which are usually multifocal and more aggressive than in MEN-2A and pheochromocytomas.

However, unlike in MEN-2A, primary hyperparathyroidism is not present. In addition, MEN-2B is accompanied by neuromas or ganlgioneuromas involving the skin, oral mucosa, eyes, respiratory tract, and GI tract, and a marfanoid habitus, w/long axial skeletal features and hyperextensible joints.

Front 266

267. What genetic mutation is responsible for MEN-2B?

Back 266

A single AA chain in RET, distinct from the mutational spectra that are seen in MEN-2A, appears to be responsible for virtually all cases of MEN-2B and affects a critical region of the tyrosine kinase catalytic domain of the protein.

Front 267

268. What is familial medullary thyroid CA, and how is it related to MEN-2A?

Back 267

Familail medullary thyroid CA is a variant of MEN-2A, in which there is a strong predisposition to medullary thyroid CA bu tnot other clinical manifestations of MEN-2A or MEN-2B.

A majority of cases are sporadic, but as many as 20% may be familial. *Familial ones develop at an older age than those occurring in the full-blown MEN-2 syndrome, and follow a more indolent course.

Front 268

269. What are the most common tumors of the pineal gland?

Back 268

Most arise from sequestered embryonic germ cells. They most commonly take the form of so-called germinomas, resembling testicular seminoma or ovarian dysgerminoma.

Front 269

270. What are pineoblastomas?

Back 269

Pineoblastomas occur predominantly in the pediatric population and are composed of primitive embryonal cells reminiscent of cerebellar medulloblastomas (i.e. "small blue cell neoplasm").

The may invade local structures and metastasize via CSF pathways. Can compress the aqueduct of Sylvius, giving rise to internal hydrocephalus. Most pts die w/in 1-2 years.

Front 270

271. What is the morphology of pineoblastomas?

Back 270

They appear as soft, friable, gray masses punctuated w/areas of hemorrhage and necrosis.

Histologically, they are composed of masses of pleomorphic cells 2-4x the diameter of an RBC.

Large hyperchromatic nuclei appear to occupy almost the entire, cell and mitoses are freq.

Front 271

272. What are pineocytomas?

Back 271

In contrast, pineocytomas occur mostly in adults and are much slower-growing than pineoblastomas. They tend to be well-circumscribed, gray, or hemorrhagic masses that compress but do not infiltrate the surrounding structures.

*Histologically, the tumors may be pure pineocytomas or exhibit divergent glial, neuronal, and retinal differentiation. The tumors are composed of pineocytes having darkly staining, round-to-oval, fairly regular nuclei. Necrosis is unusual.

Front 272

273. What are the distinctive features of pineocytomas?

Back 272

Particularly distinctive are the pineocytomatous pseudorosettes rimmed by rows of pineocytes.

The centers of these rosettes are filled w/eosinophilic cytoplasmic material. These cells are set against a background of thin, fibrovascular anastomosing septa, which confer a lobular growth pattern to the tumor.

Front 273

274. What is the name of the inhibitor of fungal nuclei acid synthesis?

Back 273

Flucytosine - it is the name of the fluorinated pyrimidine 5-fluorocytosine. Flucytosine is selectively taken up by fungal cells via cytosine-specific permeases that are expressed only in fungal membranes. Lacking these transporters, mammalian cells are protected.

Inside the fungal cell, the enzyme cytosine deaminase converts flucytosine to 5-fluorouracil (5-FU).

Subsequent reactions convert 5-FU to 5-fluorodeoxyuridylic acid (5-FdUMP), which is a potent inhibitor of thymidylate synthase. Inhibition of this synthase results in inhibition of DNA synthesis and cell division.

Thus, flucytosine appears to be fungistatic under most circumstances.

