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107 Cards in this Set

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What is the origin of the medulla?
Neural crest (ectoderm).
What is the role of the medulla?
Store and secrete catecholamines.
What is the origin of the cortex?
Mesenchymal origin.
What is the outermost layer of the cortex?
Zona glomerulosa.
What is the middle layer of the cortex?
Zona fasciculata.
What is the innermost layer of the cortex?
Zona reticularis.
What is the role of the zona glomerulosa?
This is the part of the adrenal gland where mineralocorticoids are produced.
What is the role of the zona fasciculata?
This is the part of the adrenal gland where glucocorticoids are produced.
What is the role of the zona reticularis?
This is the part of the adrenal gland where androgens are produced.
What percentage of the adrenal gland does the cortex comprise?
80-90%.
What assures rapid dissemination of adrenal hormones throughout the body?
The rich vascular supply that the adrenal gland has.
How are catecholamines produced by the adrenal medulla?
Amine precursor uptake and decarboxylation (APUD).
What is the rate limiting step of catecholamine production?
Conversion of tyrosine to 3,4-dihydroxyphenylalanine (dopa) by tyrosine hydroxylase (TH).
What is L-dopa converted to in the medulla?
Dopamine (D), norepinephrine (NE), and epinephrine (E) in that order.
What is the ratio of norepinephrine to epinephrine in the adrenal medulla?
1:4.
What is the peripheral NE:E ratio and why?
9:1 because all three catecholamines are produced within the central and sympathetic nervous systems.
How are catecholamines metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO)?
COMT converts dopamine to methoxytyramine, epinephrine to metanephrine, and norepinephrine to normetanephrine.
All of these intermediate metabolites can then be metabolized to vanillylmandelic acid by MAO.
What is the final product of dopamine metabolism?
3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid).
What are pheochromocytomas?
Rare catecholamine-producing tumors that account for <1% of secondary causes of hypertension.
Concerning pheochromocytomas, what is the rule of 10s?
10% malignant.
10% extra-adrenal.
10% familial (10% bilateral).
Familial pheochromocytomas occur as part of what diseases?
Multiple endocrine neoplasia type 2A or 2B (MEN-2A, MEN-2B), von Hippel-Lindau disease, neurofibromatosis type 1, or familial paraganglioma.
What are the features of familial pheochromocytomas?
Tend to be intra-adrenal and bilateral.
Present at a younger age (genetic testing should be done in patients younger than 50 years of age).
What are the clinical manifestations of pheochromocytomas?
90% of patients have sustained or paroxysmal hypertension, orthostatic hyportension, excessive sweating, nervousness, anxiety, labile blood pressure, weight loss, fatigue, tremor, pallor that can last seconds to several hours.
What is the definition of paroxysmal attacks of pheochromocytomas?
It is characterized by at least 2 out of 3 of the following:
Headchaes associated with palpitations and diaphoresis.
Orthostatic hypotension, excessive sweating, nervousness, anxiety, labile blood pressure, weight loss, fatigue, tremor, pallor that can last seconds to several hours.
What are the indications for screening for pheochromocytomas?
Hypertension with episodic features.
Refractory hypertension.
Prominent lability of blood pressure.
Severe pressor response during parturition, surgery, et cetera.
Family history of pheochromocytoma, multiple endocrine neoplasia, von Hippel-Lindau, or neurofibromatosis.
Incidentally discovered adrenal mass.
Idiopathic dilated cardiomyopathy.
Unexplained hypertension due to surgery, pregnancy, et cetera.
Spells during exertion, coitus, straining, micturition.
What is the best test for diagnosing pheochromocytoma?
The initial test should be chromatographic measurement of the plasma free metanephrine or normetanephrine.
Patients with pheochromocytoma should have a value that is 4X the upper limit of normal.
If this test is not available, the initial test should be chromatographic measurement of 24-hour urine collection for metanephrine, normetanephrine, fractionated free catecholamines, and creatinine. Values 2-3X the upper limit of normal are usually diagnostic.
What are the 3 catecholamines?
Dopamine, norepinephrine, epinephrine.
Which metabolite is the most sensitive and specific for the diagnosis of pheochromocytoma?
Metanephrine, the metabolite of epinephrine.
Why is the measurement of plasma catecholamine only useful if it is collected during a paroxysm?
The half-life of catecholamines is short and they are secreted episodically.
Values 2-3X the upper limit of normal are usually diagnostic.
What is the test of choice for diagnosis of pheochromocytoma in children?
Fractionated plasma free metanephrines because it is difficult to obtain a 24-hour urine sample.
Which test for the diagnosis of pheochromocytoma is more specific and should initially be used in the adult population?
