Calcium Metabolism (Week 5--Brent) Flashcards
Where do parathyroid glands develop from?
Superior parathyroid glands from 4th pharyngeal pouches (don’t descend)
Inferior parathyroid glands from 3rd pharyngeal pouch (descend)
Parathyroid hormone (PTH)
Peptide hormone
Synthesized as long peptide PrePro-PTH –> cleaved to Pro-PTH –> cleaved to PTH
Causes increase in blood Ca2+ by acting on bone and kidney
Causes loss of phosphate
Do you take PTH for treatment if you have PTH deficiency?
Not usually. Also could not take orally bc would get broken down in stomach, would have to inject IV.
Usually just take Ca2+ and PO4
Where does PTH act and how?
PTH acts primarily on kidney and bone to increase Ca2+ levels in the blood (causes Ca2+ reabsorption from kidney, stimulates Ca2+ release from bone)
PTH increases formation of 1,25(OH)2-vitamin D in the kidney (directly stimulates 1-alpha hydroxylase)
PTH also decreases PO4
Vitamin D (Calcitriol; 1,25-dihydroxycholecalciferol; 1,25(OH)2D3)
Active form of vitamin D
Provitamin D2 and D3 activated by sunlight on skin to Vitamin D2 and D3 –> go to liver –> liver 25-hydroxylates it to inactive 25(OH)D, secreted by liver –> binds to protein in circulation –> becomes active when it gets to the kidney and is alpha-hydroxylated (by enzyme 1-alpha-hydroxylase) to 1,25(OH)2D
Acts mainly on bone and intestine
Increases phosphate and Ca2+ reabsorption (to make new bone!)
Inhibits PTH release
Magnesium
Mg needed for PTH synthesis, release, action
Important for secretion and action on bone of PTH
Can have Mg deficiency if poor nutrition (alcoholic)
Bone composition
Mineral phase (hydroxyapatite) is 65%
Organic matrix (collagen 90-95%, mucopolysaccharides, sialoproteins, lipids) is 35%
What type of bone does PTH act on mostly?
Compact/cortical bone
(not trabecular/cancellous/spongy bone as much)
How do we measure Ca2+ in labs we order?
We measure total Ca2+ (sample handling is hard when measuring free Ca2+)
Have 50% bound Ca2+ (40% protein bound, 10% bound to PO4, etc?) and 50% ionized/free
Phosphorus
Mostly in bone, but also intracellularly
Measure total phosphorus, because so little bound that this is essentially telling you free P
PTH makes you lose phosphorus (phosphoturic) from kidney
Physiological importance of phosphorus
Mineralization of bone and teeth
Intermediary metabolism (phosphorylation)
pH buffer (intracellular)
Component of DNA, RNA, phospholipids
Chemical energy (ATP, creatine-phosphate)
Ca2+ and PTH relationship
Sigmoidal relationship: when Ca2+ high, PTH is low
The fact that when Ca2+ is eleveted a tiny bit above the set point, PTH goes totally down and when Ca2+ decreased tiny bit below set point, PTH goes totally up suggests that there is a RECEPTOR for Ca2+
Calcium Sensing (ion) Receptor (CaSR)
Located on parathyroid cells
Ca2+ inhibits PTH release
Extracellular, transmembrane, and intracellular portions
Responds to Ca2+: if Ca2+ high then PTH will decrease and if Ca2+ low then PTH will increase
Receptor also expressed in kidney
What if you have an inactivating mutation in the calcium sensing (ion) receptor?
Familial hypercalcemic hypocalciuria
Now receptor can’t respond to Ca2+ to tell PTH to downregulate so get too much PTH and thus elevated Ca2+
Receptor in kidney also causes decreased Ca2+ excretion (not totally understood yet)
Keeping Ca2+ in blood and not getting rid of it in your urine
What happens if you have an activating mutation (intracellular) in calcium sensing (ion) receptor?
Activating mutation in CaSR means hypoparathyroidism
Receptor thinks there’s always Ca2+ around, so will never release PTH, too low PTH
What happens to PTH if you have renal failure?
High PTH because low 1,25(OH)2-vitamin D (made in the kidney), and 1,25(OH)2-vitamin D inhibits PTH production
Chronic renal failure causes hypocalcemia even though high PTH because skeletal resistance to PTH! Also have really low vitamin D so can’t absorb any Ca2+ from intestine!
Calcimimetic
To treat secondary hyperparathyroidism
Used for patients that have excessively high PTH (renal failure)
Drug (cinacalcet) that stimulates CaSR to make you think Ca2+ is around to decrease PTH
Which type of bone cells have PTH receptors? And what type of bone does PTH affect most?
