What are the layers of the adrenal cortex and what does each layer make? What hormone controls each layer?
Glomerulosa - Salt - aldosterone
Fasciculata - sugar - cortisol
reticularis - sex - DHEA
RAS - Glomerulosa
ACTH - Fasciculata nd Reticularis
When would you diagnose cortisol deficiency vs excess?
Cortisol deficiency would be diagnosed in the morning when cortisol levels are supposed to be high
Cortisol excess would be diagnosed at night when levels should be low
In general, what would you see in primary adrenal insufficiency vs secondary?
Primary - Adrenal dysfunciton causing Mineralcorticoid defect, High K+ and salt craving
Secondary - HPA dysfunction but no mineralcorticoid defect
You're going to have to memorize this chart for boards so might as well start now. What is the Adrenal STeroidogenesis pathway?
Cholesterol Precursor taken up w/ Desmolase (CYP11A) and made into Pregnenolone
Prengnolone to 17-OH-Preg (17alpha hydroxylase CYP17) to Dehydroepiandriosterone (17,20Lysase)
ALL of which go through 30-OH dehydrog to make Progesterone/Androestnedione
then 21-Hydroxylase (CYP21) to Deoxycorticosterone/11-deoxycortisol
etc etc see picture
When does the C17 hydroxylation occur?
Zona Glomerulosa where Aldosterone synthesized
What are some causes of and what do you see with Primary Adrenal Failure?
destruction of adrenal gland primarily from autoimmune adrenalitis
Women > Men
Diagnostic ACTH high and Cortisol Low
What are some causes of and what do you see with Secondary adrenal failure?
Hypothalamic disease, pituitary lesions, exogenous steroid suppression
Most common endogenous - pituitary gland tumor
Exogenous steroid use (when you stop using) is most common overall cause
Peaks in 50s
Diagnosis is Both ACTH and Cortisol low
Signs and symptoms of acute and chronic adrenal insufficiency?
WEakness, anorexia, weight loss, salt craving, hyperpigmentation (Primary) decreased body hair
Acute - hypotension or shock, ab pain, vomit, fever, and recurrent hypoglycemia
Chronic - fatigue, loss of energy, less strenght in mussles, arthralgia/myalgia etc
Why do you get hyperpigmentation in primary adrenal insufficiency?
Hyperpigmentation in areas of friction - mouth, hands, elbows etc
ACTH made from POMC and cleaved along way to also make MSH which acts on melanocytes and increass pigmentation
When would you see electrolyte abnormalities and when would you not in Adrenal Insufficiency?
What are other lab abnormalities in Adrenal Insiufficiency?
Primary - get electrolyte abnormalties bc RAS affected vs in SEcdonary not seeing as many
Hyperkalemia - primary
Hypercalcemia - increased instestinal absorption and decreases renal excretion of Ca
Differential Dx for Primary AI?
X-linked Adrenoleukodystrophy - long chain FA deposition
Hemorrhage, infiltrative diseases, tumors, drugs
Drugs includde Ketoconazole, Mifepristone, Etomidate that case adrenal under-function
Differential Dx for secondary AI?
Most commonly tumor in Pit-Hypothal region
Autoimmune lymphocytic hypophysitis - related to pregnancy (80%)
POMC gene defects
PROPR1 defect gene encoding TF
HESX1 Gene - Septo-optic dysplasia
CAH- most common version? Classical vs Non-classical?
Most common 21-Hydroxylase Enzyme Defect
Classical CAH: present at young age w/ salt-wasting crisis bc defect in Cortisol and Aldo synthesis (clue: high 17-OH Progesterone upstream)
Non-Classical CAH: presents later in life like PCOS w/ subtle defects in women and more adrenal androgens
Autoimmune poly-glandular Syndrome 1 - causes? inheritence? Features?
Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy
- Mutations in AIRE gene (autoimmune regulator gene)
- Chronic mucocutaneous candidiasis in childhood
Autoimmune Polyglandular Syndrome 2 - inheritance? Presentation?
MORE COMMON THAN APS1!!!!
Adrenal insufficiency and autoimmune thyroid disease (hashomoto or grave)
- Primary hypogonadism
-chronic Atrophic gastritis - PErnicious Anemia
Autosomal DOMINANT w/ INcomplete Penetrance
What is the defect and presentation in XL Adrenal Leukodystrophy?
ABCD1 (aka ATP binding Casette transporter) Gene defect in Peroxisomal membrane protein (ALDP) that leads to accumulation of Very Long Chain FA's (<24C)
Adrenal Insufficiency w/ neurological impairment from White Matter Demyelination
XL so everytime you see young boy w/ AI think of this!!!!
Diagnostic testing for Adrenal Insufficiency. Primary vs Secondary?
