Calcium Flashcards
roles of calcium in the body
muscle contraction
transmission of nerve impulses
blood clottin
indirect action of PTH on the kidney
Inc the circulating VitD which inc the protein Calbindin which helps in the transport of Ca across the cell to the basolateral membrane, where it is secreted back into the circulation
diffusible vs non diffusible calcium?
nondiffusible - bound to protein - can’t be filtered by the kidney
diffusible - not bound to protein (ionized and complexed)
action of PTH on Vit D
PTH Also regulates the conversion of Vit D3 to its active form (1,25 DH Vit D) by activating the enzyme that catalyzes the conversion in the Kidney;
This active Vit D in turn facilitates increased absorption of Ca from the intestine(GIT). Thus Vit D facilitates utilization of Ca that we eat.
process of bone remodeling
Two important cells:
Osteoclasts: bone breakdown cell which is derived from a hematopoietic cell
Osteoblasts: bone formation cell, deriving from mesenchymal cells.
It’s a question of how much formation and how much breakdown that is going to determine what’s going on.
bone quality
architecture, turnover, damage accumulation, mineralization
indications for teriparatide
consider first therapy (2 years) followed by a bisphosphonate
severe osteoporosis (estabilshed and risk factors/prior fractures)
failed/intolerant of bisphosphonates)
what if PTH is high and 24h Ca is high?
primary hyperparathyroidism
blood supply to parathyroid glands?
thyroid arteries
Where is most of the calcium found in the body?
skeleton (99%)
lithium and calcium
lithium can cause hyperparathyroidism and decreased Ca
FRAX
to calculate 10 year probability ofhip fracture - takes many things into acct
bone densitiy and risk factors
intestinal Ca absorption?
With Calbindin (activated by Vit D)
where is vit D activated? How?
liver then kidney
Source-Diet or the Sun (UV light converts Vit D to active form)- Dietary 7 – dehdr cholesterol can be converted to Vit D via hydroxylation(25 hydroxy-D) (happens in the Liver) – This is still inactive à in the kidney à Hydroxylated at 25 or 24 position. If hydroxylated at the 25- its active
But if Ca/PO4 excess, it gets hydroxylated at the 24 position-leads to Inactive VIT D-Not usable/not available for activation; Points to the active form on the slide
central DXA
bone density measurement
It’s a really simple test with very low radiation, very easily done by a tech with experience.
Do the spine and do the hip (2 readings on the hip)
We only do the forearm where we think cortical bone will be more effected in a disease such a hyperparathyroidism, but otherwise we focus on the spine and the hip to get a risk profile in terms of their bone density.
The important think about DEXA’s are, in the spine if someone has significant arthritis or spinal abnormality (which you certainly will see in a lot of older people) then it may interfere and you may need to focus more on the hip reading.
Central DXA Measurement
•Dual x-ray absorptiometry (DXA) can be used to measure BMD at multiple skeletal sites, including spine, proximal femur, forearm, and total body.
–Uses x-rays of 2 different energy levels to distinguish bone from
soft tissue
–Advantage of being able to measure BMD of the central and most osteoporotic fracture-prone sites, the spine and hip
•DXA can be performed in the office. Scanning time is less than 5
minutes and the radiation dose is considerably lower than that for
conventional radiography.
•DXA has good overall accuracy and precision.
–Reproducible results make it useful for both baseline and
follow-up measurements.
–DXA has been used in most of the prospective epidemiologic
studies investigating the BMD/fracture risk relationship.
What is the activated Vit D?
1, 25
Source-Diet or the Sun (UV light converts Vit D to active form)- Dietary 7 – dehdr cholesterol can be converted to Vit D via hydroxylation(25 hydroxy-D) (happens in the Liver) – This is still inactive à in the kidney à Hydroxylated at 25 or 24 position. If hydroxylated at the 25- its active
But if Ca/PO4 excess, it gets hydroxylated at the 24 position-leads to Inactive VIT D-Not usable/not available for activation
chvostek’s sign
sign of hypocalcemia
tap the face at a point –> twitch
sign of neuromuscular excitability caused by hypocalcemia
where is the first activation step of Vit D?
liver
Treatment in hyperparathyroidism?
parathyroidectomy
based on CT scan (min invasive)
if decrease PTH by 50% during surgery - got it!
what happens if calcium levels are too low>
parathyroid releases PTH
increase Ca release from bones
increase Ca uptake in intestines
Increase Ca reabsorption from urine
calcium levels rise
Zoledronic Acid
IV bisphosphoate
1) Some patients have GI intolerance or think they have GI intolerance and can’t tolerate or won’t take these drugs.
2) And also it’s clear that some patients actually don’t take them. If you do these studies and see how many patients that are sent home with them actually take them. Large studies, not in a specialty practice like mine, but in a general medicine practice a lot of patients don’t take it.
