L92- Adrenal Disorders

Question 1

What are the layers of the adrenal cortex and what does each layer make? What hormone controls each layer?

Answer 1

Glomerulosa - Salt - aldosterone

Fasciculata - sugar - cortisol

reticularis - sex - DHEA

RAS - Glomerulosa

ACTH - Fasciculata nd Reticularis

Question 2

When would you diagnose cortisol deficiency vs excess?

Answer 2

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

Question 3

In general, what would you see in primary adrenal insufficiency vs secondary?

Answer 3

Primary - Adrenal dysfunciton causing Mineralcorticoid defect, High K+ and salt craving

vs

Secondary - HPA dysfunction but no mineralcorticoid defect

Question 4

You’re going to have to memorize this chart for boards so might as well start now. What is the Adrenal STeroidogenesis pathway?

Answer 4

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

Question 5

When does the C17 hydroxylation occur?

Answer 5

Zona Glomerulosa where Aldosterone synthesized

Question 6

What are some causes of and what do you see with Primary Adrenal Failure?

Answer 6

destruction of adrenal gland primarily from autoimmune adrenalitis

Women > Men

30s

Diagnostic ACTH high and Cortisol Low

Question 7

What are some causes of and what do you see with Secondary adrenal failure?

Answer 7

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

Women> men

Diagnosis is Both ACTH and Cortisol low

Question 8

Signs and symptoms of acute and chronic adrenal insufficiency?

Answer 8

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

Question 9

Why do you get hyperpigmentation in primary adrenal insufficiency?

Answer 9

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

Question 10

When would you see electrolyte abnormalities and when would you not in Adrenal Insufficiency?

What are other lab abnormalities in Adrenal Insiufficiency?

Answer 10

Primary - get electrolyte abnormalties bc RAS affected vs in SEcdonary not seeing as many

Hyponatremia

Hyperkalemia - primary

Azotemia

Hypercalcemia - increased instestinal absorption and decreases renal excretion of Ca

Normocytic anemia

Eosinophilia

Question 11

Differential Dx for Primary AI?

Answer 11

TB Adrenalitis

AUTOIMMUNE (80%)

X-linked Adrenoleukodystrophy - long chain FA deposition

CAH

Hemorrhage, infiltrative diseases, tumors, drugs

Drugs includde Ketoconazole, Mifepristone, Etomidate that case adrenal under-function

Question 12

Differential Dx for secondary AI?

Answer 12

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

Question 13

CAH- most common version? Classical vs Non-classical?

Answer 13

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

Question 14

Autoimmune poly-glandular Syndrome 1 - causes? inheritence? Features?

Answer 14

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

• Mutations in AIRE gene (autoimmune regulator gene)

Autosomal REcessive

Characterized by:

• AI
• Hypoparathyroidism
• Hypogonadism
• Chronic mucocutaneous candidiasis in childhood

Question 15

Autoimmune Polyglandular Syndrome 2 - inheritance? Presentation?

Answer 15

MORE COMMON THAN APS1!!!!

Adrenal insufficiency and autoimmune thyroid disease (hashomoto or grave)

Characterized by:

• Primary hypogonadism
• T1DM
• Vitelligo
• chronic Atrophic gastritis - PErnicious Anemia
• Celiac

Autosomal DOMINANT w/ INcomplete Penetrance

Question 16

What is the defect and presentation in XL Adrenal Leukodystrophy?

Answer 16

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

“Lorenzo’s Oil”

XL so everytime you see young boy w/ AI think of this!!!!

Question 17

Diagnostic testing for Adrenal Insufficiency. Primary vs Secondary?

Answer 17

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

Question 18

Treatment of Adrenal Insufficiency

Answer 18

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

Question 19

What are symptoms of Cushdings Syndrome and the physiological reason for each?

Answer 19

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

Osteoporosis

Question 20

What are the adrenal causes of Cushings and how do you treat them?

Answer 20

Unilateral Adrenal Adenoma - surgery

Bilateral Adrenal Hyperplasia that is micro or macronodular

Micro- PPNAD

Macro- Ketoconazole or Metyrapone to block cortisol synthesis or Mifapristone to block GC receptor

Question 21

Best ways to Dx Cushings?

Answer 21

Dexamethasone Suppression test or 24 hour urine free cortisol (or late night salivary cortisol)

Cortisol High and ACTH low = Primary Adrenal Hyperfunction

Question 22

Primary Aldosteronism - aka? Suspect in patients w/ what?

Diagnosis?

Answer 22

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

Question 23

Tx for Primary Aldosteronism?

Answer 23

Surgery for ADneoma

Medical therapy for bilateral disease or non-surgical candidates

aka Spironolactone/Eplerenone

Question 24

What is the most common form of Heritable Hyper-Aldo?

Cause? Inheritance? Treatment?

Answer 24

GC Remediable Aldo!!!

Autosomal Dominant

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

Question 25

What is the Adrenal Medullary Tymor called? What is the Classic Presentation? Other symptoms?

Answer 25

Pheochromocytoma!!!!

Classic Triad: Sweating, HA, Palpitations

can be paroxysmal - always assoicated w/ HTN

Other symptoms - orthostasis, pallor, tremors, Anxiety, weight loss

Question 26

How do you diagnose Pheochromocytoma?

Answer 26

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)

Question 27

How can you use imaging to spot a Pheo?

Answer 27

Tend to be LARGE, HETEROGENOUS, Bright - “light bulb sign” on MRI

vs adenoma whih are smaller, darker and homogenous

Question 28

What if you think you have a Pheo but theres no adrenal tumor?

Answer 28

Paragangliomas!!!

Sympathetic nerve chain tumors

act like pheos and secrete lots of NE (but not E!!!!!)

Question 29

What are the 3 hereditary causes of Pheochromocytoma?

Answer 29

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)

Question 30

Treatment of Pheochromocytomas

Answer 30

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

Question 31

What do you do if adrenal incidentaloma?

Answer 31

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

Question 32

Adrenocortical Carcinoma - presentation? Treatment?

Answer 32

rare often aggressive malignancy

presents w/ excess steroid secretion or abdominal mass

Treatment - Resection + Mitotane therapy (adrenolytic)