Adrenal Medulla and Pheochromocytoma

Adrenal Medulla

Anatomy – paired gland within cortex; blood supply is from cortex and rich in glucocorticoid

innervated by pre ganglionic fibers of the splanchnic nerve

Histology – Chromaffin Cells – primary cell type, columnar with cytoplasmic chromaffin granules

form cords, abutting venous sinusoids that merge to form large central vein that empties into the IVC

Significant Enzymes in the Adrenal Medulla

phenylethanolamine-N-methyl-transferase (PNMT) – converts norepinephrine to epinephrine

depends on glutocorticoid from cortex

Tyrosine hydroxylase – cytosolic enzyme, rate limiting in catecholamine synthesis

Embryology – Unlike the cortex, the medulla is derived from neural crest cells

Neural crest progenitor cells form primitive sympathetic ganglia called sympathogonia

cells that will become the adrenal medulla migrates to the fetal adrenal cortex, which engulfs them and diverts differentiation by exposing the cells to glucocorticoid

sympathogonia differentiate into two lineages:

(1) neuroblast cells which further differentiate into sympathetic ganglion cells

these can form neuroblastomas and medullary ganglioneuromas, respectively

(2) pheochromoblasts which further differentiate into chromaffin cells (both adrenal and extra-adrenal in location)

these can form pheochromocytomas

thus adrenal medullary chromaffin cells and sympathetic ganglion cells are closely related

Extra-Adrenal Chromaffin Cells

the role of these cells is not clear; they are part of enteric nervous system

Organ of Zuckerkandl – one of the most prominent paraganglia, found near the aortic bifurcation.

Carotid body – formed by these cells near the bifurcation of the carotid artery: O₂ sensor Þ stimulates breathing

Points on the diagram represent nests of these cells (sites of neoplastic potential): distinguishes 3 cell families

Physiology of Adrenal Medulla – The primary function of the adrenal medulla is catecholamine synthesis

mostly epinephrine, also small amounts of norepinephrine (neurotransmitter – acts as hormone at high conc.)

also secretes enkephalins (endogenous opiate-like substances Þ ß GI motility during "fight or flight"

Catechol refers to ortho-dihydroxybenzene group. Only made in Brain, sympathetic nerve and chromaffin cells

Biosynthetic Pathway – tyrosine is taken up into cell by large neutral amino acid carrier

Tyrosine converted by Tyrosine Hydroxylase into L-Dopa which is converted by aromatic amino acid decarboxylase into Dopamine

dopamine is actively transported into chromaffin granules (this process is inhibited by norepiephrine by negative feedback)

within the chromaffin granule, Dopamine is converted by dopamine-b-hydroxylase into norepinephrine which is released from granules into the cytosol

norepinephrine is converted by phenylethanolamine-N-methyl-transferase (PNMT) into epinephrine, which is taken up into granules with ATP and neuropeptide for release

Note: both norepinephrine and epinephrine can both be taken up from the circulation and recycled, but this is a minor pathway

Regulation of Catecholamine Release – activated in tandem with sympathetic nervous system (sympatho-adrenal system)

activation is coordinated by the Medulla oblongata pre-motor neurons in the RostroVentroLateral Medulla (RVLM)

RVLM activated by reflexes from viscera and higher region of brain (limbic system perceives threat)

these neurons control preganglionic motor neurons in the thoracic spinal cord that stimulate the chain ganglia and adrenal

chromaffin cells are essentially sympathetic ganglia that release transmitter directly into the bloodstream rather than across a synapse

nicotinic acetylcholine receptors Þ depolarization Þ influx of Ca⁺⁺ Þ exocytosis of granules

there is a huge reserve of Epi (enough to kill us) maintain by synthesis

Action of Catecholamines: via receptors a ₁, a ₂, b ₁, b ₂ and b ₃

Heart – Ý force and contractility (b₁)

Blood Vessels – Peripheral Vasoconstriction (a₁> a₂), vasodialation (b₂)

Kidney – Ý renin release (b)

GI – ß motility Ý sphincter (a and b)

Pancreas – ß Insulin (a), Ý glucagon (b)

Liver – Ý glucagon (a and b)

Adipose – Ý lipolysis (b₃)

skin – Ý sweating (a)

bronchiole – Dilation (b₂)

uterus – constrict (a), relax (b₂)

most tissues – Ý heat (b, along with thyroid hormone)

Epinephrine: causes more vasodilation/bronchodilation than constriction and increases systolic pressure more than diastolic

Catabolism of Catecholamines – two enzymes that act together (in either order) to produce vanillylmandelic acid, which is excreted unchanged or conjugated in the urine

(1) Catechol-O-methyl transferase – ubiquitous enzyme

converts catecholamines to metanephrine

converts 3,4-dihydroxymendelic acid (from action of MAO, below) into vanillylmandelic acid

(2) Monoamine Oxidase (MAO)

converts catecholamines to 3,4-dihydroxymendelic acid

converts metanephrine (from catechol-O-methyl transferase, above) into vanillylmandelic acid

Pheochromocytoma

in 1/1000 HTN patients (but can be fatal if unrecognized)

periodic fight/flight symptoms

usually secrete norepinephrine (rarely epinephrine if tumor is very superficial medulla, near cortex)

Diagnosis – 24h urinary Catecholamines, Cloridine suppression (no ß HTN = tumor), CT/ MRI/MIBG Scan

Treatment – surgery, a /b blockers

Distribution – 90% in adrenal medulla, 10% extraadrenal (Organ of Zuckerkandl); 10% are multiple

extraadrenal are 3X as likely to be malignant as medullary

Rule of 10's

10% in children, 10% extraadrenal, 10% of adrenal are bilateral, 10% of adrenal are malignant (vs. 20-40% if extraadrenal)