Adrenal

Question 1

What gene is associated with congenital adrenal hypoplasia?

Answer 1

DAX1

Question 2

Name the 3 zones of the adrenal cortex and what they produce

Answer 2

1. Zona glomerulosa: mineralocorticoid (aldosteron)
2. Zona fasciculata: glucocorticoid (cortisol) and androgens, thickest layer (75%)
3. Zona reticularis: glucocorticoid (cortisol) and androgens (possibly basal glucocorticoid production only rather than ACTH-dependent)

Question 3

Draw a picture of the adrenal gland and its layers

Answer 3

Question 4

Draw steroidogenesis

Answer 4

Question 5

When do ACTH and glucocorticoid production peak?

Answer 5

In the morning just before awakening (6th-8th hourse of sleep)

Question 6

List 5 things that may impact the timing and height of 8:00 am cortisol test

Answer 6

1. Physical stress (major illness, surgery, trauma or starvation)
2. Psychological stress (anxiety, depression, mania or psychosis)
3. CNS and pituitary disorders
4. Cushing syndrome
5. Liver disease
6. Chronic renal failure
7. Alcoholism

Question 7

What is the advantage of measuring salivary cortisol?

Answer 7

No binding proteins in saliva, so it reflects free cortisol

Question 8

What percentage of cortisol in circulation is bound?

Answer 8

• 10% free
• 75% bound to CBG
• 15% bound to albumin

Question 10

What is the difference between low dose and high dose dexamethasone suppression tests?

Answer 10

• Low dose (1 mg): screening test for Cushing syndrome, negative if <50 nmol/L
  
  • False positives in hospitalized/chronically ill patients, acute illness, depression/anxiety, alcoholism, high estrogen states, uremia
• High dose (8 mg): historically used to differentiate Cushing disease vs ectopic ACTH and adrenal tumors as Cushing disease was thought to be suppressible to <50% of baseline (HOWEVER it is not a great test and excptions are common)

Question 11

List 1 advantage and 2 disadvantages of low-dose ACTH stimulation test over high-dose

Answer 11

• Advantage: more sensitive/specific in secondary adrenal insufficiency
• Disadvantage:
  
  • Logistics (must be done in AM, with IV ACTH)
  • Technical limitations (ACTH is only available in 250 mcg vials, unstable in solution, adheres to glas and tubing)

Question 12

What is the metyrapone test used for?

Answer 12

• To diagnose suspected pituitary ACTH deficiency
• Metyrapone inhibits 11-beta hydroxylase (11-deoxycortisol –> cortisol), which should stimulate ACTH secretion

Question 13

Describe the insulin induced hypoglycemia test

Answer 13

• Hypoglycemia –> CNS stress response
• CRH –> ACTH –> cortisol

Question 14

List 4 causes of hypoglycemia and low cortisol in a 4 week old female

Answer 14

1. Congenital adrenal hyperplasia (StAR mutation, 3-beta-hydroxysteroid dehydrogenase, 21-hydroxylase)
2. Adrenal hypoplasia congenita (DAX1 mutation)
3. Hypopituitarism (PROP1, POU1F1, POMC mutation, SOD)
4. ACTH resistance syndromes/hypoplasia (familial glucocorticoid deficiencies, triple A/Algrove syndrome)
5. Peroxisome biogenesis disorders (ex. Zellweger syndrome, neonatal adrenaleukodystrophy)
6. Birth trauma
7. Infection/sepsis

Question 15

List 5 causes of primary adrenal insufficiency

Answer 15

• Autoimmune (Addisions)
• Metastatic malignancy or lymphoma
• Adrenal hemorrhage
• Coagulopathy
• Antiphospholipid antibody syndrome
• Infectious (sepsis, TB, CMV, fungi, HIV)
• Adrenaleukodystrophy
• Peroxisome disorders (Zellweger)
• Infiltrative (amyloidosis, hemochromatosis)
• Congenital adrenal hyperplasia/hypoplasia
• Familial glucocorticoid deficiency and hypoplasia
• Triple A (Algrove) syndrome
• Drugs (ketoconazole, metyrapone)

Question 16

What conditions are seen in APS type 1?

What is the gene associated?

Answer 16

• AIRE (autoimmune regulator) gene
• Addisons
• Hypoparathyroidism
• Mucocutaneous candidiasis
• Less common: autoimmune hepatitis, dystrophy of dental enamel and nails, alopecia, vitiligo, keratopathy, dysfunction of gonads, thyroid, pancreatic beta cells, gastric parietal cells)

Question 17

What conditions are seen in APS type 2?

