Rr 22 Endocrine Part 2

Front 1

What are the adrenal cortex hormones?

Back 1

1. Zona glomerulosa produces mineralocorticoids (eg, aldosterone)
2. Zona fasciculata produces glucocorticoids
3. Zona reticularis produces sex hormones

Front 2

What area of the cortex produces mineralocorticoids?

Back 2

Zona glomerulosa

Front 3

Describe the production of mineralocorticoids by the zona glomerulosa

Back 3

Angiotensin II activates 18-hydroxylase, which converts corticosterone to aldosterone

Front 4

What area of the cortex produces glucocorticoids?

Back 4

Zona fasciculata

Front 5

Describe the glucocorticoids produced by the zona glomerulosa

Back 5

11-Deoxycortisol and cortisol are 17-hydroxycorticoids

Front 6

What area of the cortex produces sex hormones?

Back 6

Zona reticularis

Front 7

Describe the sex hormones produced by the zona reticularis

Back 7

1. 17-Ketosteroids (17-KS)
-Dehydroepiandosterone (DHEA) and andostenodione

2. Testosterone
-Converted to dihydrotesosterone (DHT) by 5α-reductase in peripheral tissue sites

Front 8

Describe the adrenal medulla

Back 8

1. Of neural crest origin
2. Produces catecholamines
-Epinephrine (EPI) and norepinephrine (NOR)
3. Metabolic products of EPI and NOR
-Metanephrine and vanillylmandelic acid (VMA)
4. Metabolic product of dopamine is homovanillic acid (HVA)

Front 9

What are the metabolic products of epinephrine and NE?

Back 9

Metanephrine and vanillylmandelic acid (VMA)

Front 10

What is the metabolic product of dopamine?

Back 10

Homovanillic acid (HVA)

Front 11

What are the peripheral tissue sites that convert testosterone into dihydrotestosterone (DHT)

Back 11

1. Skin
2. Testes
3. Prostate
4. Seminal vesicles
5. Epididymis
6. Liver

Front 12

List the causes of Adrenocortical hypofunction

Back 12

1. Acute adrenocortical insufficiency
2. Chronic adrenal insufficiency (Addison's disease)
3. Adrenogenital syndrome (congenital adrenal hyperplasia)

Front 13

What is the most common cause of acute adrenocortical insufficiency?

Back 13

Abrupt withdrawal of corticosteroids

Front 14

What are the causes of acute adrenocortical insufficiency?

Back 14

1. Abrupt withdrawal of corticosteroids
2. Waterhouse-Friderichsen syndrome
3. Anticoagulation therapy

Front 15

Describe Waterhouse-Friderichsen syndrome

Back 15

1. Usually associated with septicemia from Neisseria meningitidis
2. Patients develop endotoxic shock
-Release of tissue thromboplastin causes DIC
3. Bilateral adrenal hemorrrhage
-Fibrin clots in vessels cause hemorrhagic infarction

Front 16

What are the causes of Chronic adrenal insufficiency (Addison's disease)?

Back 16

1. Autoimmune destruction
-Most common cause (80%) of cases
2. Miliary tuberculosis (15% of cases/histoplasmosis)
3. Adrenogenital syndrome
4. Metastasis
-Most often from a primary lung cancer
5. AIDS (30% of patients)

Front 17

What is the most common cause of Addison's disease in the US?

Back 17

Autoimmune

Front 18

What is the most common cause of Addison's disease in the developing world?

Back 18

Miliary TB

Front 19

What is the most common cause of Addision's disease in children?

Back 19

Adrenogenital syndrome

Front 20

Describe the clinical findings of Chronic Adrenal Insufficiency (Addison's disease)

Back 20

1. Weakness and hypotension
-Due to Na loss from mineralocorticoid and glucocorticoid deficiency

2. Diffuse hyperpigmentation
a. Increased plasma ACTH stimulates melanocytes
b. Buccal mucosa, skin, sin creases

Front 21

Describe the laboratory findings in Chronic adrenal insufficiency (Addison's disease)

Back 21

1. Short and prolonged ACTH stimulation test
-No increase in cortisol or 17-OH
2. Metyrapone test
-Increased ACTH but no increase in 11-deoxycortisol
3. Increased plasma ACTH
4. Electrolyte findings
-Hyponatremia, hyperkalemia, and metabolic acidosis
5. Fasting hypoglycemia
-Due to decrease in cortisol (cortisol is gluconeogenic)
6. Eosinophilia, lymphocytosis, and neutropenia
-Due to decrease in cortisol

