Endocrine and Calcium

Question 1

What is the job of calcium? What is the job of Vitamin D?
Can they work individually?
What goes hand in hand with Ca and Vitamin D?

Answer 1

1. Strengthen bones, all neurological functions in muscle (including cardiac)
2. Vitamin D allows one to absorb Ca from the gut.
3. No, they cannot work individually. You need both. In treatment, you need to prescribe both Ca and Vitamin D.
4. Ca and Vitamin D and PO4

Question 2

Besides structural functionality, what else is bind good for?

Answer 2

Reservoir for Ca and PO4

Question 3

Normal levels of Ca? PTH?

Answer 3

Ca: 8.5-10.5
PTH: 10 - 60

Question 4

What does TOTAL Ca represent? What is the binding protein for Ca?

Answer 4

Bound and ionized Ca. Binding protein for Ca is Albumin. Note that the majority of Ca is found bound to Albumin. Note that Ca is inactive until it is released from Albumin. In other words, Ca loss can only be fully factored upon accounting for Albumin loss.

Question 5

What keeps the ranges of Ca total and ionized and Albumin and PO4 so narrow?

Answer 5

Negative feedback

Question 6

Corrected total calcium (CTC) =

Answer 6

[(0.8)(4.0 - measured albumin)] + total calcium

Use the number you get as the actual Ca level. If it it withing 8.5 to 10.5, it is normal. Note that albumin is in this formula, confirming that if you miss out on albumin, you are getting an inaccurate measurement.

Question 7

Where is estrogen (E2) produced?

Answer 7

Both the ovaries and the testis

Question 8

What to things lead to bone demineralization (absorption)? What about bone mineralization/deposition (as in, being deposited into bone tissue)

Answer 8

1. Glucocorticoids and FSH

2. Estradiol-17B (as in, estrogen), Anabolic androgens, GH/IGF1/Insulin, Calcitonin, Load bearing exercises

Question 9

When does epiphysis fuse? Why does this matter?

Answer 9

This thing fuses at the end of puberty, stopping bone elongation. Any added GH and IGF1 and E2 and androgens (for trabecular and cortical bones) is used for bone remodeling in the trabecular region and enhancing the strength of the cortical region. Excessive you presence leads to acromegaly.

Question 10

Describe the process of bone remodeling

Answer 10

Serum Ca, bound to albumin, is split away from albumin. The Ca is then linked with PO4 and used by differentiated osteoblasts to make hydroxyapatite (mineralized bone). Osteoblasts also secrete RANKL, which causes osteoCLASTS to differentiate. Osteoblasts also produce osteoprotegerin to stop RANKL (promotes demineralization). When osteocalsts are finally differentiated, they cause hydroxyapatite to demineralize through thick chemical equation, leading to an increase in serum Ca and PO4. The equation (Ca5)(PO4)2OH PRODUCES Ca, PO4, and OH (used to make blood more basic…acid base fam…the second step in pH regularity of Acid Base Lecture)

Question 11

How does estrogen (E2) effect bone mineralization-demineralization

Answer 11

1. PROMOTES osteoclast apoptosis (so osteoclasts will not be able to chew up bone….no more demineralization)
2. Directly stops osteoclast differentiation, so osteoclast will not be able to directly chew up bone
3. Directly PROMOTES osteoprotererin, which you already know kills RANKL. If RANKL is killed, osteoclast differentiation stops and there is no more demineralization of bone.
4. Directly promotes osteoBLAST differentiation, which promotes bone MINERALIZATION

Question 12

Where does estrogen come from?

Answer 12

Men: testis
Women: ovary follicles

Question 13

Describe process of osteoclast-mediated bone absorption

Answer 13

Osteoclasts constantly undergo buffering process, converting h2o and co2 to make hco3 and H in their cytoplasm. The H is shuttled into the lacuna through and H+ atpase, lowering the lacuna’s pH. The hco3, on the other hand, is shot out into circulation, in exchange for the intake of Cl-, and the overall effect is an increase in pH of the extracellular fluid and an increased Cl concentration inside the osteoCLAST. NOW, you have a situation where the lacuna is acidic and the osteoclast cytoplasm is high in Cl. The acidic lacuna powers Cathepsin K and bone matrix proteases, which frees up calcium and Po4 at the bottom of the lacuna. The freed up Ca and PO4 now wants to get out of the lacunna and into the cytoplasm of the osteoclast. This ends up happening in exchange for the Cl, which we ssaid is now higher in concentration in the cytoplaasm because of trhe buffering process. When the Cl is exchanged, the Po4 and Ca are shot out, through the osteoclast cytoplasm and into the extracellular fluid, increasing blood Ca and PO4 concentrations (and HCO3 was already shot out.)

Question 14

Difference between resorption and mineralization. What happens to these processes in non-healthy people?

Answer 14

Resorption: kills cortical bone mass and trabecular bone mass.
Mineralization: direct opposite. In healthy people, these 2 processes balance out. IN non healthy people, one process favors the other. Isresorption is greater than mineralization, bone loses too much Ca and PO4, leading to osteopenia (little bone loss) and osteoporosis (outstanding bone loss) (both are bad at handling shear stress). If mineralzation is greater than resorption, patient gets metastatic calcifications (can cause serious pain around joints, but they also form around heart valves…regurges and stenosises).

Question 15

Describe what would normally happen in the case of a hyPOcalcemic patient.

Answer 15

Automatically, PTH woudl be summoned from the anterior pit:

1. The PTH release would increase resorption of bone Ca and PO4 (think of the osteoclasts).
2. The PTH release would directly cause Ca reabsortpion (distal tubule) and PO4 excretion…by preventing PO4 reabsorption (proximal tubule) in kidneys
3. The PTH still causes 25(OH)D to be converted by CYP27B1 (1ahydroxlase) into active vitamin D (calcitriol). This calcitriol is used to promote GI Ca absorption and renal Ca reabsorption.

