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305 Cards in this Set

  • Front
  • Back
1. Composition of the adrenal glands
1. Adrenal medulla
-secretes epinephrine and norepinephrine

2. Adrenal cortex
-secretes corticosteroids
2. Mineralocorticoids
They specially affect the electrolytes (the "minerals") of the extracellular fluids; sodium and potassium, in particular.

Aldosterone: principal mineralcorticoid
3. Glucocorticoids
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
4. Three layers of the adrenal cortex
1. zona glomerulosa
2. zona fasciculata
3. zona reticularis
5. Zona glomerulosa
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.
6. Zona fasciculata
Middle and widest layer:
Secretes glucocorticoids cortisol and corticosterone.

Controlled in large part by the HPA axis via ACTH
7. Zona reticularis
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.
8. Synthesis of adrenocortical hormones
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.
9. Difference btwn cortisol and aldosterone
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
10. Mineralocorticoids

(list them and describe their potencies)
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)
11. Glucocorticoids

(list them and their potency)
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)
12. Metabolization of adrenocortical hormones
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.
13. Functions of aldosterone (3)
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
14. Aldosterone and plasma sodium concentration
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
15. Aldosterone and arterial pressure
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.
16. Aldosterone escape
The return to normal of salt and water excretion by the kidneys as a result of pressure natriuresis and diuresis.
17. Excess aldosterone can cause what two things...?
1. Hypokalemia
2. Muscle weakness
18. Too little aldosterone can cause what two things...?
1. Hyperkalemia
2. Cardiac toxicity
19. Hypokalemia
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.
20. Excess aldosterone can also cause...?
A mild degree of alkalosis due to the increase in tubular hydrogen ion secretion
21. Effect of aldosterone on sweat and salivary glands
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.
22. Sodium-potassium adenosine triphosphatase

(what stimulates the activity of this enzyme?)
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.
23. Epithelial sodium channel proteins
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.
24. Evidence of nongenomic actions of aldosterone
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.
25. Four factors that play an important role in the regulation of aldosterone
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
26. Activation of the renin-angiotensin system
Usually occurs in response to diminished blood flow to the kidneys or to sodium loss

Activation results in a severalfold increase in aldosterone secretion
27. What happens when one blocks the formation of angiotensin II
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
28. Function of glucocorticoids
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.
29. Effects of cortisol on carbohydrate metabolism (3)
1. Stimulation of gluconeogenesis
2. Decreased glucose utilization by cells
3. Elevated blood glucose concentration
30. How does cortisol stimulate gluconeogenesis? (2 ways)
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.
31. How does cortisol decrease glucose utilization by cells?
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.
32. How does cortisol cause elevated blood glucose concentration?

What is adrenal diabetes?
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)
33. What are three effects of cortisol on protein metabolism?
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
34. What and where is the exception to the reduction in cellular protein with cortisol?
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)
35. What are two effects of cortisol on fat metabolism?
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
36. How is cortisol important in resisting stress and inflammation?
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.
37. What are the two main anti-inflammatory effects of cortisol?
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.
38. How does cortisol prevent inflammation?

5 ways...
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
39. How does cortisol resolve inflammation?
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.
40. What are four other effects of cortisol?
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
41. What is ACTH?
Controls secretion of cortisol.

Secreted by anterior pituitary gland

It is a large polypeptide w/a chain length of 39 AAs
42. How is ACTH release controlled?
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.
43. ACTH and second messengers

