Adrenal gland Physiology + Calcium Flashcards
+ clinical biochemistry of Calcium/ bone
1
Q
What are the layers of the Adrenal Gland
(GFR)
A
- Glomerulosa
- Fasciulata
- Reticularis
- Medulla
2
Q
What are the adrenal causes of hypertension?
A
- Primary Hyperaldosteronism (Conn’s syndrome)
- Zona glomerulosa
- adenoma
- hyperplasia
- rare genetic causes
- Zona glomerulosa
- Phaeochromocytoma (Phaeo)
- tumour of the adrenal medulla
- some forms of congenital adrenal hyperplasia
- enzyme defect (uncommon)
3
Q
Who should be screened for Primary Hyperaldosteronism (Conn’s syndrome)?
A
those with
- hypokalaemia
- resistant hypertension (resistant to 3 drugs)
- younger people
- they have more vascular and renal pathology than people with essential hypertension &similar blood pressure
4
Q
What investigations/ assessments would indicate Primary Hyperaldosteronism?
A
- during initial screening tests
- suppressed renin
- normal/ high aldosterone
- a confirmatory oral or IV Na+ suppression test would be done
- to get the specific aetiology the following would be done
- an adrenal CT scan
- an adrenal venous sampling
- is also secretion unilateral?
- Meeomidate PET scan
5
Q
What is the treatment for Primary Hyperaldosteronism?
- unilateral vs bilateral adenoma treatment
A
- Unilateral Adenoma
- Laparoscopic Adrenalectomy
- Medical Treatment ( sometimes )
- Bilateral Hyperplasia
- Medical Treatment ( Aldosterone Antagonists)
- Spironolactone
- Eplerenone
- Medical Treatment ( Aldosterone Antagonists)
6
Q
What are the products of the adrenal medulla?
- how is it stimulated?
A
- Catecholamines
- Dopamine
- Noraepinpherine (Noraadrenalin)
- Epinephrine (adrenalin)
- requires cortisol for the conversion from NE
- sympathetic neurons in the spinal cord stimulate the adrenal medulla
7
Q
What are the biological effects of Catecholamines?
A
- Noradrenalin (Alpha 1 & 2 )
- Vasoconstriction
- Increased BP
- Pallor
- Glycogenolysis (increased blood sugar)
- Vasoconstriction
- Adrenalin ( Alpha 1, Beta 1 & 2 )
- Vasoconstriction
- Vasodilatation in Muscle
- Increased heart rate
- Sweating
8
Q
What is the presentation of Phaeochromocytoma?
A
- “Spells” of
- Headache, Sweating
- Pallor, Palpitation
- Anxiety
- Hypertension
- Permanent
- Intermittent
- Family history
9
Q
What genetic conditions are associated with Phaeo?
A
- Neurofibromatosis Type 1 (NF1)
- tumours under the skin that grow on nerves
- Multiple Endocrine Neoplasia type 2 (MEN 2)
- a familial disorder where one or more of the endocrine glands are overactive or form a tumour.
- Von Hippel-Lindau Syndrome
- visceral cysts and benign tumours with potential for subsequent malignant transformation
10
Q
What is Neurofibromatosis Type 1 (NF1)?
A
- genetic condition where tumours grow under the skin or deeper
- appear at any age but predominantly during adolescence
- these tumours grow on nerves are made up of cell surrounding the nerve and other cell types called - neurofibromas
- varying number of tumours
- may or may not be painful
- Axillary freckling may be present
11
Q
What is this an image of?
- in which condition does it occur?
A
- Cerebellar Haemangioglioblastoma in Von Hippel - Lindau
- CT + contrast. Right Enhancing cystic Mass
12
Q
What biochemical investigation/ result would suggest Phaeochromocytoma?
A
- 24 hour urine
- Normetanephrines & Metanephrines
- 3 Methoxytyromine
- Plasma
- Noradrenalin & Adrenalin
- Metanephrines
13
Q
What factors should be considered when carrying out diagnostic tests for Phaeo?
A
- Other things can elevate catecholamines
- obstructive sleep apnoea
- amphetamine-like drugs
- L-DOPA
- Labetalol
- Urine DA comes from the kidney 7 Nervous system, not the adrenal medulla
- so the urine methoxytyramine should be measured
14
Q
What pathology is seen in this image?