24-hour urinary metanephrine and catechlamine measurements.
What substances should be avoided in a patient undergoing assay for plasma free metanephrines?
Should abstain from caffeinated beverages and alcohol for 24 hours before testing and should avoid acetaminophen, phenoxybenzamine, tricyclic antidepressants, alpha-agonists, and monoamine oxidase inhibitors for at least 5 days prior to testing.
What substances should be avoided in a patient undergoing assay for catecholamines?
Nicotine, alpha-agonists (albuterol, aldomet), levodopa/carbidopa, and sympathomimetrics (theophylline, pseudoephedrine).
What antihypertensive medications can be used in a patient underoing assay for catecholamines without fear of false-positive results?
Angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers, and selective alpha1-adrenoceptor blockers (prazocin).
In a patient with renal insufficiency or failure, what can be used to reliably diagnose pheochromocytoma?
Plasma free metanephrines.
Urinary catecholamine levels cannot be used because they will be elevated in these patients due to their renal disease.
What diseases are associated with elevated levels of catecholamines?
Acute MI, CHF, surgery, and acute cerebrovascular accident.
Which patients are most prone to have a false-positive plasma normetanephrine level?
Elderly patients because it increases with age.
Should use fractionated urinary metanephrines and catecholamines in these patients.
What level of normetanephrine suggests a high probability of pheochromocytoma?
>400 ng/liter (2.19 nmol/liter).
What level of metanephrine suggests a high probability of pheochromocytoma?
>236 ng/liter (1.20 nmol/liter).
What are the confirmatory tests of pheochromocytoma?
Clonidine suppression test, glucagon stimulation test, measurement of urinary fractionated catecholamines.
When is clonadine suppression test indicated and what is the basis of this test?
Indicated in patients in which the plasma catecholamines are greater than 1000 pg/mL (5.9 nmol/L).
Clonidine is a centrally acting alpha-adrenergic agonist that is unable to suppress catecholamine release by pheochromoctyoma.
Why is the glucagon stimulation test rarely used as a confirmatory test of pheochromoctyoma?
It can lead to dangerous rises in blood pressure.
A rise in plasma norepinephrine greater than threefold or greater than 2000 pg/mL is diagnostic. Works by stimulating glucagon-sensitive adenylate cyclase receptors on the pheochromocytoma.
Why was it thought that chromogranin A could be used to diagnose pheochromocytoma?
It is elevated in 80% of patients with pheochromocytoma and is not affected by medications used to treat the disease. However, the kidneys clear it and false-positives can results in patients with even just mild renal impairment.
Its major use is in the postoperative monitoring for recurrence of pheochromoctyoma.
Why is creatinine measured in the 24-hour urine collection?
It is used to verify the adequacy of the urine collection.
What substance should be added to the container in which a 24-hour urine will be collected?
25 mL of 6 N HCL.
How is an assay for plasma catecholamines performed?
Patient has an overnight fast with water allowed, is placed in a reclining position with an IV hepatin lock, blood is collected after 20-30 minutes in a prechilled EDTA lavender top tube and kept in ice-water until centrifuged.
Plasma should be separated within 2 hours of phlebotomy and then frozen immediately after separation.
How is the pheochromocytoma located?
CT scan or MRI of the adrenals. If negative, imaging of the abdomen, chest, and pelvis should be done.
If the tumor cannot be located, scanning with laveles meta-iodobenzyl-guanidine (MIBG) should be done.
When this fails, octreoscanning and positron emission tomography should be done.
What measurement should be used to monitor recurrence or pheochromocytoma?
Urinary metanephrines.
What laboratory values are seen with neuroblastoma?
Elevated urinary homovanillic acid, elevated vanillylmandelic acid, and occasionally elevated urinary metanephrines.
What is the chief mineralocorticoid produced by the adrenal gland?
Aldosterone, which promotes reabsorption of sodium and water to maintain blood pressure and tonicity.
Why is the synthesis of aldosterone and its intermediate 18-hydroxylated metabolites restricted to the zona glomerulosa?
Only the zona glomerulosa has the enzyme CYP11B2 (aldosterone synthetase).
What are the precursors of aldosterone?
11-deoxycorticosterone (DOC) and 11-deoxycortisol.
Where are the precursors of aldosterone produced?
Zona glomerulosa and zona fasciculata.
This is why hypertension and electrolyte disturbances can occur congenital adrenal hyperplasia.
What controls the synthesis of aldosterone?
The renin-angiotensin system.
What are glucocorticoids?
They are 21-carbon steroid compounds with a hydroxyl on carbon 17, so they are called 17-hydroxycorticoids.