What is the rate limiting step for all the adrenocortical hormones?
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
44. Where does cortisol have negative feedback inhibition? (two places)
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
45. Addison's disease
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
46. Symptoms of Addison's disease
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
47. Treatment of Addison's disease
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
48. What is an Addisonian crisis?
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.
49. What are four things that can cause Cushing's syndrome (hyperadenalism)?
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
50. Characteristics of Cushing's syndrome
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
51. What is Pituitary Cushing syndrome?
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.
52. Ectopic ACTH Cushing syndrome
Results in an elevated ACTH but its secretion is completely insensitive to low or high doses of dexamethasone
53. Adrenal tumor Cushing syndrome
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
54. Cushing syndrome effects on carbohydrate and protein metabolism
Abudance of cortisol can caused increased blood glucose concentration and high levels of glucocorticoids cause protein catabolism which results in severe weakenss.
55. Treatment of Cushing syndrome
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.
56. What is Conn's syndrome (Primary Aldosteronism)?
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.
57. What are three causes of primary aldosteronism?
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.
58. Dx criteria of primary aldosteronism
Decreased plasma renin concentration
59. Treatment of primary aldosteronism
Surgical removal of the tumor or most of the adrenal tissue when hyperplasia is the cause.
60. Androgenital syndrome
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.
61. What is the rate-limiting step in the synthesis of cortisol?
The conversion of cholesterol to pregnenolone
62. What oxidase enzyme catalyzes each step in the pathway of adrenocortical hormone synthesis?
Mitochondrial cytochromes; similar to the liver P450 oxidase system.
63. Why does the zona fasciculata synthesize cortisol, but not aldosterone or androgens?
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.
64. What are the most important plasma proteins that binds cortisol?
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
65. Where are the two primary sites of peripheral cortisol metabolism?
1. Liver
2. Kidneys
66. What are type I vs. type II glucocorticoid receptors
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
67. Regulation of cortisol production
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
68. Why is tapering to a lower dosage of exogenous glucocorticoids necessary?
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
69. Cortisol analogues (four of them)
1. Prednisone
2. Prednisolone
3. Fludrocortison
4. Dexamethasone
70. Glucocorticoid receptor agonists
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
71. Clinical application of glucocorticoid receptor agonists

1. Inflammatory conditions in many different organs

2. Autoimmune diseases

3. Replacement therapy for primary and secondary adrenal insufficiency
72. Adverse effects of glucocorticoid receptor agonists
1. Immunosuppression
2. Hyperglycemia
3. Hypercortisolism
4. Impaired wound healing
5. Hypertension
6. Fluid retention
7. Inhaled oropharyngeal candidiasis
73. 177. Contraindications of glucocorticoid receptor agonists
Systemic fungal infection
74. 178. Inhaled glucocorticoids
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
75. Glucocorticoid receptor antagonists
Competitive antagonist of cortisol action at the glucocorticoid receptor

Mifepristone (RU-486)
76. Clinical application of glucocorticoid receptor antagonists (Mifepristone)

Common adverse effects?
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
77. Contraindications of glucocorticoid receptor antagonists (Mifepristone)?
1. Chronic adrenal failure
2. Ectopic pregnancy
3. Hemorrhagic disorders
4. Anticoagulation theraphy
5. Intrauterine devices
78. Inhibitors of glucocorticoid synthesis
Inhibits various steps in the glucocorticoid hormone biosynthesis

1. Mitotane
2. Aminoglutethimide
3. Metyrapone
4. Trilostane
5. Ketoconazole
79. Mitotane
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
80. Aminoglutethimide
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
81. Metyrapone
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
82. Trilostane
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
83. Mineralocorticoid receptor agonists
Agonist at the mineralocorticoid receptor

84. Fludrocortisone
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
85. Mineralocorticoid receptor antagonists
Competetive antagonist of aldosterone action at the mineralocorticoid receptor

1. Spironolactone
2. Eplerenone
86. Adrenal sex steroid (DHEA)
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.
87. What is a key regulatory point in human sterol metabolism?
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.
88. What is the mechanism that removes unwanted or excessive cholesterol and plant sterols from the enterocyte?
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.
89. How is cholesterol eliminated from the body?
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.
90. ABC proteins
Their expression increases the amount of sterols present in the gut lumen, with the potential to increase elimination of the sterols into the feces.
91. Phytosterolemia
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.
92. Cholesterol structure
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)
93. About how much of the plasma cholesterol exists in the free or unesterified form?
Approx 1/3 of the plasma cholesterol exists in the free or unesterified form

The reamining 2/3's exist as cholesterol esters.
94. What can be inferred from cholesterol's structure?
The structure suggests that its synthesis involves multimolecular interactions and significant reducing power.

