Endocrine - Adrenal Disease Flashcards
What is secreted from the Zona Glomerulosa?
What stimulates their secretion?
Mineralocorticoids
- aldosterone
- precursors
Stimulated by:
- angiotensin II
- K+
- ACTH
What is secreted from the Zona Fasciculata?
What stimulates secretion?
Glucocorticoids
- cortisol
- corticosterone
Stimulated by: ACTH IL-1 IL-6 TNF Neuropeptidases
What is secreted from the Zona Reticularis?
What stimulates secretion?
Adrenal Androgens
- DHEA/S
- Andostenedione
Stimulated by:
ACTH
What is secreted from the Adrenal Medulla?
Catecholamines
- adrenaline
- noradrenaline
- dopamine
What is the melanocortin-2 receptor? How does it work?
The ACTH-Receptor MC2R (melanocortin-2 receptor) acts via MC2R-Accessory protein MRAP to form a complex that is transported to the adrenal cortical membrane and binds to ACTH to stimulate cAMP
This results in upregulation of protein kinase A:
1) increased importation of choelsterol esters
2) increased activity of hormone sensitive lipase which cleaves cholesterol esters
3) increased availability and phosphorylation of transcription fractor CREB which ENHANCES SYNTEHSIS OF CYP11A1
Effect of glucocorticoids on liver?
Hyperglycaemia
- stimulates gluconeogenesis
- stimulates glucose production from protein
- stimulates insulin production
Effect of glucocorticoids on muscle?
Catabolism
- mobilisation of amino acids
- inhibition of glucose uptake in muscles
Effect of glucocorticoids on adipose?
Fat deposition
- inhibition of glucose uptake promoting lipolysis
- counteracted y increased insulin stimulating lipogenesis
Effect of glucocorticoids on immune system?
Increased neutrophils
Decreased T and B cells, basophils and eosinophils
Effect of glucocorticoids on bone?
Bone catabolism
- decreased bone formation (direct inhibition of osteoblast)
- stimulation of bone resorption
Effect of glucocorticoids on vascular system?
Increased sensitivity to vasoconstrictors
Mineralocorticoid like effect
Increased free water excretion
Acute and chronic causes of adrenal failure?
Acute: haemorrhage or infarction
- heparin / warfarin
- sepsis
- coagulopathy
Chronic:
- autoimmune adrenalitis
- TB or granulomatous disease
- HIV
- drugs: ketoconazole / etomidate
- congenital adrenal hyperplasia
- adrenoleukodysplasia
- Addison’s
What is adrenoleukodysplasia?
X linked recessive with 2 phenotypes:
1) Cerebral ALD:
- childhood presentation
- dementia, blindness and quadriplegia
2) Adrenomyeloneuropathy
- spasticity and distal polyneuropathy
- young men
To diagnosed: elevated very long chain fatty acids
** screen ANY young boy/man with adrenal insufficiency
Features of glucocorticoid deficiency?
Fatigue, lethargy, weight loss and anorexia
Myalgias and joint pains
Fevers
Hypotension
Normocytic anaemia
Lymphocytosis
Eosinophilia
Hypoglycaemia
Slightly elevated TSH (loss of feedback inhibition)
Hyponatraemia (loss of feedback inhibition of vasopressin release)
Features of mineralocorticoid deficiency?
Abdominal pain, nausea and vomiting
Dizziness
Postural hypotension
Elevated Cr
Elevated K
Hyponatraemia
What are the skin changes in adrenal insufficiency?
PRMIARY: Pigmentation due to excess ACTH melanocytes
But in SECONDARY adrenal insufficiency the skin is PALE due to lack of ACTH
Screening and diagnosis of adrenal insufficiency?
Screen with morning cortisol level
Diagnose with short synacthen test
Gold standard is insulin tolerance test
- contraindicated in epilepsy or IHD
- only interpretable if hypoglycaemia is induced
Once the adrenals are found to be insufficient, how do you differentiate between primary and secondary?