So that’s where the IV drug comes – the patient who is intolerant of the oral one or someone where we’re concerned they’re not actually going to take the oral one.
●
Given through butterfly as an IV infusion once per year. It’s a long acting, potent bisphosphonate.
Vit D precursor from the sun?
7-dehydrocholesterol –> cholecalciferol
Calcitonin
secreted by C cells of the thyroid
lowers plasma calcium (can give exogenous)
stimulated by increase in plasma Ca, gastrin f
gene in familal hypocalciuric hypercalcemia?
CASR gene
oxyphill cells of PT
Oxyphill-Unknown function; Recent reports of PTH production from C cells but not yet proven, its preliminary(not in texts yet).
Where does PTH have effects?
Bone
Kidneys –> Gut
regulation of osteoclasts
RANK + RANKL\
The osteoclast precursor has on it’s surface RANK and then the osteoblast has on it’s surface RANK-L.
For that osteoclast to become activated and be able to breakdown bone – RANK has to combine with RANK-L.
These have the meet, this differentiates and becomes a mature/active osteoclast.
If RANK-L can’t combine with RANK because something is blocking it. OPG is called the decoy receptor. If there’s OPG (there’s always some around but if there’s more) it will combine with RANK-L and not allow RANK-L to combine with RANK and we won’t get our osteoclast.
teriparatide mechanism
anabolic
recombinant PTH
if high PTH all day = decrease bone BUT if pulsitile PTH - BUILD BONE!
use for 2 years only
cell target = osteoblasts
PTH binds to R - decreased apoptosis of osteoblasts, stim differentiation to osteoblasts
secrete local regulatory factors
mechanism of estrogen Tx
anti-resorptive
inhibits release of cks that activate osteoclasts
decreases RANKL, ? stimulates OPG
It also decreases RANK-L and stimulates the OPG.
So all of these things are going to affect that osteoclast and slow down breakdown.
And we know that it decreases fracture risk in the hip and the spine.
So if estrogen is indicated for other reasons, we know it’s a good bone drug and we know how it works. But the question normally is are we giving them estrogen for another reason. We use it less as a primary bone drug because of all of the other estrogen pros and cons.
3 factirs that regulate calcium metabolism
PTH
Vit D
Calcitonin
pseudohypoparathyroidism
familial disorder characterized by elevated PTH and end-organ resistance
Both have the phenotype of pseudohypoparathyroidism, i.e. the genetic defect-Obesity, round face short metacarpals
HOwever, Only daugther has the chemical abnormality, ie she is hypocalcemic- Not the mother
Mother-Pseudopseudo; daughter is Pseudo..
Pseudo means PTH is not low, its actually high
Vit D precursor from diet?
cholecalciferol
TRPV5
calcium channel in luminal membrane of kidney cell distal tubule
PTH stimulates the channel - major efffect of PTH
selective estrogen receptor modulators
raloxifene
like estrogen – antiresorptive
decreases fracture risk in the spin (no data in the hip)
less good data, BAD after menobause because exacerbates symptoms
What if PTH is high and urinary calcium excretion is low?
familial hypocalciuric hypercalcemia
granuloma and calcium
inflammation
can make 25 (OH) D3 into 1, 25
potential of 1(OH)ase
How is PTH regulated?
DIRECT by Ca on PT chief cell
ligand binds surface of cell at receptor and inhibits PTH
high Ca –> low PTH (don’t need to conserve more!)
role of Ca in muscle contraction?
in excited muscle, Ca binds to tropoining, moves tropomyosin and exposes myosin binding sites on actin
PTH action on the kidney
increases Ca reabsorption, decreases P reabsorption
to avoid precipitation
Another Imp thing PTH does is to Facilitate PO4 secretion-IMPORTANT as the CaPO4 is insoluble; If the levels of CaPO4 go above the level its soluble , its solubility product constant, it will precipitate (not good). To prevent this, PTH increases Po4 excreation, and promotes Ca reabsorption in the Kidney, thus overall, PTHà increases Ca in the blood/serum
Thus it increases PO4 secretion/Excretion at the same time as increasing Ca reabsorption
What is the inactivated Vit D?
24, 25
Source-Diet or the Sun (UV light converts Vit D to active form)- Dietary 7 – dehdr cholesterol can be converted to Vit D via hydroxylation(25 hydroxy-D) (happens in the Liver) – This is still inactive à in the kidney à Hydroxylated at 25 or 24 position. If hydroxylated at the 25- its active
But if Ca/PO4 excess, it gets hydroxylated at the 24 position-leads to Inactive VIT D-Not usable/not available for activation
Function of Vit D?
Facilitate the uptake of Ca from the GIT ..how…does that by increasing the synthesis of Calbindin (same protein that is made in the kidney)
Calbindin then facilitates intake of Ca and its transport across the intestinal cell and secretion into the blood stream.