A
Phaeochromocytoma of the adrenal medulla
15
Q
What is the management of Phaeo?
A
-
Alpha-blockers
- Phenoxybenzamine
- Doxazocin
- Beta-blockers
- Propranolol
- Laparoscopic adrenalectomy
16
Q
Go over Post Adrenalectomy care
A
- Consider Genetic testing
- 30% are genetic ( 13 mutations so far)
- Annual Metanephrines (a metabolite of epinpherine)
- 24 hour urine
- Plasma
- Additional treatment if Malignant
- 10%
17
Q
What should you do if someone has a fit/seizure for the first time?
- why?
A
- check the serum calcium levels
- hypocalcaemia can cause seizures
- decrease in extracellular Ca2+ conc. increases the neurons permeability for Na+
- allows sodium to easily depolarize the neuron’s membrane and cause an action potential
18
Q
What are physical signs of hypoglycaemia?
( the same for hypoparathyroidism)
A
- Neuromuscular inability
- Chvostek’s sign
- when the facial nerve is tapped at the angle of the jaw, facial muscles on the same side of the face contract momentarily
- Trousseau’s sign of latent tetany
- carpal spasm when the brachial artery is occluded for 3 minutes
- less sensitive than Chvostek’s sign
- Chvostek’s sign
- Neurological sign and symptoms
- Personality disturbance
- Parkinsonism
- Irritability
- Mental status disturbed
- confusion/ disorientation
- psychosis/ psychoneurosis
- Ectodermal changes
- Dry skin
- coarse hair
- brittle nails
- Psoriasis
- alopecia
- Cardiac changes
- Ophthalmologic manifestations
- smooth muscle involvement
19
Q
What are the acute and chronic consequences of hypercalcaemia
A
-
Acute
- Thirst & Polyuria
- Abdominal Pain
-
Chronic
- Constipation
- Musculoskeletal aches / weakness
- Neurobehavioral symptoms
- Renal calculi
- Osteoporosis
20
Q
What state would serum calcium be found in?
A
- Protein Bound: 40%
- Albumin bound: 90%
- Globulin Bound: 10%
- Bound to Cations: 10%
- Phosphate & Citrate
- Ionised ( free ): 50%
- this should be measured directly not through the corrected total serum Ca++
- 1.1-1.35mmol/L
21
Q
What is the serum Calcium level range?
A
2.15-2.55mmols/L
22
Q
How are blood calcium levels controlled within their range?
A
-
Parathyroid chief cells in the parathyroid glands produce parathyroid hormones
- increased secretion of PTH –> increase in serum calcium
- Calcium-sensing receptor (CaSR) in the chief cells, sense an increase in serum Ca++ and stimulate the uptake of Ca++ by the parathyroid chief cells
23
Q
How does the Calcium sensing receptor CaSR function?
A
- this is a type of G protein-coupled receptor that is activated by two major signal-transducing effects
-
Activation of phospholipase C
- leads to the generation of the second messenger diacylglycerol and inositol triphosphate
-
Inhibition of adenylate cyclase
- __suppresses intracellular conc. of cyclic AMP
-
Activation of phospholipase C
- the presence of this receptor in various areas in the body suggests that Calcium behaves like a hormone
24
Q
How does Calcium effect PTH secretion
A
25
What are the receptors for Parathyroid Hormone
and PTHrP?
* _Type 1 parathyroid hormone receptor_: Binds both parathyroid hormone and amino-terminal peptides of PTHrP
* binding activates adenylyl cyclase and phospholipase C systems
* mRNA coding for type 1 receptor is most abundant in bone and the kidneys,
* also expressed at lower levels in may other tissues
* Mutations lead to Jansen's metaphyseal chondrosplasia ad BLomstrans chondroplasia
* _Type 2 parathyroid hormone receptor_: Binds parathyroid hormone, but shows very low affinity for PTHrP
* expressed in a few tissues also coupled to adenylyl cyclase
* ligand binding induces a rise in intracellular conc. of cyclic AMP
26
What is the action of PTH in the bone?
