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Diabetes > Adrenal Insufficiency & Congenital Adrenal Hyperplasia > Flashcards

Adrenal Insufficiency & Congenital Adrenal Hyperplasia Flashcards

1
Q

Describe primary hyperaldosteronism

A

-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),

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2
Q

Describe secondary hyperaldosteronism

A

-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

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3
Q

Describe glucocorticoid over-production or excess

A

-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)

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4
Q

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

A
  • destruction of adrenal gland= smaller, denser, collapsed

- by tuberculosis, cancer metastases, autoimmune disease

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5
Q

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

A
  • disease of all three adrenocortical zones

- aldosterone, cortisol & adrenal androgens all affected

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6
Q

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

A
  • 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
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7
Q

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

A

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

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8
Q

What are the causes of Secondary Adrenal Insufficiency/ hypopituitarism?

A
  • 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
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9
Q

How does Secondary Adrenal Insufficiency/ hypopituitarism present?

A
  • malfunction of ZF & ZR, reduced cortisol & androgen secretion
  • RAS and aldosterone secretion (ZG) largely unaffected
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10
Q

Describe the phenotype of Secondary Adrenal Insufficiency/ hypopituitarism

A
  • 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
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11
Q

What is the treatment for Secondary Adrenal Insufficiency/ hypopituitarism?

A
  • hormone replacement, trans sphenoidal decompression/tumour removal
  • synthetic glucocorticoid (hydrocortisone, prednisone), thyroxine, etc.
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12
Q

What is Congenital Adrenal Hyperplasia (CAH)?

A
  • 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
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13
Q

Describe the genetics of CAH

A

-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

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14
Q

How common is CAH syndrome?

A

-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

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15
Q

How does CAH present?

A 
-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
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16
Q

When is CAH diagnosed?

A
  • Usually soon after birth
  • Less severe CAH not apparent until puberty
  • Prenatal diagnosis possible now affected genes identified
17
Q

Describe the hormonal pattern in steroid 21-hydroxylase deficiency

A
  • 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
18
Q

How does partial block in 21-OHase activity present?

A

-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.

19
Q

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

A
  • replace cortisol function
  • feed-back inhibit ACTH ‘drive’= synthetic cortisol
  • reduce ACTH-driven androgens
20
Q

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

A
  • glucocorticoid replacement
  • monitor 17-OH progesterone
  • androgen levels (most important)
21
Q

How does Complete block 21-OHase activity present?

A

-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

22
Q

How do we treat Complete block 21-OHase activity?

A
  • 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
23
Q

How do we monitor Complete block 21-OHase activity?

A
  • glucocorticoid & mineralocorticoid
  • monitor 17-OH progesterone
  • androgen levels (most important)
24
Q

Describe screening for common gene mutations for 21-hydroxylase deficiency

A
  • in UK with family history
  • ? Introduction in UK – under debate but cost.
  • early intervention in utero improves outcome
25
Q

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

A

-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

26
Q

Describe the actions of prenatal dexamethasone treatment

A
  • reduces clitoral size

- allows urethral/vaginal separation

27
Q

Describe late onset 21-OH CAH

A
  • mild inactivating mutation – less severe than in affected neonates
  • usually presents after puberty in women
  • following upsurge in ACTH & adrenal steroid secretion (adrenarche)
28
Q

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

A
  • menstrual cycle disturbances
  • polycystic ovarian syndrome & hirsutism (change in hair patterns)
  • possible infertility (key differential diagnosis for PCOS)
29
Q

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

A

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

30
Q

How to we monitor late onset 21-OH CAH?

A

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

31
Q

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

A
  • ↓ 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)
32
Q

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

A

-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

33
Q

What is the treatment for 11b=hydroxylase deficiency?

A
  • replace cortisol function
  • feed-back inhibit ACTH ‘drive’
  • reduce ACTH-driven androgen & mineralocorticoid production
34
Q

How do we monitor 11b-hydroxylase deficiency?

A

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

35
Q

Overall, what happens when androgen production is altered?

A
  • Increased= virilization, precocious puberty

- Blocked= ambiguous genitalia, no puberty

36
Q

Overall, what happens when mineralocorticoids production is altered?

A
  • Increased= salt retention and hypertension

- Blocked= salt wasting and hypotension

37
Q

Describe 3b- hydroxysteroid dehydrogenase deficiency

A

-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

38
Q

Describe StAR protein deficiency

A

=(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

Diabetes (30 decks)

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