Front 274

275. Flucytosine

Back 274

MOA: Flucytosine is converted in several steps to 5-FdUMP, which inhibits thymidylate sythase and thereby interferes w/DNA synthesis

PURPOSE: Candidiasis, cryptococcosis, chromomycosis

ADVERSE: Bone marrow suppression (leukopenia, thrombocytopenia), cardiotoxicity, GI disturbance, hepatic dysfunction

CONTRA: Pregnancy

NOTES: Mutations in cytosine permease or cytosine deaminase account for resistance;
*Combo of glucytosine and amphotericin B exhibits synergistic killing of Aspergillus
*Use w/caution in pts w/renal impairment.

Front 275

276. What is the name of the inhibitor of fungal mitosis?

Back 275

Griseofulvin, a drug derived from Penicillium griseofulvum. It inhibits fugnal mitosis by binding to tubulin and a microtubule-associated protein and thereby disrupting assembly of the mitotic spindle. The drug is also reported to inhibit fungal RNA and DNA synthesis.

Griseofulvin accumulates in keratin precursor cells and binds tightly to keratin in differentiated cells. The prolonged and tight association of griseofulvin w/keratin allows new growth of skin, hair, or nail to be free of infection.

Front 276

277. Griseofulvin

Back 276

MOA: Binds to tubulin and a microtubule-associated protein, thereby disrupting assembly of the mitotic spindle.

PURPOSE: Fugnal infection of the skin, hair, or nail, due to Trichophyton, Microsporum, or Epidermophyton

ADVERSE: Hepatotoxicity, albuminuria, leukopenia, neutropenia, monocytosis, serum sickness, angioedema, toxic epidermal necrolysis, headache, lethargy, vertigo, blurred vision, increased fecal protoporphyrin levels

CONTRA: Pregnancy, porphyria and hepatic failure

Front 277

278. What are five therapeutic considerations for griseofulvin?

Back 277

1. Continue treatment until the infected skin, hair, or nail is completely replaced by normal tissue
2. For adults, the recommended daily dose is 500 mg microsize for skin and 1,000 mg microsize for hair and nail dermatophytes
3. For children, the recommended dose is 5-10 mg/kg/day for cutaneous infections and 15-20mg/kg/day for hair and nail infections
4. Concurrent administration w/barbiturates decreases GI absorption of griseofulvin
5. Griseofulvin induces hepatic P450 enzymes, which may result in increased metabolism of warfarin and reduced efficacy of low-estrogen oral contraceptives

Front 278

279. What are the names of the three inhibitors of squalene epoxidase?

Back 278

1. Terbinafine*
2. Naftifine*
3. Butenafine^

*Allylamines
^Benzylamine

Front 279

280. Terbinafine, naftifine, butenafine

Back 279

MOA: Inhibit conversion of squalene to lanosterol by inhibiting squalene epoxidase.

PURPOSE: Onychomycosis (terbinfine); tinea corporis, tinea cruris, tinea pedis, tinea captitis

ADVERSE: Hepatotoxicity, Stevens-Johnson syndrome, enutropenia, exacerbation of psoriasis or subacute cutaneous lupus erthematosus (oral terbinafine); GI disturbance, burning sensation and local irritation of the skin.

CONTRA: Hypersensitivity to terbinafine, naftifine, or butenafine.

Front 280

281. What are the four therapeutic considerations of terbinafine, naftifine, and butenafine?

Back 280

1. Terbinafine dosage for onychomycosis is 250 mg by mouth daily for 12 weeks for fingernails or for 16 weeks for toenails.
2. Plasma levels of terbinafine are increased by coadministration w/cimetidine and decreased by coadministration w/rifampin
3. Naftifine is only available as a topical cream or gel
4. Topical allylamine and benzylamine agents are more effective than topical azole agents against common dermatophytes, especially those causing tinea pedis

Front 281

282. What are the names of the inhibitors of 14α-sterol demethylase?

Back 281

These are the imidazoles and triazoles.