Osteoblasts only!
PTH has major effect on cortical bone, but if high enough, will affect trabecular bone too
How does bone remodeling occur (pathway)?
PTH stimulates osteoblast –> osteoblast produces RANKL –> RANKL stimulates osteoclast precursor to become osteoclast
How can PTH cause both bone loss and bone growth?
Bone loss: tonic excess level of PTH (hyperparathyroidism) causes overwhelming osteoclast activity that leads to bone loss/osteoporosis
Bone growth: PTH in small doses periodically stimulates osteoblasts more and get net effect of bone growth so is used as treatment for osteoporosis
Actions of PTH
Increase bone resorption of Ca and PO4
Increase renal reabsorption of Ca
Decrease renal PO4 reabsorption
Increase renal formation of 1,25(OH)2D (by stimulating 1-alpha hydroxylase)
How does the receptor for PTH work?
G coupled protein receptor
Calcium homeostasis in kidney
Kidney filters 10g Ca per day
65% is reabsorbed in proximal tubule
20% is reabsorbed in loop of Henle
5 - 10% reabsorbed in distal tubule and this is the only place that PTH can regulate reabsorption!
Why is the net effect of hyperparathyroidism high Ca in the urine and not just in the blood?
PTH causes you to reabsorb Ca2+ in the kidney, but only acts on distal tubule which only can reabsorb 5 - 10%
So yes, you’re absorbing more Ca2+ in the kidney than usual, but you can’t reabsorb that much so you get a lot of Ca2+ in the urine
How do you know if someone has hyperparathyroidism?
No symptoms! Hard to tell!
Used to be that people would get kidney stones, but now we can measure Ca2+ so frequently and easily that people don’t get kidney stones anymore
How is vitamin D activated?
Sunlight on skin
Won’t get vitamin D activation if you’re wearing clothes over skin or sunscreen
What are some extraskeletal effects of vitamin D?
There are 1,25 hydroxylase receptors all over the body
Pancreatic islets, cancer, macrophages
Side note: if you replete vitamin D, you won’t get TB as much and you’ll respond better to treatment (?)
Regulation of 1-alpha hydroxylase
Stimulates 1-alpha hydroxylase: high PTH, low Ca2+, low PO4
Inhibits 1-alpha hydroxylase: low PTH, high Ca2+, high PO4
Vitamin D as steroid hormone
Even though it is a vitamin, it is (and acts like) a STEROID HORMONE
Binds nuclear receptor then partners with RXR receptor and regulates gene transcription
What do we measure to assess vitamin D levels?
Measure 25(OH)D (inactive form) because is most reliable
1,25(OH)2D has shorter half life so is more variable
How are vitamin D and PTH related?
If a population has low vitamin D, PTH will be higher
(Vitamin D inhibits PTH)
PTH acts on bone and kidney to increase serum Ca2+
Vitamin D acts on intestine, bone and kidney to increase serum Ca2+
PTH activates the 1-alpha hydroxylase that is needed to activate vitamin D, but then vitamin D decreases tx/production of PTH!
What’s the controversy about what normal levels of vitamin D should be?
Used to say normal serum vitamin D is 10 - 20 but that’s around flexion point, so changed it to say everyone should be over vitamin D level of 30 where the curve is flat and PTH levels are lower
However, not clear that there’s anything wrong with vitamin D levels below 30, and thus a little elevated PTH
When you give vitamin D, what do you give?
If you have normal kidneys (1-alpha hydroxylase) and PTH, you give patients 25(OH)D (you won’t get hypercalcemic)
If patient has no kidneys (thus no 1-alpha hydroxylase), have to give 1,25(OH)2D
Also if patient is hypoparathyroid then give 1,25(OH)2D (bc need PTH to activate 1-alpha hydroxylase to convert to 1,25(OH)D)
Actions of 1,25(OH)2-vitamin D
Intestine: increase intestinal absorption of Ca2+ and PO4
Bone: required for normal bone formation, provides Ca2+ and PO4, induces formation of osteoclasts, role in bone mineralization
Kidney: turns off 1-alpha hydroxylase enzyme (negative feedback on its own production), increase tubular reabsorption of PO4
(also decreases tx/production of PTH)
What happens when you get hypocalcemic?
Low serum Ca2+ –> PTH –> increase renal absorption of Ca2+ (also decrease renal PO4 reabsorption, not because you want to, just happens!) –> directly stimulates 1-alpha hydroxylase to make more vitamin D (acts on intestine to help reabsorb Ca2+ and also has kidney absorb PO4 to counteract bad effect of PTH causing PO4 loss) –> both PTH and vitamin D cause skeletal Ca2+ and PO4 reabsorption
Net effect: increase retention of Ca2+ and no net effect of PO4
What happens when you get hypophosphatemic?