All 27 C's are derived from one precursor, acetyl CoA.
95. Where does the reducing power of cholesterol synthesis come from?
NADPH provided by the G6PD of the hexose monophosphate shunt pathway.
96. Where does cholesterol synthesis occur, and what does it require?
Occurs in the cytosol

Requires hydrolysis of high energy thioester bonds of acetyl CoA and phosphoanhydride bonds of ATP.
97. What are the four stages of cholesterol synthesis?
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
98. Stage 1 part 1 of cholesterol synthesis

What is significant about this stage?
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).
99. Stage 1 part 2 of cholesterol synthesis

What is significant about this stage?
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
100. HMG-CoA reductase
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.
101. How is the rate of synthesis of HMG-CoA reductase mRNA controlled?
The rate of synthesis of HMG-CoA reductase mRNA is controlled by one of the family of sterol-regulatory element binding proteins (SREBPs)
102. SREBPs
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.
103. SCAP and regulation of transcription of the reductase gene
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
104. Proteolytic degradation of HMG-CoA reductase
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.
105. How else is the activity of HMG-CoA regulated?

Five specific influences...
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
106. Cholesterol synthesis and ATP levels
When ATP levels are low, cholesterol synthesis decreases

When ATP levels are high, it increases.
107. Stage 2

What are the two main products formed at the end of this stage?
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
108. Stage 3

What is the end product of this stage?
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.
109. Squalene
End product of stage 3

Contains 30 carbons (24 in the main chain and 6 in the methyl group branches)
110. Stage 4
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.
111. Where does most of the production of cholesterol occur?

Where else does it occur?
Liver cells

Also occurs in the gut, adrenal cortex, and the gonads (as well as the placenta in pregnant women)
112. The bulk of synthesized cholesterol is secreted from the hepatocyte as one of what three moieties?
1. Cholesterol esters
2. Biliary cholesterol
3. Bile acids
113. ACAT (acyl-CoA-cholesterol acyl transferase)
Catalyzes cholesterol ester production in the liver.

Catalyzes the transfer of a FA from CoA to the hydroxyl group on C3 of cholesterol.
114. Low vs. high cholesterol diets and their effects on cholesterol synthesis in the liver
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)
115. Bile salt synthesis reactions
Bile salts are synthesized in the liver from cholesterol by reactions that hydroxylate the steroid nucleus and cleave the side chain.
116. Bile salt synthesis (First step)

What can inhibit this step?
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
117. Bile salt synthesis (formation of two sets of bile salts)
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.
118. pKa of bile acids
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.
119. Conjugation of bile salts
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
120. Glycine vs. taurine conjugation

How does this affect ionization?
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
121. Breakdown of bile salts
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.
122. Secondary bile salts

Give an example of one...?
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.
123. Efficiency of enterohepatic circulation
Less than 5% of the bile salts entering the gut are excreted in the feces each day.

Very efficient I would say...
124. Three important functions of apoproteins...
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.
125. Chylomicrons
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.
126. What are the major apoproteins of chylomicrons?
1. ApoB-48
2. ApoC-II
3. ApoE
127. ApoC-II
Activates lipoprotein lipase which allows LPL to hydrolyze the chylomicrons, leading to the release of free FAs
128. Chylomicron remnants
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.
129. Nascent VLDLs
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
130. Mature VLDLs
The nascent VLDLs are secreted from the liver into the bloodstream, where they accept ApoCII and ApoE from circulating HDL particles
131. VLDL remnants
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.
132. What happens to the other half of the VLDL remnants?
The other half are into taken up by the liver but, instead, have additional core TAGs removed to form IDL.
133. LDLs
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.
134. Transport of LDLs
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.
135. What happens to excess LDLs in the blood?
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
136. Synthesis of HDL (3 methods)
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
137. HDL composition
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.
138. Maturation of nascent HDL
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.
139. Reverse cholesterol transport
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
140. ABC1
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.
141. How is the cholesterol trapped/modified in the HDL particle?
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.
142. Mutations in the ATP-binding cassette 1 protein
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.
143. Clearance of HDL
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.
144. What else does HDL do?
Exchanges apoproteins and lipids w/other lipoproteins in the blood via CETP
145. CEPT (cholesterol ester transfer protein)
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.
146. How do lipoproteins enter cells?
Via receptor mediated endocytosis
147. Structure of the LDL receptor

What are the six regions?
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
148. Four classes of mutations involving LDL receptors
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.
149. LDL receptor-related protein (LRP)
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.
150. Locations of LRP
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.
151. Macrophage scavenger receptor
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.
152. Layers of the artery from the inside out (6 layers)
1. Intima
2. Subintimal ECM
3. Tunica media
4. Internal elastic lamina
5. External elastic lamina
6. Adventitia
153. Cholesterol is the precursor of what five classes of steroid hormones?
1. Glucocorticoids
2. Mineralcorticoids
3. Androgens
4. Estrogens
5. Progestins
154. Synthesis of cortisol vs. aldosterone vs. adrenal androgens vs. testosterone

