Calcium Homeostasis and Parathyroid Hormone Flashcards
Where is the calcium distribution in the body?
Is the calcium extracellular or intracellular?
What is the state of calcium found in the blood?
Majority is found in bones
Extracellular calcium
60% is ultrafilterable (10mg/dl in blood)
50% free ionized state (drives calcium regulatory mechanism)
40% protein bound (albumin and globulin)
10% complexed with anions (bicarbonate, phosphate, citrate and lactate)
What is intracellular calcium used for?
Muscle contraction
Do changes in plasma protein concentration affect ionized Ca in the plasma?
Do the changes correlate?
Yes, they develop slowly over time but do not cause parallel changes in Ca concentration in a predictable manner.
NO
What does an increase in complexing anion concentration (phosphates) do?
How is anion concentration and ionized calcium correlated?
Decreases ionized Calcium
They are inversely related
What does acidemia cause?
Are there more more or less calcium bound to albumin?
Increase in ionized calcium concentration in blood
Less calcium are bound to albumin
What does alkalemia cause?
Are there more or less calcium bound to albumin?
Decrease in ionized calcium concentration in blood
More calcium are bound to albumin
What are the consequences of hypocalcemia?
What is the effect on action potential channels with low calcium?
Hyperreflexia
Spontaneous twitching
Muscle cramps
Tingling
Numbness
The channels open up more so you get more AP fires
What are the consequences of hypercalcemia?
Hyporeflexia
Constipation
Polyuria
Polydipsia
Lethargy
Coma
Death
Which 3 organs are involved in calcium homeostasis?
Bone
Kidney
Intestine
What are the three hormones involved in calcium homeostasis?
Parathyroid hormone (PTH)
Vitamin D
Calcitonin
What happens when blood calcium levels increase?
Thyroid gland releases calcitonin -> stimulates Ca2+ deposition in bones & reduces Ca uptake in kidneys
What happens when blood calcium levels decrease?
Parathyroid glands release parathyroid hormone (PTH) -> stimulates Ca release from bones & increase calcium uptake in kidneys & increases calcium uptake in intestines
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What is the effect of PTH secretion on bone?
What do osteoclasts do?
What do osteoblasts do?
Increase in bone resorption
Osteoclasts remove bone by dissolving mineral and breaking down the matrix
Osteoblasts lay down new bone
What does increase in PTH secretion do to the kidney?
Decreases phosphate reabsorption
Increases calcium reabsorption
Increases urinary cAMP
What does increase in PTH secretion do to the intestine?
Increases calcium absorption indirectly via 1,25-dihydroxycholecalciferol
What is the active form of vitamin D?
Which enzyme converts vitamin D to its active form?
1,25-dihydroxycholecalciferol
Enzyme 1 alpha hydroxylase
What is the action of PTH on bone?
What is the overall effect of PTH on bond?
Which factors are released?
What does this factor act on?
PTH binds to PTH receptors on osteoblasts, the bone forming cells.
Overall PTH promotes bone reabsorption and delivers both Ca and phosphate to ECF.
- Indirect effect
RANKL is released
RANKL acts on osteoclasts
What does RANKL stand for?
Receptor Activator for Nuclear factor xB Ligand
What does phosphate released from bone complex with?
Phosphate released from bone will complex with calcium in ECF and limit the rise in ionized Ca2+
What is the action of PTH on the kidney?
What is inhibited? What does this cause?
What is activated? What does this cause?
Stimulates calcium reabsorption in distal tubule and collecting duct
Inhibits phosphate reabsorption causing phosphaturia. Phosphate excretion prevents phosphate from forming complexes with calcium in ECF
Activates renal 1alpha-hydroxylase which makes 1,25-dihydroxycholecalciferol
What increases with PTH action on the kidney?
Nephrogenous or urinary cAMP increases
What is the pathophysiology associated with primary hyperparathyroidism?
What is the treatment?
Cause: Parathyroid adenoma leading to excessive PTH secretion
- Hypercalcemia
- Excretion of phosphate, cAMP and Ca excessively in urine
- Hypophosphatemia
- Increase in 1,25-dihydroxycholecalciferol
Tx: Parathyroidectomy
What occurs in hypercalcemia?
Increased bone resorption
Increased renal Ca resorption
Increased intestinal Ca absorption
What occurs from excretion of phosphate, cAMP and Ca in urine?
What is this excreted as?