Plasma ACTH:
if HIGH --> primary adrenal insufficiency Should also get: - elevated renin - decreased aldosterone - decreased serum DHEAS
if NORMAL or LOW --> secondary adrenal insufficiency Should also get: - normal renin - normal aldosterone - decreased DHEAS
If a diagnosis of PRIMARY adrenal insufficiency is made with short synacthen test and HIGH ACTH…what is the next step?
Do adrenal autoantibodies, thyroid studies, look for evidence of vitiligo and premature ovarian failure
If above are negative then:
- in males look for very long chain fatty acids
- CT adrenal imaging
If a diagnosis of SECONDARY adrenal insufficiency is made with short synacthen test and LOW/NORMAL ACTH…what is the next step?
MRI pituitary to measure pituitary hormones
What drugs can cause adrenal insufficiency?
by INHIBITING CORTICAL BIOSYNTHESIS:
- etomidate
- ketoconazole
- fluconazole
- metyrapone
- mititane
by INCREASING METABOLISM OF CORTISOL AND SYNTHETIC GLUCOCORTICOIDS:
- phenytoin
- barbituitates
- rifampicin
- mititane
by SUPPRESSING CRH OR ACTH
- glucocorticoids
- megestrol acetate
- opioids
HEPARIN: by HITS is a risk for bilateral adrenal haemorrhage
Etomidate causes adrenal insufficiency how?
by INHIBITING CORTICAL BIOSYNTHESIS:
Phenytoin causes adrenal insufficiency how?
by INCREASING METABOLISM OF CORTISOL AND SYNTHETIC GLUCOCORTICOIDS:
Glucocorticoids causes adrenal insufficiency how?
by SUPPRESSING CRH OR ACTH
Heparin causes adrenal insufficiency how?
HEPARIN: by HITS is a risk for bilateral adrenal haemorrhage
Ketoconazole causes adrenal insufficiency how?
by INHIBITING CORTICAL BIOSYNTHESIS:
Fluconazole causes adrenal insufficiency how?
by INHIBITING CORTICAL BIOSYNTHESIS:
Barbituates causes adrenal insufficiency how?
by INCREASING METABOLISM OF CORTISOL AND SYNTHETIC GLUCOCORTICOIDS:
Opioids causes adrenal insufficiency how?
by SUPPRESSING CRH OR ACTH
Mititane causes adrenal insufficiency how?
by INHIBITING CORTICAL BIOSYNTHESIS:
and
by INCREASING METABOLISM OF CORTISOL AND SYNTHETIC GLUCOCORTICOIDS:
Megestrol acetate causes adrenal insufficiency how?
by SUPPRESSING CRH OR ACTH
Rifampicin causes adrenal insufficiency how?
by INCREASING METABOLISM OF CORTISOL AND SYNTHETIC GLUCOCORTICOIDS:
Metyrapone causes adrenal insufficiency how?
by INHIBITING CORTICAL BIOSYNTHESIS:
What are the equivalences of steroids?
160mg cortisone acetate 100mg hydrocortisone 25mg prednisone 20mg prednisolone 2.5mg dexamethasone
Causes of LOW renin HIGH aldosterone?
Primary aldosteronism
- bilateral adrenal hyperplasia
- aldosterone producing adenoma (Conns)
- familial hyperaldosteronism
- pure aldosterone secreting carcinoma
** Bartter and Gitelman have high renin and high aldosterone but have HYPOTENSION/NORMOTENSION
Causes of HIGH renin and LOW aldosterone?
Secondary aldosteronism
- renal artery stenosis
- diuretics
- renin secreting tumour
Causes of LOW renin LOW aldosterone?
Apparent mineralocorticoid excess
- exogenous mineralocorticoid
- cushings syndrome
- liquoriche
- congenital adrenal hyeprplasia or 11beta-HSD2 defieincy
- Liddles Syndrome
What medications impact renin levels?
Renin increased by ACEi and diuretics
Renin decreased by beta blockers and CCBs
Why is it important to have a normal K level when measuring aldosterone?
Hypokalaemia causes a falsely normal aldosterone level
If CT adrenals done to investigate hyperaldosteronism, what is management of a unilateral tumour?