Front 22

Describe the effect of Aldosterone on the Kidneys

Back 22

1. Enhances the exchange of Na for K in the kidneys

2. Hence, its deficiency leads to a hypertonic loss of Na in the urine (hyponatreimia) and retention of K (hyperkalemia)

3. Aldosterone also enhances the proton pump.

4. Deficiency leads to retention of protons and metabolic acidosis (normal anion gap type)

Front 23

What is the cause of Adrenogenital syndrome (congenital adrenal hyperplasia)

Back 23

1. Autosomal recessive disorders
2. From enzyme deficiencies that cause hypocortisolism and corresponding increase in ACTH

Front 24

Describe the consequences of increase in ACTH in adrenogenital syndrome (congenital adrenal hyperplasia)

Back 24

Causes adrenocortical hyperplasia and diffuse skin pigmentation

Front 25

Describe the consequences of increase in 17-KS, testosterone and DHT in adrenogenital syndrome (congenital adrenal hyperplasia)

Back 25

1. Ambiguous genitalia in females
-Primarily due to DHT first step is to check the genetic sex of the newborn with chromosome analysis

2. Precocious puberty may develop in males and females
-In girls, excess androgens and aromatized in peripheral tissue to estrogen

3. Girls experience irregular menses and infertility as adults

4. Both sexes have rapid growth in childhood, but early fusion of epiphyses
-Majority have short stature as adults

Front 26

Describe the consequences of decrease in 17-KS, testosterone, DHT in females in adrenogenital syndrome (congenital adrenal hyperplasia)

Back 26

Females have delay in menarche and development of secondary sex characteristics (female hormones come from androgens)

Front 27

Describe the consequences of decrease in 17-KS, testosterone, DHT in males in adrenogenital syndrome (congenital adrenal hyperplasia)

Back 27

Males develop pseudohermaphroditism
-Male external genitalia development requires DHT

Front 28

Describe the consequences of increase in mineralocorticods in adrenogenital syndrome (congenital adrenal hyperplasia)

Back 28

Causes Na retention leading to hypertension

Front 29

Describe the consequences of decrease mineralocorticoids in adrenogenital syndrome (congenital adrenal hyperplasia)

Back 29

1. Na loss (hyponatremia), hyperkalemia
2. Hypotension and possible hypovoluemic shock

Front 30

Describe the general theme of substrate levels in Adrenogenital syndrome (congenital adrenal hyperplasia)

Back 30

1. Substrates proximal to the enzyme block increase

2. Substrates distal to the enzyme block decrease

Front 31

What is the most common cause of adrenogenital syndrome?

Back 31

Classic 21-hydroxylase (OHase) deficiency

Front 32

Describe Classic 21-hydroxylase (OHase) deficiency

Back 32

1. Most common enzyme deficiency in Adrenogenital syndrome (congenital adrenal hyperplasia), (90-95% of cases)
2. Increase in 17-KS, testosterone, and DHT
3. Decrease in mineralocortocoids (salt losers)
4. Decrease in 17-OH
5. iNcrease in 17-Hydroxyprogesterone

Front 33

Describe nonclassic 21-hydroxylase deficiency

Back 33

1. Impaired cortisol production but normal mineralocorticoids production (not Na wasting)

2. Ambiguous genitalia in females and virilization; precocious puberty in boys

Front 34

Describe 11-hydroxylase deficiency

Back 34

1. Increase in 17-KS, testosterone, and DHT
2. Increase in mineralocorticoids (11-deoxycorticosterone); salt retainers
3. Increase in 17-OH (11-deoxycortisol is proximal to the block)
4. Increase in 17-hydroxyprogesterone

Front 35

Describe 17-hydroxylase deficiency

Back 35

1. Decrease in 17-KS, 17-OH, 17-hydroxyprogesterone, testosterone, and DHT

2. Increase in mineralocorticoids (salt retainers)

Front 36

Describe the diagnosis of adrenogenital syndrome

Back 36

1. Serum 17-OH progesterone is an excellent screening test
a. Increased in 21- and 11-OHase deficiency
b. Decreased in 17-OHase deficiency
c. Can measure prenatally with chorionic villous sampling
d. Screening test in most but not all states on newborns

2. Urine for 17-hydroxycorticoids and 17-ketosteroids

Front 37

Describe the treatment of Adrenogenital syndrome

Back 37

1. Glucocortiocds

2. Mineralocortociods (21-OHase deficiency)

3. Estrogen or testosterone at time of puberty

Front 38

List the causes of Adrenocortical hyperfunction

Back 38

1. Cushing syndrome

2. Hyperaldosteronism

Front 39

List the causes of Cushing syndrome

Back 39

1. Prolonged corticosteroid therapy
-Most common cause

2. Pituitary Cushing Syndrome (Cushing disease)
a. 60% of cases
b. Due to a pituitary adenoma
c. Markedly decreased ACTH and increased cortisol

3. Adrenal Cushing syndrome
a. 25% of cases
b. Most often due to an adenoma
c. Markedly decreased ACTH and increased cortisol

4. Ectopic Cushing syndrome
a. 15% of cases
b. Usually small cell carcinoma of lung; less commonly thymus, thyroid
-Ectopic ACTH production
c. Markedly increased ACTH and cortisol

Front 40

What is the most common cause of Cushing syndrome?