High filtration load exceeds resorptive capacity of renal tubule.
Hypercalciuria precipitates as kidney stones
What does hypophosphatemia cause?
Excessive blockade of renal PO4 reabsorption
What is the result of 1,25-dihydroxycholecalciferol?
More vitamin D can turn to its active form which increases calcium resorption
What is secondary hyperparathyroidism?
The parathyroid glands are normal but are stimulated to secrete excessive PTH secondary to hypocalcemia which can be caused by vitamin D deficiency or chronic renal failure
What is the cause of hypocalcemia?
Due to decreased 1,25- dihydroxycholecalciferol
What occurs in secondary hyperparathyroidism due to increased bone resorption?
Does bone resorption cause significant increase in serum levels?
Increased PTH
Calcium from bone resorption not sufficient to elevate serum calcium levels to normal
No, it is not sufficient enough to cause an increase in serum levels
What is hyperphosphatemia caused from?
Renal dysfunction
What is osteomalacia?
Softening of bones
Defective re-mineralization due to vitamin D deficiency
What is the treatment for secondary hyperthyroidism?
Active form of Vit D
Phosphatebinders
Parathyroidectomy in extreme cases
Calcium supplements
What is the cause of hypothyroidism?
- Thyroidectomy
- Autoimmune and congenital anomalies of PTH
- Low PTH secretion
- Hypocalcemia
- Hyperphosphatemia
- Decrease in 1,25- Dihydroxycholecalceferol
- Reduced PTH effect on 1a- hydrolase
What does low PTH secretion lead to?
What does hypocalcemia cause?
Hypocalcemia
Causes: Reduced bone resorption, decreased renal calcium reabsorption, reduced intestinal calcium absorption
What is hyperphosphatemia?
What does it hyperphosphatemia deal with?
Increased renal phosphate reabsorption
Reduced urine phosphate
Reduce cAMP in urine
Controls serum level
What is vitamin D’s role?
How is it synthesized?
Second major regulatory hormone for Calcium and phosphate metabolism
Vitamin D (cholecaleceferol) is provided in diet: Fish, Beef, dairy products, egg yolk, mushrooms, it is also synthesized in skin
Which enzyme is needed to convert cholecalciferol?
What is cholecalciferol converted into?
1a-hydroxylase
Converted into Calcitrol
What is the role of vitamin D?
Where do the coordinated actions of vitamin D take place?
- To increase plasma concentrations of calcium and phosphate
- To promote bone mineralization (addition of calcium phosphate to extracellular bone matrix)
Actions take place in the kidney, bone, and intestine
What are the actions of vitamin D in the kidney?
What are the actions of vitamin D in the bone?
In the kidney vit D promotes calcium and phosphate reabsorption in distal tubules of the kidney
In the bone vit D stimulates osteoclast activity and bone remodeling
Which channels does vitamin D promote synthesis of? Where are the channels located?
Which protein does vitamin D induce the synthesis of?
TVRP5 calcium channels on the apical membrane
Calbindin-D28K- vitamin D dependent calcium binding protein
What is the mechanism of promoting calcium absorption in the intestine?
3 step process
1. Calcium diffusion
2. Calbindin-D-28K mediated transport
3. Calcium ATPase activity
Which type of transporters does vitamin D promote the expression of?
Energy dependent phosphate transporters on the apical membrane of intestinal epithelial cells
What are the causes of vitamin D deficiency?
- Dietary deficiency
- Absence of 1a-hydroxylase (activate Vit D can’t be synthesized)
- Chronic renal failure
- Hydroxylation step in the liver is absent
What does vitamin D deficiency cause in adults?
Osteomalacia which is defective mineralization of bone
- Large spaces inside the bone
- Joint and bone pain
- Muscle weakness
- Softening and bending -> easy fracturing
What does vitamin D deficiency cause in children?
What are the physical appearance?
Rickets which is from insufficient mineralization of bones, skeletal deformities
Curved appearances of legs and growth failure
What is calcitonin produced by?
What does calcitonin do?
What happens if there are high levels of calcitonin?
Produced by paracollicular (C) cells of the thyroid
Calcitonin is an antagonist to parathyroid hormone (PTH)
- At higher doses it inhibits osteoclast activity and release of Ca from bone matrix
- Stimulates Ca uptake and incorporation into bone matrix
What layer are mineralocorticoids secreted from?
What is the primary mineralocorticoid?
