Calcium Metabolism (Week 5--Brent) Flashcards Preview

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Flashcards in Calcium Metabolism (Week 5--Brent) Deck (62):
1


Where do parathyroid glands develop from?


Superior parathyroid glands from 4th pharyngeal pouches (don't descend)

Inferior parathyroid glands from 3rd pharyngeal pouch (descend)

 

2


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

3


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

4


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

5


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

6


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)

7


Bone composition


Mineral phase (hydroxyapatite) is 65%

Organic matrix (collagen 90-95%, mucopolysaccharides, sialoproteins, lipids) is 35%

8


What type of bone does PTH act on mostly?


Compact/cortical bone

(not trabecular/cancellous/spongy bone as much)

9


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

10


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

11


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)

12


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+

13


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

14


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

15


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

16


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!

17


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

 

18


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

19


How does bone remodeling occur (pathway)?


PTH stimulates osteoblast --> osteoblast produces RANKL --> RANKL stimulates osteoclast precursor to become osteoclast

20


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

21

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)

22


How does the receptor for PTH work?


G coupled protein receptor

23

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!

24


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

25


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

26


How is vitamin D activated?


Sunlight on skin

Won't get vitamin D activation if you're wearing clothes over skin or sunscreen

27



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 (?)

28


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

29


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

30


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

31


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!

32

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

33


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)

34

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)

35

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

36


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+

37


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

38


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)

39


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

40


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

 

41


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

42


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

43

What can you get along with primary hyperparathyroidism?


Calcium deposits:

Nephrocalcinosis (kidney stones)

Chrondrocalcinosis (in joints)

44


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)

45


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)

46


Why would you have elevated Ca in cancer?


1) Cancer in bone causes Ca release into blood

2) Tumor is secreting PTHrP

47



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

48


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)

49

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)

50


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)

51


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

52


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

53


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

54


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)

55


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

56


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

57


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

58


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

59


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

60


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

61


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

62


What stimulates 1-alpha-hydroxylase activity


1) Decreased plasma Ca2+, decreased plasma PO4

2) Increased PTH