Where does this take place?
Cortisol: zona fasciculata

Aldosterone: zona glomerulosa

Adrenal androgens: zona reticulosum

Testosterone: Leydig cells in testes
155. CAH

What are the three types?
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.
156. DOC (Deoxycorticosterone)
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.
157. DHEAS
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.
158. Rickets
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.
159. Primary hypercholesterolemia
Characterized by elevated levels of plasma cholesterol and LDL cholesterol, with normal levels of triglycerides.
160. Causes of primary hypercholesterolemia (3)
1. Familial hypercholesterolemia
2. Familial defective apoB100
3. Polygenic hypercholesterolemia
161. Clinical features of familial hypercholesterolemia (heterozygous)
1. High total plasma cholesterol concentrations
2. Tendon xanthomas
3. Arcus corneae (deposition of cholesterol in the cornea)
162. Clinical features of familial hypercholesterolemia (homozygous)
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)
163. Inhibitors of cholesterol synthesis (statins)

How do they work?
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.
164. What are the four therapeutic benefits of statins?

AKA "pleiotropic effects of statins"
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
165. What are statins used to treat?
Effective in lowering plasma cholesterol levels in all types of hyperlipidemias, except homozygous familial hypercholesterolemia
166. Fibrates

How do they work?
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.
167. Thiazolidinediones (TZD)
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.
168. How do TZDs work?
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.
169. What is metformin?
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.
170. How does metformin work?
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.
171. What are the three types of hyperadrenal clinical syndromes?
1. Cushing syndrome, characterized by an excess of cortisol
2. Hyperaldosteronism
3. Adrenogenital or virilizing syndromes caused by a n excess of androgens
172. What is the pathogenesis of Cushing syndrome?
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.
173. What are the three sources of hypercortisolism that can be categorized as endogenous Cushing syndrome?
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
174. What accounts for 70-80% of cases of endogenous hypercortisolism?
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.
175. What about primary adrenal neoplasms and primary cortical hyperplasia?
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.
176. In what populations are adenomas and CAs common?

What is the main difference btwn cortical carcinomas and adenomas or hyperplastic processes?
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.
177. What causes a majority of hyperplastic adrenal processes?

What are the two types?
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)
178. What is massive macronodular adrenocortical disease (MMAD)?
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.
179. What is primary pigmented nodular adrenal disease (PPNAD)?
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).
180. What about secretion of ectopic ACTH by nonpituitary tumors as a cause of Cushing syndrome?
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.
181. What is the morphology of the pituitary in Cushing syndrome?
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.
182. What is the morphology of the adrenal glands in Cushing syndrome?
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
183. What is the morphology of cortical atrophy of the adrenal glands?
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.
184. What is the morphology of diffuse hyperplasia of the adrenals?
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.
185. What is the morphology of nodular hyperplasia of the adrenals?
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.
186. What is the morphology of primary adrenocortical neoplasms?
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.
187. What is the morphology of adrenocortical adenomas?
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.
188. What is the morphology of the carcinomas associated w/Cushing syndrome?
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.
189. What is the clinical course of Cushing syndrome?
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
190. How is Cushing syndrome diagnosed?
1. The 24-hour urine free cortisol level, which is increased
2. Loss of normal diurnal pattern of cortisol secretion.
191. What are the ACTH levels in pituitary Cushing syndrome?
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.
192. What are the ACTH levels in ectopic and adrenal tumor Cushing syndrome?
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.
193. What is primary hyperaldosteronism?
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.
194. What are the three ways in which primary hyperaldosteronism can be caused?
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
195. What is Conn syndrome?
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.
196. What is primary adrenocortical hyperplasia?

What is the genetic basis?
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.
197. What is glucocorticoid-remediable hyperaldosteronism?

What is the genetic basis?
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.
198. What are the three cases in which secondary hyperaldosteronism occurs?
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).
199. What is the morphology of aldosterone producing adenomas?
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).
200. What is a characteristic feature of aldosterone producing adenomas?
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.
201. What is bilateral idiopathic hyperplasia?
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.
202. What is the clinical course of primary hyperaldosteronism?
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.
203. What is adenogenital syndrome?
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.
204. Adrenocortical neoplasms associated w/virilization are more likely to be...?
Androgen-secreting adrenal carcinomas than adenomas.

