Adrenal Insufficiency & Congenital Adrenal Hyperplasia

Question 1

Describe primary hyperaldosteronism

Answer 1

-Different causes:
=Conn’s syndrome, bilateral adrenal hyperplasia, Glucocorticoid-Remediable Aldosteronism (GRA)
-Common phenotype:
=high plasma aldosterone, inappropriate MR activation,
=high Na+, low K+, ECF expansion, hypertension, low renin (RAS),

Question 2

Describe secondary hyperaldosteronism

Answer 2

-Different causes:
=renin-secreting JG cell tumour; renal arterial stenosis
-Common phenotype:
=high plasma renin, high aldosterone, inappropriate MR activation,
=high Na+, low K+, ECF expansion, hypertension

Question 3

Describe glucocorticoid over-production or excess

Answer 3

-Different causes:
=Cushing’s Syndrome, Cushing’s Disease, ectopic ACTH, steroids, Apparent Mineralocorticoid Excess, drugs, liquorice
-Common phenotype:
=high local kidney cortisol = inappropriate MR activation
=high plasma Na+, low K+, ECF expansion, hypertension, low renin (RAS)

Question 4

What are the causes of Primary Adrenal Insufficiency/ Addison’s disease?

Answer 4

• destruction of adrenal gland= smaller, denser, collapsed

- by tuberculosis, cancer metastases, autoimmune disease

Question 5

How does Primary Adrenal Insufficiency/ Addison’s disease present?

Answer 5

• disease of all three adrenocortical zones

- aldosterone, cortisol & adrenal androgens all affected

Question 6

Describe the phenotype of Primary Adrenal Insufficiency/ Addison’s disease?

Answer 6

• low plasma aldosterone = lack of MR activation
• low Na+, high K+, reduced ECF, hypotension,
• Low plasma cortisol, low glucose, high ACTH (lack of cortisol feedback) so skin pigmentation at pressure points/ stress

Question 7

What is the treatment for Primary Adrenal Insufficiency/ Addison’s disease?

Answer 7

-Fluid & hormone replacement
=synthetic glucocorticoid (hydrocortisone, prednisone)
=synthetic mineralocorticoid (fludrocortisone- synthetic aldosterone)

Question 8

What are the causes of Secondary Adrenal Insufficiency/ hypopituitarism?

Answer 8

• partial or complete loss of anterior lobe pituitary function
• tumour, pituitary apoplexy= caused by untreated tumour, bleeding so pressure which traumatises tissue, suppression by long-term corticosteroids (feedback on corticotrophs)
• lack of pituitary ACTH secretion & adrenocortical trophic stimulation

Question 9

How does Secondary Adrenal Insufficiency/ hypopituitarism present?

Answer 9

• malfunction of ZF & ZR, reduced cortisol & androgen secretion
• RAS and aldosterone secretion (ZG) largely unaffected

Question 10

Describe the phenotype of Secondary Adrenal Insufficiency/ hypopituitarism

Answer 10

• low plasma ACTH & cortisol due to pituitary & adrenal failure
• Increased vasopressin release from posterior pituitary (cortisol feedback regulates)
• ECV expansion low Na+, low K+ (dilutional hyponatraemia) as vasopressin

Question 11

What is the treatment for Secondary Adrenal Insufficiency/ hypopituitarism?

Answer 11

• hormone replacement, trans sphenoidal decompression/tumour removal
• synthetic glucocorticoid (hydrocortisone, prednisone), thyroxine, etc.

Question 12

What is Congenital Adrenal Hyperplasia (CAH)?

Answer 12

• Inherited condition present at birth (congenital) in which the adrenal gland is larger than usual (hyperplasia)
• A form of primary adrenal insufficiency
• Usually caused by an inherited defect in gene for any steroidogenic enzyme
• Inactivating mutations partial or complete

Question 13

Describe the genetics of CAH

Answer 13

-Autosomal recessive (both parents carriers)
-Heterozygote ‘carriers’ usually asymptomatic (may affect immune system)
-Affected individuals usually compound heterozygotes:
=both alleles altered, but different mutations inherited from mother & father (so 2 genes affected)
-BUT also see genuine homozygotes
=e.g. from consanguineous marriages, first cousin, same mutation in both alleles in gene

Question 14

How common is CAH syndrome?