Answer 17

• HLA-related disorders
• Type 1 diabetes
• Autoimmune thyroid disease
• Alopecia areata
• vitiligo
• Primary hypogonadism
• Pernicious anemia
• Celiac disease

Question 18

Describe familial glucocorticoid deficiency

Answer 18

• Hereditary adrenocortical unresponsiveness to ACTH (high ACTH, low cortisol)
• Aldosterone secretion is preserved
• 2 subtypes:
  
  • ACTH receptor mutation
  • Allgrove/ Triple A syndrome with achalasia and alacrima
    *

Question 19

List 3 drugs that can cause primary adrenal insufficiency

Answer 19

• Antifungals (ketoconazole)
• Etomidate
• Antiparasitic agent suramin
• Metyrapone

Question 20

Differential diagnosis for hypoglycemia and low cortisol in a 4 week old female infant

Answer 20

• Hypopituitarism
  
  • PROP1, PIT1, POMC, POU1F1
• ACTH resistance syndrome & hypoplasia
  
  • Familial glucocorticoid deficiencies
  • Triple A (Algrove) syndrome
• Congenital adrenal hypoplasia (DAX1)
• CAH
  
  • StAR mutation, 3 beta hydroxysteroid dehydrogenase, 21 hydroxylase (but expect virilization)
• Sepsis, infection
• Peroxisome disorders (Zellweger)
• Birth trauma

Question 21

Where should you look for hyperpigmentation in a patient with Addisons?

Answer 21

• Buccal mucosa
• Palmar creases
• Nipples/areolae
• Perivaginal and perianal mucosa
• Sun-exposed areas
• Scars (will be hyperpigmented)
• Pressure areas (knuckles, toes, elbows, knees)

Question 22

What is the differential diagnosis for Cushing syndrome?

Answer 22

• ACTH dependent: Cushing disease, nonpituitary neoplasm (ectopic ACTH)
• ACTH independent
  
  • Iatrogenic (glucocorticoids)
  • Adrenal carcinoma
  • Adrenal neoplasm/adenoma
  • Macronodular adrenal hyperplasia
  • McCune albright syndrome
  • Primary pigmented nodular adrenal disease
  • Isolated micronodular adrenocortical disease

Question 23

What tumors are associated with ectopic ACTH secretion?

Answer 23

Mostly thoracic origin

• Bronchial carcinoid
• Small and non-small cell lung cancer

Question 24

What tests can you do to diagnose Cushing syndrome

Answer 24

• 24 hour urinary free cortisol
• Overnight 1 mg Dex suppression test
• Late night salivary cortisol

Question 25

List the clinical features of Cushing syndrome

Answer 25

* Obesity * Hypertension * Skin: plethora, hirsutism, striae, acne, bruising * MSK: osteopenia, weakness * Neuropsychiatric: emotional lability, euphoria, depression, psychosis * Gonadal: menstrual disorders, impotence, decreased libido * Metabolic: glucose intolerance, diabetes, hyperlipidemia, polyuria, kidney stones

Question 26

List 4 long-term complications of CAH 21-hydroxylase deficiency

Answer 26

* Short stature * Infertility * Sexual dysfunction * Metabolic syndrome & increased CVD risk * Hypertension if over-treated * Decreased BMD * Hyperandrogenism if poorly controlled * Reduced quality of life

Question 27

4 issues related to CAH to discuss during pregnancy

Answer 27

* Risk of transmission (offer genetic counselling) * Consider testing partner. If carrier, consider risks/benefits of dexamethasone treatment * Continue treatment with glucocorticoid that does not cross the placenta * Increased risk for pregnancy loss * Need stress dosing during pregnancy (hyperemesis, delivery) * May need c-section if any genital surgery

Question 28

What 3 lab tests are the best indicators of adequacy of CG treatment in CAH?

Answer 28

* 17 OHP * Androstenedione * Testosterone

Question 29

List 8 lab findings seen in Addisons disease

Answer 29

* Low cortisol * High ACTH * Hypoglycemia * Hyponatremia * Hyperkalemia * High renin * Low aldosterone * Positive adrenal antibodies * Mild acidosis * Increased Cr and urea (dehydration) * Hypercalcemia * Hematologic: normocytic normochromic anemia, neutropenia, eosinophilia, relative lymphocytosis