If <40yrs: adrenalectomy
If >40yrs: ? incidentaloma –> needs adrenal vein sampling
If CT adrenals done to investigate hyperaldosteronism what is the next diagnostic step if there is no visualised tumour?
Adrenal vein sampling.
Lateralisation if aldosterone:cortisol is >2 x on one side
If lateralisation then do adrenalectomy
If no lateralisation then medical treatment with spironolactone or amiloride
What is the hormonal dysfunction that results from congenital adrenal hyperplasia?
group of autosomal recessive disorders
affect adrenal steroid biosynthesis
in response to resultant low cortisol levels the anterior pituitary secretes high levels of ACTH
ACTH stimulates the production of adrenal androgens that may virilize a female infant
What are the possible types of congenital adrenal hyperplasia?
21-hydroxylase deficiency (90%)
–> gene is CYP21A2
11-beta hydroxylase deficiency (5%)
–> gene is CYP11B1
17-hydroxylase deficiency (very rare)
– gene is CYP17A1
Gene and features of 21-hydroxylase deficiency features
gene is CYP21A2
virilisation of female genitalia
precocious puberty in males
60-70% of patients have a salt-losing crisis at 1-3 wks of age
Gene and features of 11-beta hydroxylase deficiency
gene is CYP11B1
virilisation of female genitalia
precocious puberty in males
hypertension
hypokalaemia
Gene and features of 17-hydroxylase deficiency features
gene is CYP17A1
non-virilising in females
inter-sex in boys
hypertension
Indications for surgery for adrenal incidentaloma
Size >6cm and/or imaging characteristics suggestive of malignancy
Increased size
Functioning tumour
Pheochromocytoma
Which corticosteroid has:
MINIMAL glucocorticoid activity
VERY HIGH mineralocorticoid activity
Fludrocortisone
Which corticosteroid has:
Glucocorticoid activity
HIGH mineralocorticoid activity
Hydrocortisone
Which corticosteroid has:
PREDOMINANT glucocorticoid activity
LOW mineralocorticoid activity
Prednisolone
Which corticosteroid has:
VERY HIGH glucocorticoid activity
MINIMAL mineralocorticoid activity
Dexmethasone
Betamethasone
What steroid activity does it have:
Fludrocortisone
MINIMAL glucocorticoid activity
VERY HIGH mineralocorticoid activity
What steroid activity does it have:
Hydrocortisone
Glucocorticoid activity
HIGH mineralocorticoid activity
What steroid activity does it have:
Prednisolone
PREDOMINANT glucocorticoid activity
LOW mineralocorticoid activity
What steroid activity does it have:
Dexamethasone
Betmethasone
VERY HIGH glucocorticoid activity
MINIMAL mineralocorticoid activity
What is Waterhouse-Friderichsen syndrome
Adrenal gland failure secondary to previous adrenal haemorrhage that was caused by severe bacterial infection.
Causes of Waterhouse-Friderichsen syndrome
meningococcus
Haemophilus influenzae
Pseudomonas aeruginosa
Escherichia coli
Streptococcus pneumoniae
In Adrenocortical Carcinoma
- genetics?
- Prognostic marker?
- Treatment?
GENETICS:
- somatic mutations in tp53 (25%)
- germline mutation in tp53 in Li Fraumeni Syndrome
IGF-2 overexpression in 90%
Most important prognostic marker is Ki67 proliferative index
- if <10% = slow-mod growth
- if >10% = POOR prognosis
Treat:
- surgery
- Mitotane: need to give steroid as well as mitotane disrupts cortisol synthesis, so need >2x normal insufficiency doses
What to be aware of if giving mitotane?
need to give steroid as well as mitotane disrupts cortisol synthesis, so need >2x normal insufficiency doses
What HLA class are associated with Addison’s Disease?
HLA DR3/4 and DQ2/8
What antibodies are seen in Addison’s Disease?
Anti-21-hydroxylase (in 50-80%)
Factors that increase and decrease plasma corticosteroid-binding globulin (CBG)
INCREASE:
- pregnancy
- oestrogen administration
- hyperthyroid
- inflammation/acute illness
DECREASE:
- protein deficiency
- diminished synthetic capability