Decreased serum PO4 –> increase 1,25(OH2)-vitamin D –> increase renal PO4 reabsorption, increase intestinal Ca2+ and PO4 absorption –> 1,25(OH2)-vitamin D directly decreases PTH –> decreased PTH causes decrease in Ca2+ absorption (counteracting 1,25(OH2)-vitamin D that just raised it!) –> 1,25(OH2)-vitamin D also increases skeletal Ca2+ and PO4 reabsorption
Net effect: increase PO4 retention but no net effect on Ca2+
How does 1,25(OH2)-vitamin D act on PTH?
1,25(OH2)-vitamin D physically binds to region upstream of PTH gene to suppress its transcription
What causes hypercalcemia?
Primary hyperparathyroidism (most common)
Malignancy (tumors secrete PTH-rP)
Vitamin D intoxication
Sarcoidosis (extra 1-alpha hydroxylase)
Familial hypocalciuric hypercalcemia (inactivating mutation of CaSR)
Thiazide diuretics
Lithium (interferes with Ca2+ interacting with PTH)
Symptoms of hypercalcemia
Sometimes have no symptoms (80% of people with primary HPT)
GI: dry mouth, thirst, polydipsia, anorexia, nausea, vomiting, constipation
GU: polyuria, nocturia, renal stones, nephrocalcinosis, renal failure
PTH-rP (PTH related peptide)
Different from PTH but acts through same receptor
Required for normal bone development
Promotes proliferation (and inhibits apoptosis) of chondrocytes
Induces breast development in lactation and stimulates placental transport of Ca (maybe?)
Released in cerebellum
Lots of tumor cells secrete this and that’s why you get hypercalcemia when you have cancer
How do you image the parathyroid glands?
Use Sestamibi (which is radioactive) to show metabolic activity
Then let other organs (heart, thyroid, parotid etc) wash out radioactivity then can see parathyroid glands
What are some characteristics of primary hyperparathyroidism?
Most cases (95%) are just sporadic, not part of syndrome or familial disorder
80-85% are solitary adenomas
10-15% is 4 gland hyperplasia
<1% carcinoma
What can you get along with primary hyperparathyroidism?
Calcium deposits:
Nephrocalcinosis (kidney stones)
Chrondrocalcinosis (in joints)
What do levels of PTH and Ca2+ tell you?
High Ca, high PTH: primary hyperparathyroidism (hyperplasia, adenoma, carcinoma)
High Ca, low PTH: tumor secreting PTHrP; vitamin D intoxication (elevates Ca2+ which suppresses PTH), just excess Ca2+ ingestion
Low Ca, low PTH: primary hypoparathyroidism (surgical removal, autoimmune destruction)
Normal/low Ca, high PTH: secondary hyperparathyroidism (due to renal failure, thus low 1,25(OH)2-vitamin D)
Categories of hyperparathyroidism and their characteristics
Single gland parathyroid adenoma: high PTH, high Ca, normal/high urinary Ca, treat w/surgery
Multiple gland hyperplasia: high PTH, high Ca, normal/high urinary Ca, can be part of Multiple Endocrine Neoplasia 1 or 2, treat w/surgery
Familial hypercalcemic hypocalciuria: high/normal PTH, only mildly elevated Ca, low/normal urinary Ca, due to heterozygous inactivating mutation of CaSR, follow medically (remember, inactivating mutation means Ca won’t stimulate/show its around so PTH will INCREASE)
Why would you have elevated Ca in cancer?
1) Cancer in bone causes Ca release into blood
2) Tumor is secreting PTHrP
What do you do when a patient comes in with high Ca?
First measure PTH (if elevated, this is the problem)
If PTH normal, measure PTHrP and vitamin D
Hypercalcemia falls into one of these 3 categories
What is a common pattern we see with what cancer cells secrete?
Something important in development comes back and is secreted by cancer cells (like alphafetoprotein in hepatocellular carcinoma)
PTHrP is example of this because is known to be involved in bone development (changing from cartilage to bone)
Causes of hypercalcemia
Hyperparathyroidism: mild/moderate increase in Ca, high urine Ca, high 1,25-vit D, high PTH
Vitamin D-mediated: due to exogenous, rare leukemias, granulomatous disease, mild/moderate increase in Ca, high urine Ca, high 1,25-vit D, very low PTH
Malignancy: moderate/severe Ca, high urine Ca, normal 1,25-vit D, very low PTH (very high PTHrP)
Causes of hypocalcemia
Chronic renal failure (no Vit D)
Mg deficiency (no PTH)
Hypoparathyroidism
Pseudohypoparathyroidism (can’t respond to PTH)
Osteomalacia due to vitamin D deficiency
“Hungry bone” syndrome (after parathyroidectomy get lots of bone turnover/Ca deposition in bone so blood Ca drops)
Acute hemorrhagic/edematous pancreatitis
Hyperphosphatemia (decrease vitamin D?)