In absence of calbindin u wont have this uptake of Ca and will result in Hypocalcemia;
Thus one way to traet hypocalcemia is to give massive doses of Vit D
acidemia effect on calcium
less Ca will be bound to albumin (because it will be displaced by H+, so there will be increased ionized calcium
how you correct ionized Ca is to correct for albumin
more H+ –> more ionized Ca
thiazide diuretics and calcium
increase calcium reabsorption
pseudopseudohypoparathyroidism
same phenotypic appearance as pseudohypothyrodism but normal PTH and PTH response
Both have the phenotype of pseudohypoparathyroidism, i.e. the genetic defect-Obesity, round face short metacarpals
HOwever, Only daugther has the chemical abnormality, ie she is hypocalcemic- Not the mother
Mother-Pseudopseudo; daughter is Pseudo..
Pseudo means PTH is not low, its actually high
what does total calcium measure?
- bound to anions
- bound to albumin
- ionized Ca
albumin is low - total Ca might be low but ionized will be normal
·Measuring total Ca2+ can be misleading – we need to interpret values based on other clinical entities pts have
oIf albumin is low, total Ca can be low but ionized Ca2+ can be normal
oEx: Calcium is 7.8 but albumin is 2, so we must correct for it. Patient is not necessarily hypocalcemic
oEx2: Multiple myloma ↑ albumin, so total Ca is high, but ionized Ca may be normal
chief cells of PT
C cells-secrete PTH; And they Have receptors called Ca sensing receptors-which are Able to monitor the levels of circulating Ca in blood
OPG
Osteoprotegerin is a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL). By binding RANKL, OPG prevents RANK
OPG can reduce the production of osteoclasts by inhibiting the differentiation of osteoclast precursors (osteoclasts are related to monocytes/macrophages and are derived from granulocyte/macrophage-forming colony units (CFU-GM)) into osteoclasts and also regulates the resorption of osteoclasts in vitro and in vivo. OPG binding to RANKL on osteoblast/stromal cells, blocks the RANKL-RANK interaction between osteoblast/stromal cells and osteoclast precursors. This has the effect of inhibiting the differentiation of the osteoclast precursor into a mature osteoclast.
primary hyperparathyroidism
80% benign single adenoma, 15% chief cell hyperplasia (carcinoma rare!)
High Ca, Low P
PTH stimulates osteoclasts –> bone breakdown
Estrogen Tx
decreases fracture risk in hip and spine!
not primary bone drug but good if going on it anyway
It also decreases RANK-L and stimulates the OPG.
So all of these things are going to affect that osteoclast and slow down breakdown.
And we know that it decreases fracture risk in the hip and the spine.
So if estrogen is indicated for other reasons, we know it’s a good bone drug and we know how it works. But the question normally is are we giving them estrogen for another reason. We use it less as a primary bone drug because of all of the other estrogen pros and cons.
alkalemia effect on calcium
less H+ –> more calcium bound to albumin –> decreased ionized calcium
direct effect of PTH on the kidney
Increase the no of channels in the Luminal/Apical membrane in the Distal tubule. These are increases in no/more are inserted in the Apical membrane, more syntheiszed in the presence of PTH; allowing more Ca to enter the cells.
What happens if calcium levels are too high?
thyroid releases calcitonin
increase deposition in bones
decrease ca uptake in intestines
decrease ca reabsoprption from urine
decrease calcium
Familial hyprecalcemic hypercalceuria
PTH secretion depends on levels of Ca and the Ca sensing receptors that detect these levels
Some people are born with defects in these receptors, then one needs higher levels of harmone to stimulate the same receptors, this results in FHH(Familial hyprecalcemic hypercalceuria). These Pt’s have hypercalcemia as the Ca levels have to be pretty high before the PTh is turned off.
desensitized! set point moved to the right
Effects of Vit D on the distal tubule cell
- increase TRPV5 channel on lumenal membrane so Ca can enter
- increase calbindin - binds calcium
- stimulate Ca transporter on basolateral membrane
vit D = steroid-like, transcription and translation of many things
ionized vs complexed calcium
all is diffusible calcium
most is ionized (active form) - only kind that is accessible to cells
some is insoluble - bound to phosphate!!
familal hypocalciuric hypercalcemia
rare
LOF of CASR gene –> decreased sensitivity to Ca
hypercalcemia and rel hypocalciuria
no typical complications of high serum Ca
action of PTH on bone
increase Ca resprption
effect-of PTh is to Increase resorption of bone; As bone is being resorbed, it Increases not only Ca++ but also PO4 levels in the blood- both go up in the serum as bone is being resorbed/broken down.
What are they hydroxylation points of Vit D?
1,24,25
PTHrP
Parathyroid hormone-related protein (or PTHrP) is a protein member of the parathyroid hormone family. It is occasionally secreted bycancer cells (breast cancer, certain types of lung cancer including squamous cell lung carcinoma)