Zona glomerulosa
Aldosterone
What layer are glucocorticoids secreted from?
What is the primary glucocorticoid?
Zona fasciculata
Cortisol
What layer are androgens secreted from?
Zona reticularis
Can mineralocorticoids, glucocorticoids or androgens be secreted from any level?
Why?
No, they are only secreted from their distinct layer because certain enzymes are only present in certain zones
What zone of the kidney is aldosterone found in?
Zona glomerulosa in the cortex
What zone of the kidney are cortisol and androgens found in?
Zona fasciculata of the cortex
What zone of the kidney are epinephrine and norepinephrine found in?
Adrenal medulla of the medulla
What are adrenocortical steroids synthesized from?
Cholesterol
What are the primary androgens in females?
What is the primary androgen in males?
DHEA and androstenedione
Testosterone
How is cholesterol converted to pregnenolone?
Without pregnenolone which hormones would you not have?
Cholesterol desmolase
Aldosterone, progesterone, cortisol, dehydroepiandrosterone, androstenedione, and corticosterone
What enzyme converts pregnenolone into dehydroepiandrosterone and androstenedione?
17a-hydroxylase
What can progesterone be converted into?
What enzyme is needed for progesterone conversion to corticosterone and 11-deoxycortisol?
What does corticosterone convert into?
Aldosterone, cortisol, and androstendione
21B- hydroxylase
Aldosterone
What enzyme is needed to convert corticosterone into aldosterone?
Aldosterone synthase
What are the 5 necessary enzymes needed to make Aldosterone, cortisol, androstenedione, and dehydroepiandrosterone?
- Cholesterol desmolase
- 17a- hydroxylase
- 21B- hydroxylase
- Corticosterone
- Aldosterone synthase
What is pathway of the overall biosynthesis of adrenocortical hormones?
How are adrenocortcial hormones regulated?
All adrenocorticotophic hormones use cholesterol desmolase that is activated by adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary
What is the rate limiting step in glucocorticoid synthesis?
How is the physiological regulation maintained?
Cholesterol desmolase
Regulated mainly by hypothalamic-pituitary axis
What is the rate limiting step in mineralocorticoid synthesis?
Aldosterone synthase
Is there a rate limiting step in adrenal androgen secretion?
Unclear if cholesterol desmolase is a rate limiting step, the mechanism of physiological regulation is poorly understood.
Synthesis is altered by the hypothalamic pituitary axis
What type of pattern do ACTH, glucocorticoids and adrenal androgens exhibit?
When are these hormones low?
When are these hormones at their peak?
Diurnal patters of secretion
Low while sleeping
Peak in the morning around 7am
What are the actions of cortisol?
- Stimulation of glucogenesis
- Anti-inflammatory effects and suppression of the immune system
- Helps resist stress
- Maintenance of vascular respoonsiveness of catecholamines
- Inhibition of bone formation: osteoperosis
- Increase in glomerular filtration rate (GFR)
- Effects on CNS
What is cortisol’s role in the maintenance of vascular responsiveness of catecholamines?
What happens in the absence of cortisol?
Needed for vasoconstriction
Alpha-1 receptors are upregulated (epinephrine & norepinephrine)
Hypotension occurs in the absence of cortisol.
Why are glucocorticoids needed?
They are essential for survival during fasting
What happens during the stimulation of glucogenesis?
- Increases protein catabolism in muscle and decreases new protein synthesis
- provides additional amino acids to the liver for glucogenesis - Increases lipolysis which provides additional glycerol to the liver for gluconeogenesis. Redistribution of fat can occur here
- Decreases glucose utilization by tissues and decreases the insulin sensitivity of adipose tissue. Diabetogenic
What are the anti-inflammatory effects and suppression of the immune system?
- Suppresses proinflamatory mediators by activating lipocortins
- Inhibits production of interleuikin-2 and T-lymphocute proliferation
- Inhibits release of histamine and serotonin
Where are histamine and serotonin release inhibited from?
Inhibited from mast cells
What does activation of lipocortins block?
What are examples of glucocorticoids?
Phospholipase A2 thus no arachidionic acid will be made
Lipocortins, COX-1, COX-2
If some arachidonic acid is made will prostaglandins, thromboxanes, and leukotrienes be made?
No, because glucorticoids block COX-2.
What occurs to cortisol levels in stressful situations?
Levels increase greatly
How is cortisol secretion regulated?
CRH (Corticotropin- releasing hormone) and ACTH
What occurs during osteoperosis?