Morning Cortisol/ACTH - supposed to be high in the morning
Primary - low aldo, high renin, low DHEA
ACTH Stimulation Test:
Primary - no rise at all bc adrenal can't make cortisol
Secondary - some response (however overtime w/o ACTH get atrophy so less than normal
Treatment of Adrenal Insufficiency
5-10 mg/m2 cortisol production per day matched to 15-25 mg hydrocortisone (say structure as endogenous but short acting to multiple doses/day) but WAY lesser amounts of Prednisolone or Dexamethasone (which are more toxic to bone)
Fludrocorticosterone - Aldosterone
Androgens in women - DHEA or T
What are symptoms of Cushdings Syndrome and the physiological reason for each?
Stretch marks - darker and wider from impaired synthesis of collagen
Moon Facies, Buffalo humps, cervial fat, buffalo hump - from increased insulin from increased glucose that makes icnreased storage of fat in visceral areas
Immunosuppression - inhibits Phosholipase A2 and so no Arachidonic Acid metab, inhibits IL2 production, Inhibits Histamine release
HTN - increases alpha1 rec on arterials
Muscle WEakness - cortisol breaks down muscle for gluconeogenesiss
What are the adrenal causes of Cushings and how do you treat them?
Unilateral Adrenal Adenoma - surgery
Bilateral Adrenal Hyperplasia that is micro or macronodular
Macro- Ketoconazole or Metyrapone to block cortisol synthesis or Mifapristone to block GC receptor
Best ways to Dx Cushings?
Dexamethasone Suppression test or 24 hour urine free cortisol (or late night salivary cortisol)
Cortisol High and ACTH low = Primary Adrenal Hyperfunction
Primary Aldosteronism - aka? Suspect in patients w/ what?
Conn's Disease = Overproduction of aldosterone
*Suspect in pts w/ HTN and Hypokalemia - weakness, cramps, periodic paralysis, LVH
Diagnosis: Screen w/ Adlo/Renin ratio and > 30: 1
Confirm w/ Saline suppression
Gold STandard: ADRENAL VEIN SAMPLING
Tx for Primary Aldosteronism?
Surgery for ADneoma
Medical therapy for bilateral disease or non-surgical candidates
What is the most common form of Heritable Hyper-Aldo?
Cause? Inheritance? Treatment?
GC Remediable Aldo!!!
see severe, early onset HTN and Hypokalemia
Cuase: Aldosterone secretion under control of ACTH from chimeric gene duplication
Treat w/ Lose-dose STeroids to suppress ACTH
What is the Adrenal Medullary Tymor called? What is the Classic Presentation? Other symptoms?
Classic Triad: Sweating, HA, Palpitations
can be paroxysmal - always assoicated w/ HTN
Other symptoms - orthostasis, pallor, tremors, Anxiety, weight loss
How do you diagnose Pheochromocytoma?
Measureing Metanephrines - breakdown product in urine or in blood but might miss if it is secreting dopamine in blood so check urine!
Clonidine Suppression Test - should suppress MEtanephrines (clonidine acts on Pre-ganglionic Alpha2 receptors to stop release of catecholamines from neurons and so if it doesn't then Pheo)
How can you use imaging to spot a Pheo?
Tend to be LARGE, HETEROGENOUS, Bright - "light bulb sign" on MRI
vs adenoma whih are smaller, darker and homogenous
What if you think you have a Pheo but theres no adrenal tumor?
Sympathetic nerve chain tumors
act like pheos and secrete lots of NE (but not E!!!!!)
What are the 3 hereditary causes of Pheochromocytoma?
Von-hippel-Lindau: AD germline loss of VHL tunor suppressor gene causing angiomas, Renal carcinoma, cysts in kidney/pancreas, and Cerebellar Hemangioblastoma
Neurofibromatosis 1: Peripheral nerve sheath tumors
MEN2: Autosomal Dominant germline mutation of RET proto-oncogene
2a - Medyllary thyroid carcinoma, Pheo, Hyperparathyroidism
2b - Medyllary thyroid carcinoma, Pheo, Mucosal neuromas (marfinoid)
Treatment of Pheochromocytomas
ALPHA BLOCKERS!!!! several weeks before surgery and before beta blockers
Calcium channel blockers for vasodilation
Mettyrosine - blcoks catecholamine synthesis
PHENOXYBENZAMINE is non-specific Alpha blocker used prior to surgical excision
What do you do if adrenal incidentaloma?
Common and prevalence increses w/ age
80% are non-functioning so just watch
functioning ones repeat testing and imaging
Surgery indicated if hormonally active or > 4 cm
Adrenocortical Carcinoma - presentation? Treatment?
rare often aggressive malignancy
presents w/ excess steroid secretion or abdominal mass
Treatment - Resection + Mitotane therapy (adrenolytic)