Conversely, functioning adrenal cortical CAs are most often associated w/a virilization syndrome, usually in combo w/hypercortisolism.
205. What is CAH?
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.
206. What is 21-Hydroxylase deficiency?

What are the three distinctive syndromes associated w/this deficiency?
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
207. What is the mechanism of CYP21B gene inactivation?
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.
208. What causes the salt-wasting syndrome?
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.
209. What are the features of the salt-wasting syndrome?
There is salt wasting, hyponatremia, and hyperkalemia, which induce acidosis, hypotension, cardiovascular collapse, and possibly death.
210. Male vs. female differences in virilization in salt-wasting adrenogenitalism
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.
211. What is simple virilizing adrenogenital syndrome w/o salt wasting?
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.
212. What is the nonclassic or late-onset adrenal virilism?
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.
213. What is the morphology of the adrenals in CAH?
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.
214. What is the clinical course of CAH?
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.
215. What is the treatment for CAH?
Pts w/CAH are treated w/exogenous glucocorticoids.

Mineralocorticoid supplementation is required in the salt-wasting variants of CAH.
216. What is adrenomedullary dysplasia?
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.
217. What are the three patterns of adrenal insufficiency?
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
218. In what three settings does primary acute adrenocortical insufficiency occur?
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.
219. What is Waterhouse-Friderichsen syndrome?

What are the four characteristics of this syndrome?
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***
220. What is primary chronic adrenocortical insufficiency (Addison disease)?
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.
221. What are the four most common causes of primary adrenal insufficiency?
1. Autoimmune adrenalitis
2. Tuberculosis
4. Metastatic cancers
222. What is autoimmune adrenalitis?
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.
223. What are the three clinical settings in which autoimmune adrenalitis can occur?
1. Autoimmune polyendocrine syndrome type 1 (APS1) AKA autoimmune polyendocrinopathy
2. Autoimmune polyendocrine syndrome type 2 (APS2)
3. Isolated autoimmune Addison disease
224. What is autoimmune polyendocrine syndrome type 1 (APS1) AKA autoimmune polyendocrinopathy?
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).
225. What is the function of the AIRE protein?
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.
226. What is APS2?
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.
227. What is isolated autoimmune Addison disease?
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.
228. What infections can cause primary chronic adrenocortical insufficiency?
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).
229. What about metastatic neoplasms and the adrenals?
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.
230. What are the genetic disorders of adrenal insufficiency?
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.
231. What is the morphology of the adrenals in autoimmune adrenalitis?
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.
232. What is the morphology of adrenal insufficiency caused by tuberculous and fungal diseases, as well as that caused by metastatic CA?
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.
233. What is the clinical course of Addison disease?
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.
234. What is secondary adrenocortical insufficiency?
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.
235. What is the morphology of secondary adrenocortical insufficiency?
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.
236. What is the morphology of adrenocortical adenomas?
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.
237. What are adrenocortical carcinomas?
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.
238. What is the morphology of adrenocortical CAs?
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.
239. Which CA may metastasize to the adrenals and be difficult to differentiate from primary cortical CAs?
CAs of bronchogenic origin.
240. What are two rare inherited causes of adrenal cortical CAs?
1. Li-Fraumeni syndrome
2. Beckwith-Wiedemann syndrome
241. What are adrenal cysts?
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.
242. What are adrenal myelolipomas
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.
243. What is an adrenal incidentaloma?
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.
244. What is pheochromocytoma?
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.
245. What are the five "rule of 10's" for pheochromocytomas?
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.
246. What are the components of MEN-2A
1. Medullary thyroid CAs and C-cell hyperplasia
2. pheochromocytomas and adrenal medullary hyperplasia
3. Parathyroid hyperplasia
247. What are the components of MEN-2B?
1. Medullary thyroid CAs and C-cell hyperplasia
2. Pheochromocytomas and adrenal medullary hyperplasia
3. Mucosal neuromas
4. Marfanoid features
248. What are the components of von Hippel-Lindau syndrome?
1. Renal, hepatic, pancreatic, and epididymal cysts
2. Renal cell CAs
3. Pheochromocytomas
4. Angiomatosis
5. Cerebellar hemangioblastomas
249. What are the components of von Recklinghausen syndrome?
1. Neurofibromatosis
2. Cafe au lait skin spots
3. Schwannomas, meningiomas, gliomas
4. Pheochromocytomas
250. What are the components of Sturge-Weber syndrome?
1. Cavernous hemangiomas of fifth cranial nerve distribution
2. Pheochromocytomas
251. What is the morphology of pheochromocytomas?

