180. Adrenal Medulla

Question 1

How does the adrenal gland develop embryologically?

What is the physiology of the adrenal gland? What does it function like?

Answer 1

Cortex = derived from mesoderm; secretes steroid hormones

Medulla = derived from neural crest ectoderm (chromaffin tissues); secretes catacholamines (migrate into cortex)

Developement:
Wk 7: chromaffin cells from celiac plexus collect medially to cortex and migrate inward
Mo 4: chromaffin tissue occupies central position in gland

Physiology
Fx link to ANS
Fx like a postganglionic symp neuron, but EPI released to blood (ENDOCRINE) instead of synaptic junction
Receptors and effector cells located throughout the body

Question 2

Paraganglia

• what are they?
• what do they consist off?
• how do they develop?
• where are they located?

Answer 2

Sympathetic pre-ganglionic nerve fibers that terminate in paravertebral/prevertebral nerve ganglia
Post-ganglionic fibers ONLY secrete NE
Consist: chromaffin cells in close approximation to autonomic ganglia and plexuses
Location: mediastinum, abd (along symp nerve chains in paravertebral and prevertebral positions), around celiac axis, renal medullae, aortic bifurcation (organ of Zuckerkandl), adjacent to bladder

Question 3

Pheochromocytes

• what are they
• fx
• regulation
• diseases
• what are chromogranins
• lab tests

Answer 3

• axonless neurons producing catecholamines
• fx: use synaptic activation to release preformed catecholamines (80% EPI, 20% NE)
• regulated by symp cholinergic fibers acting on nicotinic receptors
• catecholamine half life short (10s - 2 min)

PCC: 80-85% Chromaffin cell tumors
PGL: 15-20% Chromaffin-cell tumors

Chromogranins: chromaffin-cell proteins - clinical markers for adrenal medulla or ganglia tumors (elevated chromograffin A)

Lab: circulating catecholamines metabolized in neuronal and non-neuronal tissue (liver)
Metabolites excreted in urine = 24hr urine metanephrines

Question 4

How are catecholamines synthesized? What is their source? How are they metabolized?

How is adrenal medulla innervated and what does it secrete?

Answer 4

Tyrosine = source
Phenylethanolamine N-methyl transferase = converts NE to EPI (adrenal medulla is only organ that expresses this!)

Metabolism: COMT converts NE to NMN and EPI to MN
MAO converts EPI/NE to DMA and MN/NMN to VMA (nonspecific marker)

Adrenal medulla innervated by thoracic splanchnic nerves and secretes EPI to blood

Question 5

What is the action of the different catecholamine receptors?

What are the effects of EPI and NE?

Answer 5

B receptors: CV - raise HR, contractility, AV node conduction
Vascular - arterial VD
Pulm - bronchiodilation
Liver - more gluconeogenesis, glycogenolysis
Pancreas - stim endocrine secretion (ins, glucagon)
Fat - stim lipolysis
Salivary Gland - stim amylase secretions

A receptors: vascular - VC (arteries and veins)
Pancreas: decrease exocrine/endocrine secretion

EPI: increase BP/HR, decrease GI motility (diverts to limb muscle), bronchodilation, mydriasis, hyperglycemia
NE: increase BP, DECREASE HR, hyperglycemia

Question 6

PCC

• what is it
• location
• prevalence among all adrenal masses

PGL

• what is it
• prevalence/incidence
• location

Answer 6

PCC

• intra-adrenal PGL arising from chromaffin-cells of adrenal medulla
• producing 1+ catecholamines (EPI, NE, DA)
• means “dusky-colored” tumor due to color change from immersion in chromate salts
• location: 10% bilateral, 90% unilateral
• prevalence: RARE (1/2500-1/6500), 5% of all adrenal masses

PGL

• tumors from extra-adrenal symp and parasymp ganglia
• 30-50% of pts with disease-causing germline mutations have PGL
• location: symp paraganglia, organ of Zuckerkandl, bladder

Question 7

MEN 2

• genetics
• 2A vs 2B

Answer 7

AD inheritance of familial endocrine neoplasms
Germ-line mutation: activation of RET proto-oncogene (cell surface RTK), found in >95% pts with MEN 2A/2B, screening is easy (few/clustered mutations), significant geneotype/phenotype correlation
Tumors often bilateral/multifocal +/- hyperplasia

MEN2A: most uncommon of MEN2

• MTC (>90%) - most common component
• Primary Hyperparathyrodism (20%)
• PCC (50%)

MEN2B

• MTC
• PCC
• mucosal neuroma
• GI tract ganglioneuromatosis
• Marfanoid Habitus: thin face, big lips, nodular tongue, big ears, long face

Question 8

Von Hippel Lindau Disease

• genetics
• signs
• subtypes

Answer 8

genetics: missense mutation in VHL gene (Ch 3) = tumor suppressor gene, encodes protein regulating hypoxia-induced proteins (300 germline mutations identified)
signs: retinal angioma, CNS hemangioblastoma, renal cysts, carcinomas, pancreatic cysts, PCC
subtypes: 1 = low PCC risk, 2A/B/C = high PCC risk

Question 9

Neurofibromatosis 1 (NF1)
- signs

Answer 9

AD disorder with neurofibromas, cafe au lait spots, axillary or inguinal freckling, iris hamartomas (Lisch nodules), 2% develop PCC

Question 10

Paraganglioma

• two types
• presentation
• location
• genetics of familial PGL

Answer 10

1. Symp PGL: from chromaffin cells of paraganglia of symp chain in chest, abd, pelvis
2. Parasymp PGL: from glomera along parasymp nerves in head, neck, upper mediastinum (usually non-fxn’l, not producing catecholamines)
   CP: slow-growing, painless cellular mass, many pts asx (mass effect esp in head/neck)
   Location: 50% abd, 5% head/neck

FPGL: AD mutations in SDH gene (component of mito ETC - complex II, and oxidation step in Krebs)
SDHA - catalytic core of enzyme, neurodegenerative disease
SDHB - catalytic core, FPGL syndrome (develops EARLY, HIGHEST risk of malignancy)
SDHC/D - anchor complex to matrix side of mito inner membrane - predispose to FPGL syndromes
Screenings for SDH-B/C/D commercially available

Question 11

PCC/PGL Clinical Presentation, Labs, DDx, Tx

Answer 11

CP: headaches, palpitations, diaphoresis, HTN, Abd Pain
Labs: 24hr urine collection for fractionated catecholamines and metanephrines; plasma-free metanephrines (if no MNs, 100% not PCC - 100% NPV)

DDx: conditions that increase catecholamine stim: hypoglycemia, drugs (caffeine, marijuana, nicotine), thyrotoxicosis

Tx: surgical resection
pre-op prep:
1. ALPHA BLOCK (phenoxybenzamine) FIRST to stop VC, normalize BP/expand BV
2. High Na diet = increase BV, counteracts catecholamine-induced volume contraction and orthostasis assoc with a-block
3. NEVER start B-block BEFORE a-block = can cause unopposed a-stim = VC = HIGH BP (give B-block second to slow HR)