* increases renal calcium reabsorption and posphate excretion
* PTH blocks reabsorption of phosphate in the proximal tubule while promoting calcium reabsorption in the ascending loop of Henle, distal tubule, and collecting tubule
* promotes the absorption of calcium from the bone
* In the rapid phase when PTH binds to receptors on these cells, the osteocytic membrane pumps calcium ions from the bone fluid into the extracellular fluid
* In the slow phase which happens over several days osteoclasts are activated to digest formed bone, and second, proliferation of osteoclasts occurs - stimulates cytokines released by by differentiation of immature osteoclast precursors that possess PTH and it. D receptors
27
What is Rank Ligand?
**Receptor activator of nuclear factor kappa B ligand**
* RANKL, produced by osteoblasts and other cells, causes osteoclast precursors to form and differentiate into active (mature) osteoclasts
* implicated in altering the adherence of osteoclasts to the bone surface and suppresses apoptosis of mature osteoclasts
* _body naturally produces a protein called osteoprotegerin (OPG) that neutralizes the effects of RANKL, keeping the bone loss process in check_
* RANKL has direct catabolic effects on cortical and trabecular bone including reductions in bone density, volume and strength
28
Renal Synthesis of Active Vitamin D
29
How is vitamin D production regulated in the kidney?
* PTH stimulates and
* FGF23 inhibits 1,25(OH)2D
* leads to renal phosphate excretion
* In turn 1,25(OH)2D _inhibits PTH production and secretion_ from the parathyroid glands and _stimulates FGF23 production_ from bone
30
What is Primary Hyperparathyroidism?
- what are its causes
* excess production/ secretion of Parathyroid hormone (PTH) --\> increased calcium levels
_Causes_
* enlargement of one or more parathyroid gland
* most common in over 60's
* women are more likely to be affected than men
* radiation to the head and neck increases risk
* rarely caused by parathyroid cancer
31
What are the symptoms of Primary Hyperparathyroidism?
* Fatigue
* Fractures
* Decreased height
* Upper abdominal pain
* Loss of appetite/ Nausea
* Muscular weakness/ Muscle pain
* Depression/ Personality changes
* Stupor and possibly coma
* Kidney stones/ Increased urination
Complications: Osteoporosis, bone cysts in severe cases
32
What investigations can be done to confirm Primary Hyperparathyroidism?
* A test called radioimmunoassay shows an increased level of PTH.
* Serum calcium is increased.
* Serum phosphorus may be decreased.
* Serum alkaline phosphatase may be increased.
* Bone x-ray may show bone reabsorption (the body breaks down the bone), or fractures.
* Imaging of the kidneys or ureters may show calcification or blockage.
* ECG may show abnormalities.
* This disease may cause changes in the results of the following tests:
* Calcium - urine
* Calcium (ionized)
* Bone density
* Markers of bone resorption (N-telopeptide, pyridinoline, and deoxypyridinoline)
33
What is the treatment for Primary Hyperparathyroidism?
- treatment depends on the severity of the disease
* If calcium levels are minimally raised, they may simply be monitored,
* unless renal dysfunction, renal calculi or osteoporosis are present.
* Treatment may include:
* Drinking more fluids to prevent the formation of kidney stones
* Avoiding immobilization
* Avoiding thiazide-type diuretics
* Using Bone protective treatment if osteoporosis is present
* Treating with a calcium-receptor sensitizer (cinacalcet) to decrease levels of PTH
* Surgery: if indicated by
* osteoporosis, renal calculi, \<50yrs, serum Ca++ \>2.8mmol/l
* dependent on patient
34
What type of scan is this?
- what does it show?
Sesta Mibi Parathyroid scan
Ectopic Parathyroid adenoma
35
What is this a scan of?
- type of scan?
Parathyroid adenoma
4D CT scan
36
What are the causes of Hypoparathyroidism?
* Iatrogenic
* thyroidectomy
* radical neck surgery
* Autoimmune
* Hypomagnesaemia
* Genetic mutations
37
What are the common causes of secondary Hyperparathyroidism?