Imidazoles:
1. Ketoconazole
2. Butoconazole
3. Clotrimazole
4. Econazole
5. Miconazole
6. Oxiconazole
7. Sertaconzole
8. Sulconazole

Triazoles:
1. Fluconazole
2. Itraconzole
3. Posaconazole
4. Terconazole
5. Voriconazole

Front 282

283. How do the inhibitors of 14α-sterol demethylase work?

Back 282

The azoles are antifungal agents that inhibit fungal 14α-sterol demethylase. The resulting decrease in ergosterol synthesis and accumulation of 14α-methyl sterols disrupt the tightly packed acyl chains of the phospholipids in fungal membranes.

Destabilization of the fungal membrane leads to dysfunction of the membrane-associated enzymes, including those in the ETC, and may ultimately lead to cell death.

Azoles are not completely selective for the fungal P450 enzyme, however, and they can also inhibit hepatic P450 enzymes.

*Thus, drug-drug interactions are an important consideration whenever an azole antifungal agent is prescribed.

Front 283

284. Imidazoles: MOA and PURPOSE

Ketoconazole
Butoconazole
Clotrimazole
Econazole
Miconazole
Oxiconazole
Sertaconzole
Sulconazole

Back 283

MOA: Inhibit the ultimate conversion of lanosterol to ergosterol by inhibiting 14α-sterol demethylase; the resulting decrease in ergosterol synthesis and accumulation of 14α-methyl sterols disrupt the tightly packed acyl chains of the phospholipids in fungal membranes.

PURPOSE: Coccidiodes immitis, Cryptococcus neoformans, Candida species, Histoplasma capsulatum, Blastomyces dermatidis, and a variety of dermatophytes (ketoconazole); Superficial fungal infections of the stratum corneum, squamous mucosa, and cornea

Front 284

285. Imidazoles: ADVERSE AND CONTRA

Ketoconazole
Butoconazole
Clotrimazole
Econazole
Miconazole
Oxiconazole
Sertaconzole
Sulconazole

Back 284

ADVERSE: GI disturbance, hepatic dysfunction, gynecomastia, decreased libido, menstrual irregularities (ketoconazole); pruritus and burning (all the others)

CONTRA: Concurrent administration of amphotericin B or oral triazolam (ketoconazole); Hypersensitivity

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286. What are five therapeutic considerations for the imidazoles?

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1. Ketoconazole is available both orally and topically (oral forms cannot penetrate the CNS and urinary tract).
2. Ketoconazole inhibits P450 3A4 and increases levels of many drugs, including warfarin, tolbutamide, phenytoin, cyclosporine, H1-antihistamines, and others
3. Agents that decrease gastric acidity interfere w/ketoconazole administration (pts with achlorhydia or bicarbonate, antacids, or PPIs)
4. Butoconazole, clotrimazole, econazole, miconazole, oxiconazole, sertaconazole, and sulconazole are topical antifungal agents
5. Topical azoles should be applied to the skin 2x/day for 3-6 weeks, whereas vaginal preparations should be used 1x/day for 1-7 days at bedtime.

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287. What is a possible dose-dependent adverse effect in ketoconazole therapy?

Back 286

At therapeutic doses, it inhibits the P450 enzymes 17,20-lyase and side chain cleavage enzyme in the adrenal gland and gonads and thereby decreases steroid hormone synthesis.

Persistent adrenal insufficiency has been reported; at high doses of the drug, significant inhibition of androgen synthesis can result in gynecomastia and impotence.

*This dose-dependent effect has been exploited therapeutically for use to inhibit androgen production in pts with advanced prostate CA and to inhibit corticosteroids in pts w/advanced adrenal CA.

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288. What about topical ketoconazole?

Back 287

Widely used to treat common dermatophyte infections and seborrheic dermatitis (dandruff). Topical forms has been shown to have anti-inflammatory activity comparable to that of hydrocortisone.

The cream formulation contains sulfites and therefore should be avoided in pts w/sulfite hypersensitivity b/c cases of asthma, and even anaphylaxis have been reported.

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289. What's special about miconazole?

Back 288

In addition to inhibiting 14α-sterol demethylase, miconazoel affects fatty acid synthesis and inhibits fungal oxidative and peroxidase enzymes.

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290. What is the main difference between the imidazoles and triazoles?