Answer 14

-Common (90-95% of cases):
=Steroid 21-hydroxylase (21-OHase)= penultimate enzyme in both aldosterone and cortisol production
=population frequency 1 : 14,500 = heterozygote frequency of 1 : 61
- (NB: 21-OHase pseudogene, gene duplication and one is inactivated, potential for crossing over)
=selection pressure= less cortisol for survival?

-Less common (5% of cases):
=11β-OHase (ultimate gene in glucocorticoid synthesis)

-Rare (0.1-1% of cases):
=17α-OHase
=3β-HSD
=StAR (lipoid CAH)= fat gets imported but cant be imported into mitochondria so fat builds up

Question 15

How does CAH present?

Answer 15

-Block in cortisol synthetic pathway:
=reduced cortisol
=impaired stress response
=reduced plasma glucose
=reduced feedback on CRH-ACTH
-Elevated ACTH:
=increased pituitary ACTH secretion
=adrenal stimulation & hyperplasia (pathophysiological growth)
-Also changes in other steroids:
=excess intermediates before block
=reduced hormones after block

Question 16

When is CAH diagnosed?

Answer 16

• Usually soon after birth
• Less severe CAH not apparent until puberty
• Prenatal diagnosis possible now affected genes identified

Question 17

Describe the hormonal pattern in steroid 21-hydroxylase deficiency

Answer 17

• Partial inactivation: ↓ Cortisol, ↓ feedback, ↑ACTH;
• Complete inactivation: ↓ Cortisol + Aldo, ↓ feedback, ↑ACTH;
• Steroid accumulation= ↑Progesterone, ↑17α-OH progesterone, ↑DHEA & androstenedione
• ↑adrenal androgen feedback on pituitary → ↓FSH, ↓LH so lack of fertility

Question 18

How does partial block in 21-OHase activity present?

Answer 18

-Symptoms reflect mainly a lack of cortisol (enough aldo still made)
=remember: cortisol is made at 100x higher levels than aldosterone
-Increased androgens in utero
=virilisation in boys; masculinisation in girls (sex determination before adrenal gland formed)
-Most common cause of ambiguous genitalia due to prenatal masculinisation of genetically female (XX) infants.

Question 19

What is the treatment for partial block in 21-OHase activity?

Answer 19

• replace cortisol function
• feed-back inhibit ACTH ‘drive’= synthetic cortisol
• reduce ACTH-driven androgens

Question 20

How do we monitor partial block in 21-OHase activity?

Answer 20

• glucocorticoid replacement
• monitor 17-OH progesterone
• androgen levels (most important)

Question 21

How does Complete block 21-OHase activity present?

Answer 21

-Severe classical ‘salt wasting’ form … aldo synthesis also blocked
-Symptoms reflect a lack of cortisol AND aldosterone
=low plasma aldosterone = lack of MR activation
=low plasma Na+ , high plasma K+, H+ = hyperkalaemia acidosis
=ECF deficit, hypotension & vascular collapse (cant maintain vasoconstriction)
=Life-threatening vomiting & dehydration in new-borns – treatment essential

-Increased androgens
=virilisation in boys; masculinisation in girls

Question 22

How do we treat Complete block 21-OHase activity?

Answer 22

• replace cortisol & mineralocorticoid
• reduce ACTH-driven androgens (dexamethasone= synthetic glucocorticoid, can be given in utero if known disease as can cross placenta barrier)
• normalise plasma Na+, ECF & bp

Question 23

How do we monitor Complete block 21-OHase activity?