Back 40

Corticosteroid therapy (iatrogenic)

Front 41

Describe the clinical findings Cushing syndrome

Back 41

1. Weight gain
2. Muscle weakness
3. Diastolic hypertension
4. Hirsutism
5. Purple abdominal stria
6. Osteoporosis

Front 42

Describe the weight gain in Cushing syndrome

Back 42

1. Due to hyperinsulinism from hyperglycemia
-Insulin increases storage of fat (triglyceride) in adipose; also has mineralocorticoid effects and retains Na

2. Fat deposition in face (moon facies), upper back (buffalo hump), and trunk (truncal obesity)

Front 43

Describe the muscle weakness in Cushing syndrome

Back 43

1. Cortisol breaks down muscles in th eextremities (thin extremities)

2. Muscles supply amino acids (eg, alanine) for gluconeogenesis

Front 44

Describe the Diastolic hypertension in Cushing syndrome

Back 44

1. Due to increase in weak mineralocorticoids and glucocorticoids

2. Aldosterone is not increased (required angiotensin II)

Front 45

Describe the Hirsutism in Cushing syndrome

Back 45

Due to increased androgens

Front 46

Describe the purple abdominal stria in Cushing syndrome

Back 46

Cortisol weakens collagen, causing rupture of blood vessels in stretch markes

Front 47

Describe the osteroporosis in Cushing syndrome

Back 47

Hypercortisolism causes increased breakdown of bone

Front 48

Describe the laboratory findings in Cushing syndrome

Back 48

1. Increased urine for free cortisol
-Very high positive and negative predictive values
2. Low-dose dexamethasone (cortisol analogue) suppression test
-Cannot suppress cortisol in all types
3. High dose dexamethasone suppression test
-Can suppress cortisol in pituitary Cushing syndrome but not the other types
4. Hyperglycemia
a. Cortisol enhances gluconeogenesis
b. Stimulates the release of insulin
5. Hypokalemic metabolic alkalosis
-Due to increased weak mineralocorticoids

Front 49

Describe Nelson's syndrome

Back 49

1. Bilateral adrenalectomy causes enlargement of a preexisting pituitary adenoma
-Sudden drop in cortisol causesan increase in synthesis of ACTH
2. Clinical findings of headache and diffuse hyperpigmentation

Front 50

Describe cause of primary aldosteronism (Conn's syndrome)

Back 50

Most often due to a benign adenoma in the zona glomuerlosa

Front 51

Describe the clinical findings of Primary aldsoteronism (Conn's syndrome)

Back 51

1. Diastolic hypertension
2. Muscle weakness, tetany (from metabolic acidosis)

Front 52

Describe the laboratory findings of Primary aldosteronism (Conn's syndrome)

Back 52

1. Hypernatremia, hypokalemia, metabolic alkalosis
2. Decreased plasma renin activity

Front 53

Describe how primary hyperaldosteronism leads to metabolic alkalosis

Back 53

1. There is increased exchange of Na (hypernatremia) for K (hypokalemia)

2. Na exchanges with hydrogen ions when K is depleted, causing a loss of H ions in the urine and a corresponding increase in bicarbonate reabsorption (metabolic alkalosis)

Front 54

Describe how primary aldosteronism leads to hypertension

Back 54

1. Hypernatremia increases plasma volume, which increases renal blood flow and inhibits plasma renin activity

2. Chronic retention of Na produces hypertension

Front 55

Describe secondary aldosteronism

Back 55

1. Compensatory reaction related to a decrease in cardiac output

2. Decreased renal blood flow activates the renin-angiotensin-aldosterone system

3. Plasma renin activity is increased

Front 56

List the causes of adrenal medulla hyperfunction

Back 56

1. Pheochromocytoma
2. Neuroblastoma

Front 57

Describe the epidemiology of pheochromocytomas

Back 57

1. Unilateral (~90% of cases)
2. Benign adenoma (~90% of cases)
3. Arises in the adrenal medulla (~90% of cases)
-Other sites: bladder, organ of Zuckerkandl near the bifurcation of the aorta, posterior medastinum
4. N-methytranferase converts NE to EPI

Front 58

Describe N-methytranferase in pheochromocytomas

Back 58

1. Converts NE to EPI
2. Adrenal medulla and the organ of Zuckerkandle contain the enzyme
-Pheochromocytoma produces NE and Epi
3. Other sites lack the enzyme
-Pheochromocytoma produces only NE

Front 59

What conditions are pheochromocytomas associated with?