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.
252. What is the morphology of pheochromocytomas?

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.
253. How can one test for the immunoreactivity of pheochromocytomas?
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.
254. What is the criteria for determining malignancy in pheochromocytomas?
*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.***
255. What is the clinical course of pheochromocytomas?
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.
256. What are the complications of pheochromocytoma-associated hypertension?

What is catecholamine cardiomyopathy?
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).
257. What are paragangliomas?

What are chemodectomas?

What are carotid body tumors?
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.
258. What is a neuroblastoma?
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.
260. What are five distinct features of the tumors arising in the context of MEN syndromes that separate them from their sporadic counterparts?
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.
261. What is MEN-1, or Wermer syndrome?
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)
262. What are the 3P's of MEN-1?
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.
263. What causes MEN-1 syndrome?
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.
264. What are the clinical manifestations of MEN-1?
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).
265. What is MEN-2A?

What are the genetic alterations associated w/MEN-2A?
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***
266. What is MEN-2B?
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.
267. What genetic mutation is responsible for MEN-2B?
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.
268. What is familial medullary thyroid CA, and how is it related to MEN-2A?
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.
269. What are the most common tumors of the pineal gland?
Most arise from sequestered embryonic germ cells. They most commonly take the form of so-called germinomas, resembling testicular seminoma or ovarian dysgerminoma.
270. What are pineoblastomas?
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.
271. What is the morphology of pineoblastomas?
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.
272. What are pineocytomas?
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.
273. What are the distinctive features of pineocytomas?
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.
274. What is the name of the inhibitor of fungal nuclei acid synthesis?
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.
275. Flucytosine
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.
276. What is the name of the inhibitor of fungal mitosis?
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.
277. Griseofulvin
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
278. What are five therapeutic considerations for griseofulvin?
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
279. What are the names of the three inhibitors of squalene epoxidase?
1. Terbinafine*
2. Naftifine*
3. Butenafine^

280. Terbinafine, naftifine, butenafine
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.
281. What are the four therapeutic considerations of terbinafine, naftifine, and butenafine?
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
282. What are the names of the inhibitors of 14α-sterol demethylase?
These are the imidazoles and triazoles.

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

1. Fluconazole
2. Itraconzole
3. Posaconazole
4. Terconazole
5. Voriconazole
283. How do the inhibitors of 14α-sterol demethylase work?
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.
284. Imidazoles: MOA and PURPOSE

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
285. Imidazoles: ADVERSE AND CONTRA

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
286. What are five therapeutic considerations for the imidazoles?
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.
287. What is a possible dose-dependent adverse effect in ketoconazole therapy?
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.
288. What about topical ketoconazole?
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.
289. What's special about miconazole?
In addition to inhibiting 14α-sterol demethylase, miconazoel affects fatty acid synthesis and inhibits fungal oxidative and peroxidase enzymes.
290. What is the main difference between the imidazoles and triazoles?
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.
291. Triazoles: MOA and PURPOSE

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)
292. Triazoles: ADVERSE and CONTRA

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
293. What are four therapeutic considerations for the triazole antifungals?
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
294. What What is the most widely used antifungal drug?
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.
295. What is the DOC for systemic candidiasis and cryptococcal menigitis?
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.
296. What about fungal resistance to fluconazole?
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.
297. What is the DOC for invasive aspergillosis and other molds such as Fusarium and Scedosporium?
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.
298. What is Amphotericin B and nystatin?
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.
299. Amphotericin B
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
300. What are three therapeutic considerations for amphotericin B?
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
301. What limits the use of amphotericin B?
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.
302. What is nystatin?
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.
303. Nystatin
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.
304. What are the inhibitors of fungal wall synthesis called?
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.
305. Caspofungin, micafungin, anidulafungin
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
306. What are three therapeutic considerations for the echinocandins?
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