Adrenal Endocrinology for the Pathologist

Neural crest (ectoderm).

Store and secrete catecholamines.

Mesenchymal origin.

Zona glomerulosa.

Zona fasciculata.

Zona reticularis.

This is the part of the adrenal gland where mineralocorticoids are produced.

This is the part of the adrenal gland where glucocorticoids are produced.

This is the part of the adrenal gland where androgens are produced.

80-90%.

The rich vascular supply that the adrenal gland has.

Amine precursor uptake and decarboxylation (APUD).

Conversion of tyrosine to 3,4-dihydroxyphenylalanine (dopa) by tyrosine hydroxylase (TH).

Dopamine (D), norepinephrine (NE), and epinephrine (E) in that order.

1:4.

9:1 because all three catecholamines are produced within the central and sympathetic nervous systems.

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.

3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid).

Rare catecholamine-producing tumors that account for <1% of secondary causes of hypertension.

10% malignant.
10% extra-adrenal.
10% familial (10% bilateral).

Multiple endocrine neoplasia type 2A or 2B (MEN-2A, MEN-2B), von Hippel-Lindau disease, neurofibromatosis type 1, or familial paraganglioma.

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).

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.

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.

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.

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.

Dopamine, norepinephrine, epinephrine.

Metanephrine, the metabolite of epinephrine.

The half-life of catecholamines is short and they are secreted episodically.
Values 2-3X the upper limit of normal are usually diagnostic.

Fractionated plasma free metanephrines because it is difficult to obtain a 24-hour urine sample.

24-hour urinary metanephrine and catechlamine measurements.

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.

Nicotine, alpha-agonists (albuterol, aldomet), levodopa/carbidopa, and sympathomimetrics (theophylline, pseudoephedrine).

Angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers, and selective alpha1-adrenoceptor blockers (prazocin).

Plasma free metanephrines.
Urinary catecholamine levels cannot be used because they will be elevated in these patients due to their renal disease.

Acute MI, CHF, surgery, and acute cerebrovascular accident.

Elderly patients because it increases with age.
Should use fractionated urinary metanephrines and catecholamines in these patients.

>400 ng/liter (2.19 nmol/liter).

>236 ng/liter (1.20 nmol/liter).

Clonidine suppression test, glucagon stimulation test, measurement of urinary fractionated catecholamines.

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.

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.

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.

It is used to verify the adequacy of the urine collection.

25 mL of 6 N HCL.

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.

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.

Urinary metanephrines.

Elevated urinary homovanillic acid, elevated vanillylmandelic acid, and occasionally elevated urinary metanephrines.

Aldosterone, which promotes reabsorption of sodium and water to maintain blood pressure and tonicity.

Only the zona glomerulosa has the enzyme CYP11B2 (aldosterone synthetase).

11-deoxycorticosterone (DOC) and 11-deoxycortisol.

Zona glomerulosa and zona fasciculata.
This is why hypertension and electrolyte disturbances can occur congenital adrenal hyperplasia.

The renin-angiotensin system.

They are 21-carbon steroid compounds with a hydroxyl on carbon 17, so they are called 17-hydroxycorticoids.

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.

Androgens are 18-carbon structures with saturated A rings.
Estrogens are 17-carbon steroids with unsaturated A rings.

LDL.

Steroid acute regulatory protein (StAR).

Hydroxylases.

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.

P450, 3-beta-hydroxysteroid dehydrogenase, 21-hydroxylase, 11-hydroxylase, 17-hydroxylase.

Cortisol.

Salt wastin, shock, hirsutism, infertility, ambiguous genitalia.

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.

Wait 60 minutes and administer 0.25 mg IV ACTH and remeasure steroid levels.

21-hydroxylase deficiency.

It catalyzes the conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to 11-deoxycorticosterone.

17-hydroxyprogesterone and pregnanetriol.
These are shunted toward the androgenic pathway, with resultant excess androgen and testosterone.

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).

Dysplasia of the medulla and catecholamine hyposecretion have been reported.

The administration of steroids at an early age can stop the development of virilization of a female.

Measurement of 17-hydroxyprogesterone in amniotic fluid or genotyping cells for the genes responsible for the deficiency, CYP21 and CYP21P on chromosome 6.

A heelstick blood sample collected on filter paper with measurement of 17-hydroxyprogesterone or cell genotyping for the deficiency.

>8000 ng/dL, rising to 100,000 ng/dL after ACTH administration.

10,000-30,000 ng/dL (300-1000 nmol/L).

1500-10,000 ng/dL (50-300 nmol/L).

Morning.

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.

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.

Glucocorticoids keeps 17-hydroxyprogesterone between 100-1000 ng/dL and ACTH <100 ng/L. This ultimately prevents shunting toward testosterone synthesis.

It normalizes the plasma renin activity.

11-hydroxylase deficiency.

It converts 11-deoxycortisol to cortisol and deoxycorticosterone to corticosterone.

Deoxycorticosterone (DOC).

Hypertension and hypokalemia occur due to the mineralocorticoid activity of deoxycorticosterone.

Yes, due to the compensatory increase in ACTH with resultant adrenal hyperplasia and shunting toward testosterone synthesis.

It is an autosomal recessive disorder caused by mutation of CYP11B1 and CYP11B2 on chromosome 8q21-q22.

High basal and high ACTH-stimulated 11-deoxycortisol, elevated urinary tetrahydro-11-deoxycortisol.

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.

They are decreased due to high deoxycorticosterone, causing salt and water retention.

No.

Measurement of tetrahydro-11-deoxycortisol in maternal urine or amniotic fluid.

First trimester.

Glucocorticoid replacement, which normalizes deoxycorticosterone and plasma renin.

HSD3BI and HSD3BII.

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.

It converts delta-5 steroids ( pregnenolone, 17-hydroxy pregnenolone, and dihydroepiandrosterone) to delta-4 steroids (progesterone, 17-hydroxyprogesterone, androstenedione).

Glucocorticoid deficiency with or without salt wasting.
Females are normal or have ambigious genitalia.
Males have incomplete masculinization.

ACTH-stimulated delta-5-17 pregnenolone levels, delta-5-17 pregnenolone to cortisol ratio.

Glucocorticoid and mineralocorticoid replacement and sex steroids.

17-alpha-hydroxylase and 17,20-lyase.

It converts pregnenolone and progesterone to their 17-hydroxy derivatives (17-hydroxy pregnenolone and 17-hydroxy progesterone).

It converts 17-hydroxy pregnenolone to dihydroepiandosterone (DHEA) and 17-hydroxy progesterone to androstenedione.

Hypertension and hypokalemic alkalosis, incomplete masculinization (males), decreased testosterone and cortisol.

High deoxycorticosterone, pregnenolone, and progesterone.
Also decreased urinary 17-ketosteroids and 17-hydroxycorticosteroids.

CYP17 on chromosome 10q.