Back 59

1. Neurofibromatosis (5% in type 1)
2. MEN IIa and IIb (MEN III)
-Mutation in RET protooncogene
3. Von Hippel-Lindau disease (often bilateral tumors)
-Mutation in VHL gene

Front 60

Describe the characteristics of the pheochromocytoma tumor

Back 60

Brown, hemorrhagic, and often necrotic

Front 61

Describe the clinical findings of a pheochromocytoma

Back 61

1. Diastolic hypertension
a. Sustained (55%)
b. Paroxysmal bursts (45%)
-Not present in essential hypertension
2. Pounding headache (80%)
3. Palpitations (70%)
a. With or without tachycardia
b. Palpitations are not present in essential hypertension
4. Drenching sweats (hyperhydrosis; 70%_
a. Correlates with paroxysm of hypertension
b. Hyperhidrosis is not present in essential hypertension
5. Anxiety
a. Correlated with paroxysms of hypertension
b. Anxiety is not present in essential hypertension
6. Chest pain from subendocardial ischemia
7. Orthostatic hypotension
-Plasma volume is reduces owing to vasoconstriction of arterioles/venules
8. Ileus
-Catecholamines inhibit peristalsis

Front 62

Describe the laboratory findings of a pheochromocytoma

Back 62

1. Increased plasma free metanephrins
-Best test to screen and confirm pheochromocytoma
2. Increased plasma normetanephrine
3. Increased 24hr urine for metanephrine (100% sensitivity)
4. Increased 24hr urine for VMA
5. Lack of suppression of plasma NE with clonidine
6. Hyperglycemia
-Increased glycogenolysis and gluconeogenesis
7. Neutrophilic leukocytosis
-Inhibition of neutrophil adhesion molecules

Front 63

Describe the treatment of pheochromocytomas

Back 63

1. Treatment is surgery
a. Preoperative stabilization
i. Phenoxybenzemine
ii. Beta blocker
iii. Metyrosine (catecholamine synthesis inhibitor)
iv. Liberal fluid and Na intake
b. Preoperative or intraoperative hypertensive crisis
-Phentolamine or nitroprusside in concert with a beta-adreneric blocker

Front 64

Describe neuroblastomas

Back 64

Malignant neoplasm of postganglionic sympathetic neurons

Front 65

Describe the epidemiology of neuroblastomas

Back 65

1. Most often occurs in children <5 yo
a. Third most common cancer
b. Mean age of onset 18 months

Front 66

Where are neuroblastomas usually located?

Back 66

Primarily located in the adrenal medulla
-Occasionally located in the posterior mediastinum (paraspinal)

Front 67

Describe the genetics of neuroblastomas

Back 67

Associated with amplification of N-MYC oncogene (nuclear transcriber)

Front 68

Describe opsoclonus-myoclonus syndrome

Back 68

1. Paraneoplastic syndrome
2. Myoclonic jerks of extremities
3. Chaotic eye movements in all directions
4. Associated with neuroblastoma in 20% to 50% of cases

Front 69

Where do neuroblastomas metastasize to?

Back 69

They commonly metastasize to skin and bones
-Approx. 70% have metastases at time of diagnosis

Front 70

Describe the prognosis of neuroblastomas

Back 70

Depends on age
-Children <1 year old have a good prognosis (90% cure rate)
-Overall survival is 40%

Front 71

Describe neuroblastomas as "small cell" tumors

Back 71

1. Composed of malignant neuroblasts
2. Presence of Homer-Wright rosettes
-Neuroblasts are located around a central space
3. EM shows neurosecretory granules

Front 72

Describe the clinical and laboratory findings of neuroblastomas

Back 72

1. Papable abdominal mass
2. Diastolic hypertension
3. Increased urine VMA and HVA (90-95% sensitivity)

Front 73

Describe the diagnosis of neuroblastomas

Back 73

1. Urine collections for VMA and HVA
2. Imaging studies
a. Body scan with 131I-MIBG (metaiodobenzylguanidine)
-Malignant cells pick up the radioactive material
b. Bone scans to detect lytic lesions

Front 74

Describe the treatment of neuroblastomas

Back 74

1. Depends on age, stage of disease
2. Surgery; irradiation; multiagent chemotherapy