Adrenal Insufficiency & Congenital Adrenal Hyperplasia Flashcards
Describe primary hyperaldosteronism
-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),
Describe secondary hyperaldosteronism
-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
Describe glucocorticoid over-production or excess
-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)
What are the causes of Primary Adrenal Insufficiency/ Addison’s disease?
- destruction of adrenal gland= smaller, denser, collapsed
- by tuberculosis, cancer metastases, autoimmune disease
How does Primary Adrenal Insufficiency/ Addison’s disease present?
- disease of all three adrenocortical zones
- aldosterone, cortisol & adrenal androgens all affected
Describe the phenotype of Primary Adrenal Insufficiency/ Addison’s disease?
- 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
What is the treatment for Primary Adrenal Insufficiency/ Addison’s disease?
-Fluid & hormone replacement
=synthetic glucocorticoid (hydrocortisone, prednisone)
=synthetic mineralocorticoid (fludrocortisone- synthetic aldosterone)
What are the causes of Secondary Adrenal Insufficiency/ hypopituitarism?
- 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
How does Secondary Adrenal Insufficiency/ hypopituitarism present?
- malfunction of ZF & ZR, reduced cortisol & androgen secretion
- RAS and aldosterone secretion (ZG) largely unaffected
Describe the phenotype of Secondary Adrenal Insufficiency/ hypopituitarism
- 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
What is the treatment for Secondary Adrenal Insufficiency/ hypopituitarism?
- hormone replacement, trans sphenoidal decompression/tumour removal
- synthetic glucocorticoid (hydrocortisone, prednisone), thyroxine, etc.
What is Congenital Adrenal Hyperplasia (CAH)?
- 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
Describe the genetics of CAH
-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
How common is CAH syndrome?
-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
How does CAH present?
-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
When is CAH diagnosed?
- Usually soon after birth
- Less severe CAH not apparent until puberty
- Prenatal diagnosis possible now affected genes identified
Describe the hormonal pattern in steroid 21-hydroxylase deficiency
- 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
How does partial block in 21-OHase activity present?
-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.
What is the treatment for partial block in 21-OHase activity?
- replace cortisol function
- feed-back inhibit ACTH ‘drive’= synthetic cortisol
- reduce ACTH-driven androgens
How do we monitor partial block in 21-OHase activity?
- glucocorticoid replacement
- monitor 17-OH progesterone
- androgen levels (most important)
How does Complete block 21-OHase activity present?
-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
How do we treat Complete block 21-OHase activity?
- 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
How do we monitor Complete block 21-OHase activity?
- glucocorticoid & mineralocorticoid
- monitor 17-OH progesterone
- androgen levels (most important)
Describe screening for common gene mutations for 21-hydroxylase deficiency
- in UK with family history
- ? Introduction in UK – under debate but cost.
- early intervention in utero improves outcome
What happens if excess androgen production in females is left untreated?
-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
Describe the actions of prenatal dexamethasone treatment
- reduces clitoral size
- allows urethral/vaginal separation
Describe late onset 21-OH CAH
- mild inactivating mutation – less severe than in affected neonates
- usually presents after puberty in women
- following upsurge in ACTH & adrenal steroid secretion (adrenarche)
What does excess adrenal androgen in late onset 21-OH CAH result in?
- menstrual cycle disturbances
- polycystic ovarian syndrome & hirsutism (change in hair patterns)
- possible infertility (key differential diagnosis for PCOS)
What is the treatment for late onset 21-OH CAH?
-Hydrocortisone replacement
=replace cortisol function
=feed-back inhibit ACTH ‘drive’
=reduce ACTH-driven androgens
How to we monitor late onset 21-OH CAH?
-titrate glucocorticoid replacement
-monitor 17-OH progesterone &
androgen levels (most important)
Describe the hormonal pattern in 11b-hydroxylase deficiency in ZF
- ↓ 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)
How does increased 11b-hydroxylase enzyme substrates present as?
-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
What is the treatment for 11b=hydroxylase deficiency?
- replace cortisol function
- feed-back inhibit ACTH ‘drive’
- reduce ACTH-driven androgen & mineralocorticoid production
How do we monitor 11b-hydroxylase deficiency?
-monitor 17-OH progesterone & androgen
-levels, as for 21-OH CAH
also measure plasma Na+ concentration
Overall, what happens when androgen production is altered?
- Increased= virilization, precocious puberty
- Blocked= ambiguous genitalia, no puberty
Overall, what happens when mineralocorticoids production is altered?
- Increased= salt retention and hypertension
- Blocked= salt wasting and hypotension
Describe 3b- hydroxysteroid dehydrogenase deficiency
-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
Describe StAR protein deficiency
=(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