Answer 23

• glucocorticoid & mineralocorticoid
• monitor 17-OH progesterone
• androgen levels (most important)

Question 24

Describe screening for common gene mutations for 21-hydroxylase deficiency

Answer 24

• in UK with family history
• ? Introduction in UK – under debate but cost.
• early intervention in utero improves outcome

Question 25

What happens if excess androgen production in females is left untreated?

Answer 25

-gender mis-assignment
-psychological problems
-may need corrective surgery
=ambiguous genitalia
=single urethral/vaginal orifice (surgery to allow fluids to flow)
=fused labia & enlarged clitoris

Question 26

Describe the actions of prenatal dexamethasone treatment

Answer 26

• reduces clitoral size

- allows urethral/vaginal separation

Question 27

Describe late onset 21-OH CAH

Answer 27

• mild inactivating mutation – less severe than in affected neonates
• usually presents after puberty in women
• following upsurge in ACTH & adrenal steroid secretion (adrenarche)

Question 28

What does excess adrenal androgen in late onset 21-OH CAH result in?

Answer 28

• menstrual cycle disturbances
• polycystic ovarian syndrome & hirsutism (change in hair patterns)
• possible infertility (key differential diagnosis for PCOS)

Question 29

What is the treatment for late onset 21-OH CAH?

Answer 29

-Hydrocortisone replacement
=replace cortisol function
=feed-back inhibit ACTH ‘drive’
=reduce ACTH-driven androgens

Question 30

How to we monitor late onset 21-OH CAH?

Answer 30

-titrate glucocorticoid replacement
-monitor 17-OH progesterone &
androgen levels (most important)

Question 31

Describe the hormonal pattern in 11b-hydroxylase deficiency in ZF

Answer 31

• ↓ Cortisol (partial block), ↓ feedback, ↑ACTH;
• ↑ 11β-OH substrates: deoxycortisol & deoxycorticosterone (DOC) in ZF (precursor for cortisol and corticosterone)
• excess adrenal androgens
• hypertension due weak mineralocorticoid activity of DOC (deoxycorticosterone) at the MR (both mineralocorticoid and glucocorticoid actions)

Question 32

How does increased 11b-hydroxylase enzyme substrates present as?

Answer 32

-11-deoxycortisol
-11-deoxycorticosterone (DOC); weak mineralocorticoid
=(active at the kidney MR; NOT inactivated by 11β-HSD-2)
-Inappropriate MR activation causes Na+ retention, ECF expansion, hypertension, low renin (RAS) & inhibition of aldo production in the ZG
-hypertension the clinical clue that a patient has 11OH-CAH (rather than 21-OH CAH)
-Increased androgens
=virilisation in boys; masculinisation in girls

Question 33

What is the treatment for 11b=hydroxylase deficiency?

Answer 33

• replace cortisol function
• feed-back inhibit ACTH ‘drive’
• reduce ACTH-driven androgen & mineralocorticoid production

Question 34

How do we monitor 11b-hydroxylase deficiency?

Answer 34

-monitor 17-OH progesterone & androgen
-levels, as for 21-OH CAH
also measure plasma Na+ concentration

Question 35

Overall, what happens when androgen production is altered?

Answer 35

• Increased= virilization, precocious puberty

- Blocked= ambiguous genitalia, no puberty

Question 36

Overall, what happens when mineralocorticoids production is altered?

Answer 36

• Increased= salt retention and hypertension

- Blocked= salt wasting and hypotension

Question 37

Describe 3b- hydroxysteroid dehydrogenase deficiency

Answer 37

-Mineralocorticoid, glucocorticoid & androstenedione synthesis blocked
=leading to salt loss, ambiguous genitalia and absence of puberty
-BUT excess DHEA (androgen)
=Treatment: total hormone replacement inc. cortisol to reduce ACTH drive

Question 38

Describe StAR protein deficiency

Answer 38

=(lipoid congenital hyperplasia)

• cytoplasmic lipid accumulation, synthesis of all steroids blocked leading to salt loss and rapidly fatal postnatally if not treated
• Treatment: total hormone replacement inc. cortisol to reduce ACTH drive