What is the most important glucocorticoid?
Cortisol.
It regulates its secretion through negative feedback of the hypothalamic-pituitary-adrenal axis.
In times of stress, cortisol is needed to maintain blood pressure and blood sugar.
What are androgens and estrogens?
Androgens are 18-carbon structures with saturated A rings.
Estrogens are 17-carbon steroids with unsaturated A rings.
From what type of cholesterol are the hormores of the adrenal cortex derived?
LDL.
What protein shuttles LDL across the mitochondrial membrane in the adrenal cortex to begin the steroidogenic pathway?
Steroid acute regulatory protein (StAR).
What group of enzymes are involved with inborn errors of metabolism of the adrenal cortex?
Hydroxylases.
Why are CRH and ACTH elevated in cases of congenital adrenal hyperplasi?
Cortisol is not produced, so there is no negative feedback on CRH and ACTH production.
These results in adrenal hyperplasia as well as a build-up of the hormonal precursors directly preceding the affected enzyme.
What are the five enzymes that are affected in congenital adrenal hyperplasia?
P450, 3-beta-hydroxysteroid dehydrogenase, 21-hydroxylase, 11-hydroxylase, 17-hydroxylase.
What substance is not produced in congenital adrenal hyperplasia?
Cortisol.
What are some symptoms of congenital adrenal hyperplasia?
Salt wastin, shock, hirsutism, infertility, ambiguous genitalia.
How is the diagnosis of congenital adrenal hyperplasia made?
Measurement of the various hormone levels and differentiating which steroids are produced in excess or are deficient.
Also calculate the precursor/product ratio and compare to age- and sex-matched normal levels.
What should be done if the hormone levels in a patient suspected of having congenital adrenal hyperplasia should come back normal?
Wait 60 minutes and administer 0.25 mg IV ACTH and remeasure steroid levels.
What is the most common cause of congenital adrenal hyperplasia?
21-hydroxylase deficiency.
What is the role of 21-hydroxylase?
It catalyzes the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to 11-deoxycorticosterone.
Which steroid precursors are elevated in cases of 21-hydroxylase deficiency?
17-hydroxyprogesterone and pregnanetriol.
These are shunted toward the androgenic pathway, with resultant excess androgen and testosterone.
How does 21-hydroxylase deficiency present?
Adrenal insufficiency and virilization in the newborn with or without salt wasting.
Presents in late childhood as hirsutism, amenorrhea, and infertility (presentation is similar to PCOS in women).
What affect does 21-hydroxylase deficiency have on the medulla?
Dysplasia of the medulla and catecholamine hyposecretion have been reported.
Why is prenatal diagnosis of 21-hydroxylase deficiency important?
The administration of steroids at an early age can stop the development of virilization of a female.
How is the prenatal diagnosis of 21-hydroxylase deficiency made?
Measurement of 17-hydroxyprogesterone in amniotic fluid or genotyping cells for the genes responsible for the deficiency, CYP21 and CYP21P on chromosome 6.
How is neonatal screening for 21-hydroxylase deficiency performed?
A heelstick blood sample collected on filter paper with measurement of 17-hydroxyprogesterone or cell genotyping for the deficiency.
What is the level of 17-hydroxyprogesterone in a patient with 21-hydroxylase deficiency and salt wasting?
>8000 ng/dL, rising to 100,000 ng/dL after ACTH administration.
What is the level of 17-hydroxyprogesterone in a patient with 21-hydroxylase deficiency and virilization?
10,000-30,000 ng/dL (300-1000 nmol/L).
What is the level of 17-hydroxyprogesterone in a patient with 21-hydroxylase deficiency with nonclassic disease?
1500-10,000 ng/dL (50-300 nmol/L).
At what time of the day should 17-hydroxyprogesterone be measured in a patient being tested for 21-hydroxylase deficiency?
Morning.
What should be done in a patient being tested for 21-hydroxylase deficiency if the results are equivocal?
17-hydroxyprogesterone levels should be compared before and 60 minutes after the administration of 0.25 mg ACTH (Cortrosyn).
Post-ACTH 17-OHP <330 g/dL is normal.
Post-ACTH 17-OHP 330-1000 ng/L is heterozygote carrier.
Post-ACTH 17-OHP >2000 ng/L is nonclassic CAH.
Why are glucocorticoid and mineralocorticoid replacement therapies used in patients with 21-hydroxylase deficiency?
In children, it is used so that the child can gain normal adult height, weight, and puberty.
In an adult, it is used to lessen signs of virilization and to resume fertility.
How does glucocorticoid relacement therapy in patients with 21-hydroxylase deficiency work?
