Lec 14 Adrenal III Flashcards
How common is primary aldosteronism?
5-10% of all cases of “essential” hypertension
What are syndromes of apparent mineralocorticoid excess?
neither DOC or aldosterone is elevated
- cortisol made in excess or not properly inactivated to cortisone [in 11B-HSD deficiency] and is acting on the mineralocorticoid receptor
What are the actions of aldosterone?
- exchange Na and H for K at distal collecting tubule [DCT]
- increase Na and volume, BP, decrease K [hypokalemia]
What are some things that regulate aldosterone levels?
- RAAS [primary]
- hyperkalemia
- ACTH
What is the escape phenomenon?
atrial natriuretic factor [ANF} made in heart gets stimulated by high BP and modulates clinical effects of excess mineralocorticoid [aldosterone]
What should you with if high BP and unprovoked hypokalemia or severe diuretic-induced hypokalemia?
primary aldosteronism = 50% of cases
What are the two major causes of primary hyperaldosteronism?
- aldosterone producing adenoma [1/3]
- idiopathic hyperaldosteronism [bilateral] [2/3]
What number value tells you primary aldosteronism?
high aldosterone in setting of suppressed renin
aldosterone: renin ratio > 20
WHat are characteristics of aldosteronomas?
very small; may not be seen on imaging
up to 50% have bilateral disease so have to identify source of excess aldosterone
What is medical therapy for aldosteronoma?
aldosterone antagonists [spironolactone or epleronone]
What is familial aldosteronism?
recombination of genes encoding CYP11B1 and CYP11B2 –> chimeric gene that encodes hybrid proteins/steroids
What is treatment for familial aldosteronism?
suppress ACTH with glucocorticoids [b/c the chimeric gene is under ACTH control]
How do you localize site of aldosteronoma?
bilateral adrenal venous sampling; compare ratio
What mutation found in aldosterone producing adenomas?
CNJJ5 mutation in gene encoding the K channel
What is adrenal medulla derived from?
neuroectoderm –> phechromoblasts
What is the adrenal cortex derived from?
true glandular tissue
What is role of adrenal medulla in sympathetic nervous system?
serve as amplifiers of SNS
WHat 3 major hormones secreted by adrenal medulla?
- epinephrine
- norepinephrine
- dopamine
What is the rate limiting step in steroid hormone production in medulla?
conversion of tyrosine to dihydroxyphenlalanine [DOPA] cautalzyed by tyrosine hydroxylase
From what AA are catecholamines synthesized?
tyrosine
What converts NE to Epi? What induces it?
PNMT [phenylethanolamine N-methyltransferase] converts NE to Epi
induced by cortasol
Does adrenal medulla secrete more epinephrine or NE?
secretes 4x more Epi
[NE total circulating levels higher b/c of NE release from postganglionic sympathetic neurons]
What stimulates catecholamine release from adrenal medulla?
- postural changes [supine to standing]
- low intravascular volume
- hypoglycemia
- severe illness
- emotional stress [fear or rage]
- tumors [pheochromocytomas and paragangliomas]
What are the major signals for catecholamine release?
- decrease BP, blood volume, or glucose
What is epi/NE affinity for a1/a2 receptors?
epi > NE for a1/a2
What is epi/NE affinity for B1 receptors?
epi = NE
What is epi/NE affinity for b2 receptors?
epi > > > NE
overall effect = increased contractility and vasodilation
Do adrenal medulary tumors that hypersecrete primarily Epi cause hypertension or hypotension?
hypotension b/c have super high affinity for B2 which causes vasodilation
What things do catecholamines increase?
- blood glucose
- lipolysis
- skeletal muscle blood flow/contractility
- HR
- CO
- BP
What things do catecholamines decrease?
- visceral blood flow
- GI motility
- urine output
What is a pheochromocytoma?
adrenal medullary tumor derived from neural crest = chromaffin cells
What is a paraganglioma?
catecholamine secreting tumor arising from sympathetic paraganglion OR extra-adrenal pheochromocytomas
What kind of hormones are secreted by paragangliomas?
often don’t secrete at all; if they do its NE
What kind of hormones are secreted by pheochromocytomas?
NE and/or epi
b/c of high PNMT due to cortisol
What is effect of pheochromocytomas?
triad: headache, sweating, palpitations in person with hypertension
- blanching
- tachycardia
- chest pain
- arrhythmia
- postural hypotension
Which pheos are more likely to be malignant?
- extra-adrenal [paraganglioma]
- tumors > 6 cm
- more dense = > 10 hounsfield units
What percent of pheos are associated with familial cause?
> 25%
How do you diagnose pheochromocytoma?
- plasma free metanephrines
- 24 hr urine metanephrine
What are metanephrines?
metabolites of catecholamines
How do you localize where pheochromocytoma is secretin?
MRI T2 = lights up bright highly metabolically active tissue
PET scan
I-meta-iodobenyzlgunaidine [MIBG] scan
What is adrenal incidentaloma?
adrenal mass > 1cm discovered during radiologic exam incidentally
> 4cm be suspicious of cancer
What percent of adrenal incidentalomas are functional?
10-25%
What hormone is primarily secreted by subclinical adrenal incidentalomas?
5-47% secrete cortisol
What are the three Ps of MEN1?
- pituitary tumor
- parathyroid tumor
- pancreatic endocrine tumors
What are the 4 genetic syndromes associated with pheochromocytoma?
- nerufibromatosis I
- MEN 2a
- MEN 2b
- Von Hippel Lindau
What causes Von Hippel Lindau?
inactivating mutation in VHL tumor suppressor gene
What causes MEN1?
autosomal dominant deletion 11q13 = inactivation of tumor suppressor gene MENIN
What causes MEN2?
activating RET-proto-oncogene mutation –> activation of receptor tyrosine kinase
autosomal dominant
What kind of tumors associated with von hippel lindau?
- pheochromocytoma
- renal cell carcinoma
What is presentation of MEN2 syndromes?
- pheochromocytomas
- hyperparathyroidism [4 gland hyperplasia]
- medullary cancer of thyroid
What is unique to MEN2B clinical presentation?
marfanoid habitus
mucosal neuromas
ganglioneuromas
What is presentation of MEN1?
- pituitary tumors
- pancreatic endocrine tumors [zollinger ellison or insulinoma or glucagonoma]
- parathyroid tumors [hyperplasia]
What causes neurofibromatosis 1?
mutation in gene encoding parafibromin = tumor suppresso
What is presentation of neurofibromatosis I?
- pheochromocytomas
- skin neurofibromas
- iris hamartomas
- cafe au lait spots
What is familial paraganglioma syndrome?
mutations in genes encoding succinate dehydrogenase complex –> uncouples mitochondrial e- transport and causes hypoxic state
have
- pheochromocytomas
- paragangliomas
can result in malignant and metastatic disease
What percent of adrenal incidentalomas are malignant?
< 3%
What is the differential diagnosis for bilateral adrenal tumors?
- metastatic disease
- congenital adrenal hyperplasia [CAH]
- cortical adenomas
- lymphoma
- infeciton
- hemorrhage
- ACTH dependent cushing
- pheo
- amyloidosis
What is BMAH?
bilateral macronodular hyperplasia –> causes metabolic syndrome and mild hypercortisolism
