Calcium homeostasis and adrenal causes of hypertension Flashcards
Consider primary hyperaldosteronism (Conn’s syndrome)
How is it caused?
Zona glomerulosa
- adenoma (secreting)
- hyperplasia (bilateral)
To differentiate, adrenal CT or venous sampling (is aldosterone secreting bilateral?; metomidate PET CT
Consider primary hyperaldosteronism (Conn’s syndrome)
Outline the RAAS
Potential pharmacological inhibition sites?
Liver secretes angiotensinogen which is converted to angiotensin 1 by RENIN ( from liver)
Angiotensin 1 –> Angiotensin 2 by ACE
Angiotensin 2 —> Aldosterone secretion
- RENIN inhibitor
- ACE inhibitor
- Aldosterone inhibitor
- AT2 receptor –> vasodilation, ADH secretion
- AT1 receptor –> vasoconstriction, symp activation
- ARB
Consider primary hyperaldosteronism (Conn’s syndrome)
Who should be screened?
Tests?
Those with hypokalaemia, resistant hypertension (>3 drugs), young people
- People with hyperaldosteronism have increased vascular and renal pathology than those with essential HT & similar BP
Initial screening tests: suppressed RENIN, normal/ high aldosterone
Confirmatory tests: oral or IV Na+ suppression test
Consider primary hyperaldosteronism (Conn’s syndrome)
Treatment?
Unilateral adenoma: laparoscopic adrenalectomy, drugs
Bilateral hyperplasia: aldosterone antagonists (spinolactone, eplerinone)
Consider phaeochromocytoma.
What is it?
Prevalence in autopsy?
How is this adrenal medulla innervated? What does innervation cause?
Tumor of the adrenal medulla
In the adrenal medulla post ganglionic nerve cells are invvervated by preganglionic nerves. This sympathetic innervation –> ACh –>
Tyrosine -> LDOPA -> DA -> NA -> Adrenaline(under cortisol control)
Therefore, the products of AM = catecholamines
NA (alpha1, alpha2)- vasoconstriction (increases BP, pallor), glycogenolysis
Adrenaline (alpha1, beta1 and 2)- vasoconstriction, vasodilation in muscle, increased HR, sweating
Consider phaeochromocytoma.
How does it present?
Associated genetic conditons?
“spells” - headache, sweating, pallor, palpitations, anxiety, hypertension (permanent or intermittent), family history
- Neurofibromatosis type 1 (NF1) - axillary freckling, subdermal tumours in teens
- Von Hippel-Lindau syndrome
- Multiple endocrine neoplasia type 2 (MEN2)
Consider phaeochromocytoma.
How is it diagnosed?
How is it managed?
24 hour urine: normetanephrines, metanephrines, 3-methoxytyromine
Plasma: NA, Adrenaline, metanephrines
- Alpha blockers (phenoxybenzamine, doxazocin)
- Beta blockers (Propanolol)
- Laparoscopic adrenalectomy
Consider phaeochromocytoma.
What other things may cause raised catecholamines?
Why do we measure urine methoxytyromine?
obstructive sleep apnoea
amphetamine like drugs
L-Dopa
Labetalol
Urine dopamine comes from the kidney and NS not the adrenal medulla
Why is calcium important?
What happens in its disregulation?
Exocytosis of neurotransmitters and hormones
Physical properties of bone
Hypo-
- Destabilises neurones (can cause seizures)
- Physical signs: Chvostek’s sign (low plasma calcium leads to increased permeability of neuronal membranes to Na+) and Carpopedal spasm/Trousseau’s sign
Hyper-
- Acute: thirst and polyuria, abdominal pain
- Chronic: constipation, MSK aches/weakness, neurobehaviour symptoms, renal calculi, osteoporosis
How can Trousseau’s sign be elicited?
Occlude brachial artery
How is calcium carried in the blood?
Why is this important in practice?
40 % protein bound (90% albumin, 10% globulin)
- Ca2+ binds to negative sites on protein, competes with H+. Binding is pH dependent, alkalosis increases protein binding which decreases [Ca2+ plasma]
10% bound to cations (PO43-, Citrate)
50% ionised (free)
Lab reports TOTAL Ca2+ serum corrected for the [albumin] but this may be inaccurate if [albumin] <20g/L or in severe acute illness (In this case, measure ionised Ca2+ directly)
Reference range for plasma calcium : 2.15-2.55 mmol/L
How is this tightly controlled?
- Chief cells of parothyroid gland produce and secrete pTH which increases [Ca2+ serum]
- Ca2+ sensing receptor (CaSR) is sensitive to high [Ca] and stimulates uptake of Ca2+ by parathyroid chief cells
PHYSIOLOGICAL FEEDBACK LOOP
- Gprotein expressed also in C cells of thyroid, osteoblasts, haemotopoietic cells, kidney cells, bone marrow, GI mucosa, squamous cell oesophagus
- Changes in blood [PO43-] indirectly effect PTH release
- Low levels of PTH secreted even when [Ca2+] high
Outline how low [Ca2+] in the blood causes PTH secretion
Less Ca2+ molecules –> altered Ca2+ sensing receptor formation –> modified chief cell processes –> PTH secretion in presence of Mg2+
Therefore low [Magnesium] prevents PTH release
How does PTH work?
Consider its receptor, action at bone and kidney
Type 1 PTH receptor binds PTH and amino-terminal peptides of PTHrP
- G protein coupled receptor binding activates adenylyl cyclase (PKA) and phospphipase C (PKC)
- @Bone- rapid action of PTH via osteocytic membrane pump stimulation of osteoclasts
PTH –> osteoblast –> rank ligand –> RANK(regulates bone remodelling and primary mediatory of osteoclast formation, function and survival - @Kidney, Rapid Ca2+ reabsorption in LoH, DT and CD as well as descreased PO43- reabsorption (in PT)
- Renal synthesis of active vitamin D
What is an osteoclast?
Type of bone cell that removes bone tissue by removing the bones mineralised matrix (bone resorption). They are formed by the fusion of cells of the monocyte -macrophage cell line, characterised by high expression of trap AND cathepsin K