Low serum albumin (causes “apparent” hypocalcemia bc actually free fraction of Ca normal, just total lower because lower amt albumin to bind to)
Causes of hyperphosphatemia
Because of too little vitamin D:
Renal failure
Cell lysis
Excessive PO4 administration
Hypoparathyroidism
Pseudohypoparathyroid
Remember Ca and PO4 inhibit 1,25(OH)2-vit D synthesis
Chronic renal failure (“secondary hyperparathyroidism”)
Kidneys make 1,25(OH)2-vitamin D, so if no vitamin D then get decreased Ca2+ and can’t use vitamin D to inhibit PTH so get elevated PTH (usually)
Get hyperphosphatemia (kidneys can’t secrete phosphate), skeletal resistance to PTH (because of uremia), elevated BUN and creatinine (like usual for renal failure)
Here decreased Ca2+ (and decreased vitamin D) CAUSES increased PTH
Magnesium deficiency
Causes impaired PTH secretion (Mg needed for PTH secretion)
Renal and skeletal resistance to PTH
Impaired formation of 1,25(OH)2-vitamin D
Resistance to vitamin D
End result is hypocalcemia
How can you get hypoparathyroidism?
Accidentally remove during surgery (post-surgical in general most common, 90%)
Idiopathic (autoimmune, 10%)
Congenital
Infiltrative disease (tumor, Fe, Cu)
Radiation therapy
Activating mutation of CaSR (think Ca2+ is always around)
Pseudohypoparathyroidism
Defect in G coupled protein receptor of PTH so PTH can’t signal
Get hypocalcemia and hyperphosphatemia (remember PTH reduces PO4), get increased secretion of PTH, get end-organ resistance to PTH
Type Ia: inactivating mutation of GNAS1 gene (autosomal dominant), also get resistance to TSH, LH, FSH, glucagon, get 50% reduction in Gsa, see Albrights Hereditary Osteodystrophy
What is Albright’s Hereditary Osteodystrophy?
Main phenotype of pseudohypoparathyroidism
Short stature, delayed sexual maturation, shortened 4th/5th metacarpal or metatarsal due to early epipheaseal closure
Osteomalacia
Vitamin D deficiency in adults (sometimes PO4 deficiency?)
Excess of unmineralized bone (osteoid) which results from impairment of bone mineralization
Alkaline phosphatase elevated (increased osteoblast activity?), Ca and/or PO4 decreased (more bone resorption?)
May have no symptoms, or bone pain, muscle weakness/pain, fractures/pseudofractures, hypocalcemia if severe
Radiologically, decreased bone density may lok like osteoporosis
This is often seen in renal failure
Rickets
Only vitamin D deficiency and resistance (not PO4 deficiency..?)
Developmental, seen in children
Decreased Ca absorption in intestine
Skeletal PTH resistance
Secondary hyperparathyroidism
Clinical features: short stature, deformities of lower extremities (genu valgum and genu varus), swelling of wrists, rachitic rosary (swelling of cartilage-bone (costochondral) junction), frontal bossing, flattening of skull, bone pain, hypocalcemia if severe
Simple explanation of Vitamin D, PTH and calcitonin on Ca2+ homeostasis
Vitamin D: increase extracellular Ca2+; absorb from small intestine, resorb bone
PTH: increase extracellular Ca2+; reabsorb from kidney, resorb bone
Calcitonin: decrease extracellular Ca2+; prevent bone resorption
Why is it actually very important that PTH causes excretion of phosphate in urine (phosphaturia)?
Because PO4 complexes with Ca2+ in the blood and doesn’t allow free Ca2+ to increase like PTH wants it to!
In bone resorption action of PTH get Ca2+ and PO4 released, but have to use kidneys to get rid of PO4 in order to actually increase extracellular Ca2+ concentration
Ultimate role of Vitamin D vs. PTH
PTH: maintain plasma Ca2+ concentration
Vitamin D: promote mineralization of new bone so increase Ca2+ and phosphate concentration to deposit new bone mineral
What stimulates 1-alpha-hydroxylase activity
1) Decreased plasma Ca2+, decreased plasma PO4
2) Increased PTH