Back 289

These share the same MOA and similar antifungal spectrum.

B/c systemically administered triazoles tend to have less effect than systemically administered imidazoles on human sterol synthesis, recent drug developments have focused primarily on the triazoles.

Front 290

291. Triazoles: MOA and PURPOSE

Fluconazole
Itraconazole
Posaconazole
Terconazole
Voriconazole

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MOA: Inhibit the ultimate conversion of lanosterol to ergosterol by inhibiting 14α-sterol demethylase; the resulting decrease in ergosterol synthesis and accumulation of 14α-methyl sterols disrupt the tightly packed acyl chains of the phospholipids in fungal membranes.

PURPOSE: Aspergillosis, blastomycosis, candidiasis, histoplasmosis, onychomycosis (itraconazole); Candidiasis, cryptococcal meningitis (fluconazole); Aspergillosis, candidiasis, Fusarium, Monosporium apiospermum (voriconazole); Vulvovaginal candidiasis (terconazole)

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292. Triazoles: ADVERSE and CONTRA

Fluconazole
Itraconazole
Posaconazole
Terconazole
Voriconazole

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ADVERSE: Hepatic toxicity, Stevens-Johnson syndrome, GI disturbance, rash, hypokalemia, hypertension, edema, headache (itraconazole)

CONTRA: Coadministration w/dofetilide, oral midazolam, pimozide, levacetylmethadol, quinidine, lovastatin, simvastatin, or triazolam (itraconazole and fluconazlole); Coadministration w/ergot alkaloids metabolized by P450 3A4 (itraconazole and fluconazole);
*Pregnancy, and hypersensitivity

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293. What are four therapeutic considerations for the triazole antifungals?

Back 292

1. Itraconazole dosage for onychomycosis is 400 mg 2x/day for one week/month, repeated to complete a 3mo course for fingernail infections or a 4mo course for toenail infections
2. Fluconazole and itraconazole inhibit P450 3A4
3. The 0.4% terconazole cream is used for 7 days, whereas the 0.8% cream is used for 3 days for vulvovaginal candidiasis
4. Ravuconazole is in clinical trials

Front 293

294. What What is the most widely used antifungal drug?

Back 293

Fluconazole; it is hydrophilic and the oral bioavailability is nearly 100%, and unlike ketoconazole and itraconazole, its absorption is not influenced by gastric pH.

Once absorbed, fluconazole diffuses freely into CSF, sputum, urine, and saliva. It is excreted primarily by the kidneys.

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295. What is the DOC for systemic candidiasis and cryptococcal menigitis?

Back 294

Its relatively low adverse-effect profile and excellent CSF penetration make fluconazole the DOC for systemic candidiasis and cryptococcal menigitis.

It is also the DOC for Coccidioidal meningitis.

*It is not effective against aspergillosis.

Front 295

296. What about fungal resistance to fluconazole?

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Fungal resistance develops readily, and Candida species are the most notable pathogens to develop resistance.

Mechanisms of drug resistance include mutation of fungal P450 enzymes and overexpression of multidrug efflux transporter proteins.

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297. What is the DOC for invasive aspergillosis and other molds such as Fusarium and Scedosporium?

Back 296

Voriconazole; it is associated with better outcomes;; however, the IV form should not be used in pts w/renal failure b/c the cyclodextrin excipient accumulates and causes CNS toxicity.

Unusual visual symptoms (photophobia and colored lights) can occur at peak plasma concentrations; typically, these symptoms last 30-60 minutes.

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298. What is Amphotericin B and nystatin?

Back 297

Amphotericin B and nystatin are polene macrolide antifungal agents. These drugs act by binding to ergosterol and disrupting fungal membrane stability. The binding to ergosterol produces channels or pores that alter fungal membrane permeability and allow for leakage of essential cellular contents, leading to cell death.

Both its therapeutic effects and its toxicity are related to its affinity for plasma membrane sterols.

Fortunately the affinity of amphotericin B for ergosterol is 500x greater than its affinity for cholesterol.