* Low / low normal serum Calcium + HIGH PTH
* Low serum 25 OH vitamin D
* Lack of sun exposure
* Gastrointestinal problems
* Malabsorption
* Extensive surgery ( small bowel )
* Renal Failure
38
What is rickets?
* A softening of the bones in children potentially leading to fractures and deformity predominantly due to vitamin D deficiency
* lack of adequate calcium may also lead to rickets
* majority of cases occur in children suffering malnutrition- famine/ starvation
* Osteomalacia is used to describe a similar condition occurring in adults
39
What is the overall physiological effect of Parathyroid Hormone?
* Mobilisation of calcium from bone
* Enhancing absorption of calcium from the SI
* works indirectly by stimulating the production of the active form of vitamin D in the kidney.
* Vitamin D induces synthesis of a calcium-binding protein in intestinal epithelial cells that facilitates efficient absorption of calcium into the blood
* Suppression of calcium loss in urine
* loss of phosphate ions in urine in exchange for calcium
40
What can cause a disruption to calcium homeostasis?
* Disorders of the gut, kidney, skeleton
* Disorders of the parathyroid glands
* Abnormal vit D metabolism
* intake
* synthesis
* metabolism to 1,25-dihydroxycholecalciferol
41
Give an overview of Parathyroid Hormone
* it's secreted as Intact-PTH (1-84 AA)
* this is metabolised in the periphery mainly the liver and kidney and stored in the gland and some goes into circulation
* the active form is PTH 1- 30 AA
* release stimulated in
* low plasma ionised calcium (acute stimuli)
* rise in plasma phosphate (chronic hypocalcemia)
42
What are the key actions of PTH?
* Increase in calcium via
* renal tubular reabsorption
* bone resorption (action of osteoclasts)
* GI tract absorption
* increased renal generation of active vit D
* acts as a Hypophosphataemic agent
* reduces proximal tubular reabsorption of phosphate by decreasing activity of type II sodium-phosphate co-transporter
43
How is intestinal absorption of calcium facilitated?
- biological reaction
* 1alpha-hydroxylation of 25 hydroxyvitamin D in the kidney forms **calcitriol** which
* **1,25 vitD (calcitriol)** increases calcium and phosphate uptake,
* it also stimulates bone resorption, intestinal absorption and renal reabsorption
44
What is the calculation to give the corrected plasma calcium?
**corrected calcium = calcium + 0.02(40-albumin)**
* disturbances in albumin (the bound fraction of calcium) can cause misinterpreted values
* abnormally high albumin levels may indicate hypocalcaemia
* abnormally low albumin levels may indicate hypercalcaemia
45
What are the causes of Hypercalcaemia?
* Malignancy - 65%
* may be due to local bone resorption due to metastases, or the production of PTH-related protein which activates osteoclasts
* Hyperparathyroidism - most common in ambulatory patients
* Hypervitaminosis D
* Familial hypoclaciuric hypercalcaemia
* autosomal dominant - inactivation of calcium genes coding for calcium-sensing receptors on the parathyroid cells and the kidney
46
what does plasma PTH levels in hypercalcaemia indicated about the cause of the pathology?
* If there is **suppressed PTH**
* non-parathyroid cause: malignant, it D excess, sarcoidosis
* if there is **Raised or detectable PTH**
* PTH mediated cause: 1y or 3y hyperparathyroidism + calcium receptor defects
47
What are the different Hyperparathyoid states?
* **Primary**
* adenoma, hyperplasia
* _plasma calcium is high_
* **Secondary**
* a normal response to chronic hypocalcaemia: CRF malabsorption
* _plasma calcium is low/normal_
* **Tertiary**
* ****developed from prolonged secondary state
* PTH secretion becomes autonomous
* _plasma calcium is high_
48
What does the plasma PTH levels in hypocalcemia indicate about the cause of the pathology?
* increased PTH
* non-parathyroid cause: vit D deficiency, renal failure
* low/normal PTH
* parathyroid cause: hyperparathyroidism, Mg deficiency
49
What are the markers of bone formation?
* increase osteoblast activity
* alkaline phosphatase
* bone alkaline phosphatase
* collagen peptides
50
What are the markers of bone resorption?
* Osteoclast activity
* collagen peptides
* pyridinolines (x-links)
* urine hydroxyproline