Decrease in osteoblast production
Osteoclasts are stimulated
Decrease in intestinal calcium 2+ absorption-> less calcium gets to the bone
What occurs in order to increase glomerular filtration rate (GFR)?
Dilation of renal afferent arteriole and increasing glomerular blood flood
What are the effects of cortisol on the CNS?
Decreases sleep time and increases wake time
What does the hypothalamus release to the anterior pituitary?
CRH- Cortisol releasing hormone
What does the anterior pituitary release to the adrenal cortex?
ACTH
What does the adrenal cortex release?
If there is too much cortisol, what happens?
Cortisol
Direct inhibition of CRH secretion. Cortisol blocks the hypothalamus and anterior pituitary
What is CRH?
Corticotropin- releasing hormone
- Polypeptide released by hypothalamus
- Hypothalamic hypophyseal poral nlood
- Acts on corticotrophs in anterior pituitary
What is ACTH?
What does ACTH promote the synthesis of?
What does excessive ACTH stimulation cause?
What is the result of chronic reduction of ACTH secretion?
- Polypeptide released by corticotrophs
- Cholesterol desmolase
- Hypertrophy and hyperplasia of adrenal cortical cells
- Adrenal gland atrophy
What does excess aldosterone lead to?
Hypertension because you lose a lot of potassium, absorb lots of sodium which brings in excess water and get an increase in blood volume
Where are the sodium and potassium channels located?
Where is the alodosterone released?
On the apical membrane and basolateral membranes
Aldosterone is released into the capillary membrane and then goes into the principal cell to increase K/Na absorption
What is hypokalemic alkalosis?
When you lose too much potassium and secrete potassium into the urine thus you have acidic urine
How is aldosterone secretion regulated?
- Increased angiostensin II
- Increased potassium ion conc.
- ACTH from the anterior pituitary gland
What does an increase in angiotensin II cause?
increases aldosterone secretion and activates aldosterone synthase to promote aldosterone synthesis
What does an increase in potassium ion concentration cause?
Increases aldosterone secretion due to the depolarization of cells and opening of voltage gated calcium channels
Where is ACTH secreted from? Why is ACTH secretion needed?
Which enzyme is activated by ACTH?
ACTH from the anterior pituitary gland which is needed for aldosterone secretion
Cholesterol desmolase
What is the rate limiting step in aldosterone synthesis?
Aldosterone synthase
What is released from a drop in blood pressure or fluid volume?
Renin is released from the kidney which converts angiotensinogen into angiotensin I
Which enzyme works on angiotensin I? What is it converted into?
ACE (angiotensin- converting enzyme) which is released from lungs and converts angiotensin I into angiotensin II
What does angiotensin II act on?
Angiotensin II acts on the adrenal gland to stimulate the release of aldosterone
Angiotensin II acts directly on blood vessels to stimulate vasoconstriction
What are the main androgenic steroids?
Where are they produced?
Which gender do they play a small role in ? Why?
What do they produce in the main gender?
DHEA and androstenedione
Produced by zona reticularis and zona fasciculata
They play a small role in males because testosterone is directly synthesized from cholesterol in the tested
In females they make pubic hair and libido
What are the actions of glucocorticoids?
What are the actions of mineralocorticoids?
What are the actions of adrenal androgens?
What is the cause of Cushing’s Syndrome?
Chronic excess of glucocorticoids
1. Increased exogenous administration of glucocorticoids
2. Increase in ACTH due to primary tumor (Cushing’s disease)
3. Tumor of adrenal glands (adenoma/carcinoma)
4. Small cell carcinoma of the lungs (ectopic ACTH)
What happens with ACTH levels in Cushing’s syndrome?
What is the treatment? What do the drugs do?
ACTH levels are decreased by negative feedback if problem is directly with the adrenal gland over activity
ACTH levels are also elevated in Cushing’s disease or lung tumors
Tx: Ketoconazole (blocks cortisol synthesis)
- Metyrapone (blocks 11 B-hydrozylase)
- Surgical removal of the tumor
What is the pathophysiology of cushing’s syndrome?
Buffalo Hump
Moon face
Increased abdominal fat
Thin arms and legs
Poor wound healing
Osteoperosis
Hyperglycaemia
What happens if mineralcorticoids and androgen levels are elevated?
Hypokalemia
Metabolic alkalosis
Virilization
Menstrual disorders