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299. Amphotericin B

Back 298

MOA: Bind to ergosterol and form pores that alter fungal membrane permeability and stability

PURPOSE: Potentially life-threatening aspergillosis, cryptococcosis, North American blastomycosis, systemic candidiasis, coccidoidomycosis, histoplasmosis, systemic candidiasis, zygomycosis

ADVERSE: Renal toxicity (renal tubular acidosis, cylinduria, hypokalemia), cytokine storm (fever, chills, hypotension), anemia; weight loss, GI disturbance.

CONTRA: Hypersensitivty

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300. What are three therapeutic considerations for amphotericin B?

Back 299

1. Amphotericin B is supplied as a buffered deoxycholate colloidal suspension, which must be administered via IV; intrathecal therapy may be necessary for serious meningeal disease (b/c penetration to the CSF is extremely low).
2. Lipid formulations of amphotericin B are designed to reduce drug exposure to the proximal tubule of the nephron and thereby minimize nephrotoxicity
3. Amphotec, Abelcet, and Ambisome are all FDA-approved lipid-containing preparations of amphotericin B

Front 300

301. What limits the use of amphotericin B?

Back 300

Its toxicity; adverse effects are divided into three groups:

1. Immediate systemic reactions (cytokine storm, b/c of release of TNF-a and IL-2) *can be minimized via administration of antipyretic meds or slowing rate of administration
2. Renal effects*** (renal tubular acidosis, cylindruria [renal casts in the urine], and hypokalemia
3. Hematologic effects (anemia is probably secondary to decreased production of erythropoietin.

Front 301

302. What is nystatin?

Back 301

Nystatin is a structural relative of amphotericin B, and is a polyene antifungal agent that also acts by binding ergosterol and causing pore formations in fungal cell membranes.

The drug is used topically to treat candidiasis involving the skin, vaginal mucosa, and oral mucosa.

Nystatin is not absorbed systemically from the skin, vagina, or GI tract.

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303. Nystatin

Back 302

MOA: Binds to ergosterol and causes pore formations in fungal cell membranes.

PURPOSE: Mucocutaneous candidiasis

ADVERSE: Rare contact dermatitis

CONTRA: Hypersensitivity

NOTES: The drug is used topically to treat candidiasis involving the skin, vaginal mucosa, and oral mucosa. Nystatin is not absorbed systemically from the skin, vagina, or GI tract.

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304. What are the inhibitors of fungal wall synthesis called?

Back 303

Echinocandins, such as caspofungin, micafungin, and anidulafungin

These agents target fungal wall synthesis by noncompetitively inhibiting the synthesis of β-(1,3)-D-glucans. Disruption of the cell wall integrity results in osmotic stress, lysis of the fungal cell, and ultimately fungal cell death.

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305. Caspofungin, micafungin, anidulafungin

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MOA: Noncompetitively inhibit syntehsis of β-(1,3)-D-glucans, which leads to disruption of cell wall integrity

PURPOSE: Esophageal candidiasis, candidemia, slavage therapy of Asperigullus infections, empiric therapy of febrile neutropenia (caspofungin); Esophageal candidiasis, antifungal prophylaxis for recipients of hematopoietic stem cell transplants (micafungin); esophageal candidiasis, candidemia (anidulafungin)

ADVERSE: Pruritus, rash, GI disturbance, increased liver enzymes, thrombophlebitis, headache, fever

CONTRA: Hypersensitivity

NOTES: Caspofungin is highly protein bound (97%) in the plasma; it is metabolized in the liver via peptide hydrolysis and N-acetylation; and it penetrates poorly into the VSF

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306. What are three therapeutic considerations for the echinocandins?

Back 305

1. All three echinocandins are fungicidal against Candida species, including Candida glabrata and Candida krusei, and fungistatic against Aspergillus species
2. Coadministration of cyclosporine w/caspofungin significantly increases plasma concentration of caspofungin and elevates liver function enzymes
3. Caspofungin dose should be adjusted for pts w/moderate liver dysfunction