Glucocorticoids keeps 17-hydroxyprogesterone between 100-1000 ng/dL and ACTH <100 ng/L. This ultimately prevents shunting toward testosterone synthesis.
How does mineralocorticoid replacement therapy in patients with 21-hydroxylase deficiency work?
It normalizes the plasma renin activity.
What is the second most common congenital adrenal hyperplasia?
11-hydroxylase deficiency.
What is the role of 11-hydroxylase?
It converts 11-deoxycortisol to cortisol and deoxycorticosterone to corticosterone.
What metabolite builds up in 11-hydroxylase deficiency?
Deoxycorticosterone (DOC).
What results from the build up of deoxycorticosterone in 11-hydroxylase deficiency?
Hypertension and hypokalemia occur due to the mineralocorticoid activity of deoxycorticosterone.
Does virilization occur with 11-hydroxylase deficiency?
Yes, due to the compensatory increase in ACTH with resultant adrenal hyperplasia and shunting toward testosterone synthesis.
What causes 11-hydroxylase deficiency?
It is an autosomal recessive disorder caused by mutation of CYP11B1 and CYP11B2 on chromosome 8q21-q22.
How is the diagnosis of 11-hydroxylase deficiency made in the neonate?
High basal and high ACTH-stimulated 11-deoxycortisol, elevated urinary tetrahydro-11-deoxycortisol.
How is the diagnosis of 11-hydroxylase deficiency made in children and young adults?
Elevated early morning and ACTH-stimulated levels of 11-deoxycortisol more than 3X the upper limit of normal for age. Also elevated deoxycorticosterone and adrenal androgens.
What are the levels of renin and aldosterone in patients with 11-hydroxylase deficiency?
They are decreased due to high deoxycorticosterone, causing salt and water retention.
Do patients with 11-hydroxylase deficiency have a rise in precursors following ACTH stimulation?
No.
How is the prenatal diagnosis of 11-hydroxylase deficiency made?
Measurement of tetrahydro-11-deoxycortisol in maternal urine or amniotic fluid.
When do the levels of tetrahydro-11-deoxycortisol begin to rise in amniotic fluid of a pregnancy affected by 11-hydroxylase deficiency?
First trimester.
What is the treatment for 11-hydroxylase deficiency?
Glucocorticoid replacement, which normalizes deoxycorticosterone and plasma renin.
Which genes are responsible for the development of 3-beta-hydrosteroid dehydrogenase deficiency?
HSD3BI and HSD3BII.
Where are the genes responsible for the development of 3-beta-hydrosteroid dehydrogenase deficiency located?
HSD3BI is found in placenta, skin, and other peripheral tissue and remains intact with congenital adrenal hyperplasia.
HSD3BII is found in the adrenals and gonads.
What is the role of 3-beta-hydroxysteroid dehydrogenase deficiency?
It converts delta-5 steroids ( pregnenolone, 17-hydroxy pregnenolone, and dihydroepiandrosterone) to delta-4 steroids (progesterone, 17-hydroxyprogesterone, androstenedione).
What are the clinical manifestations of 3-beta-hydroxysteroid dehydrogenase deficiency?
Glucocorticoid deficiency with or without salt wasting.
Females are normal or have ambigious genitalia.
Males have incomplete masculinization.
How is 3-beta-hydroxysteroid dehydrogenase deficiency diagnosed?
ACTH-stimulated delta-5-17 pregnenolone levels, delta-5-17 pregnenolone to cortisol ratio.
What is the treatment for 3-beta-hydroxysteroid dehydrogenase deficiency?
Glucocorticoid and mineralocorticoid replacement and sex steroids.
What are the two enzymes encoded by 17-hydroxylase (CYP17)?
17-alpha-hydroxylase and 17,20-lyase.
What is the role of 17-alpha-hydroxylase?
It converts pregnenolone and progesterone to their 17-hydroxy derivatives (17-hydroxy pregnenolone and 17-hydroxy progesterone).
What is the role of 17,20-lyase?
It converts 17-hydroxy pregnenolone to dihydroepiandosterone (DHEA) and 17-hydroxy progesterone to androstenedione.
What are the clinical manifestations of 17-hydroxylase deficiency?
Hypertension and hypokalemic alkalosis, incomplete masculinization (males), decreased testosterone and cortisol.
How is 17-hydroxylase deficiency diagnosed?
High deoxycorticosterone, pregnenolone, and progesterone.
Also decreased urinary 17-ketosteroids and 17-hydroxycorticosteroids.
What is the gene associated with 17-hydroxylase deficiency?
CYP17 on chromosome 10q.