Question 16

You know that PTH fosters PO4 excretion though the kidneys (renal) but you also know that PTH leads to demineralization of PO4 in the lacunas of osteoclasts. So, which one predominates?

Answer 16

PTH’s ability to promote excretion of PO4 DOMINATES.

Question 17

What happens in the case that you have hyper or eucalcemia?

Answer 17

PTH is not released.

Question 18

How does PTH affect the proximal tubules of kidneys? What about Calcitriol? What about normal Ca reabsorption?

Answer 18

1. Stimulates calcitriole synth from 25-OH vitamin D and blocks PO4 reabsorption.
2. Calcitriole has a very weak effect on PO4 reabsorption. compared to PTH. PTH causing PO4 excretion is predominant.
3. Ca reabsorptions normally occurs through NKCC channels

Question 19

How does PTH and calcitriole affect the distal kidneys?

Answer 19

They both stimulate Ca reabsorption.

Question 20

What is the job of CaSR? Why would it kick in?

Answer 20

Acts as negative feedback to CYP27B! (remember that this CYP27B facilitates calcitriole formation, which then promotes PO4 and Ca2+ reabsorption). When there is an increased filtered load of Ca, CaSR allows Ca into the cytoplasm from the proximal tubule and the Ca kills CYP27B1. CaSR kicks in because PTH demineralized Ca from bone, thus putting more Ca in circulation and ultimately raising the Ca filtered load.

Question 21

How does PTH work in the proximal tubule?

Answer 21

1. It binds to PTH receptors on basolateral (blood) side of proximal tubule, causing the production of CYP27B1, which then produced calcitriole.
2. PTH also kills NaPi, a secondary active transport which reabsorbs PO4 and Na (the Na would then be further reabsorbed by Na/K atpase, which would then excrete K.). By killing this, PO4 stays in the forming urine, despite the presence of calcitriole, and is then excreted.

Question 22

Difference between intermittent (3-5 hrs), low doses of PTH and continuous (24hr) dose of PTH.

Answer 22

Intermittent dose: mineralization of trabecular bone, pausing trabecular bone resorption.
Continuous: Demineralization (resorption) of trabecular bone, lowering trabecular bone mass.

Question 23

Describe the difference between PTH in acute, intermittent concentrations than in chronic, continuous concentrations.

Answer 23

PTH works anabolically in acute conditions, stimulating osteoBLAST differentiation (remember RANKL), mitiosis, and impairing osteoBLAST apoptosis. In chronic amounts, PTH flips this entirely.

Question 24

What happens in situations where the patient is hypocalcemic?

Answer 24

Parathyroid glands sense this with CaSR (think macula densa for Glomerulus). CaSR summons parathyroid chef cells and then proliferates its parathyroid cells and simultaneously secretes PTH. The PTH then goes off to directly affect bone (osteoblasts stimulate osteoclast, start demineralization process in lacunas and such) and the kidneys (which make calcitriole in the proximal tubules).

Question 25

How is CaSR affected whtn the patient is eu or hypercalcemic?

Answer 25

CaSR senses the normal or high Ca levels and increases vitamin D receptor presence on the parathyroid (Calcitriol would have also done this.). CaSR would also simultaneously kill PTH secretion and kill chief cell proliferation. This is negative feedback.

Question 26

What is calciTONIN?

Answer 26

Hormone secreted from parafollicular C cells. WOrks to impair tubular reabsorption of Ca. It downmodulates osteoclast-mediated bone absorption. Long -term pathologies associated with its deficiency IN HUMANS has not been found (it’s necessary in fish and rodents tho). It serves as a potential tumor marker, and its helps treat osteoporosis.

Question 27

What is the job of FGF-23?

Answer 27

Regulates serum PO4. WHen PO4 is too high, calcitriol stimulates osteoCYTE presence, which stimulates FGF-23. FGF-23 then kills PTH secretion, kills CYP27B1 expression (and effectively kills calcitriol production), and promotes PO4 excretion directly.

Question 28

Where does FGF-23 work , and how does it do its job?

Answer 28

FGF-23 works in the proximal tubule. It works specifically by killing CYP27B1 (so no more calcitriol) and causing 24-OH to be inert (so it can’t be converted to active vitamin D.) Also, remember how calcitriol acts on NaPi to reabsorb PO4 and Na in the same proximal tubule? Well, FGF-23 kills NaPi, so not more PO4 reabsorption (and Na reabsorption, at least from this specific channel).

Question 29

Describe the progression of bone development

Answer 29

Bone both grows longitudinally and remodels.up until the end of puberty/adolescence. IGF1 and GH are solid at this point. By about 30, you are done with bone growth, IGF1 and GH start to dwindle, and are strictly remodeling bone. This is why you need to rack up the Ca and vitamin D before hand. Once you reach 30, you are stuck with what you got, and bones will start to deteriorate.

Question 30

Which gender produces estrogen? testosterone? Which is more important for bone development?

Answer 30

Both male and female produce both estrogen and testosterone. Estrogen is more important for bone growth and development.

Question 31

How would one treat osteoporosis?

Answer 31

Prescribe estradiol-17B (estrogen). This would bind to estrogen receptor-alpha, thus increasing trabecular bone mass mineralization. Note that there are specific drugs that promote bone mineralization, drugs which promote estrogen receptor-alpha binding/prevalnce, and kill off RANKL (promoting osteoclasts production and this Ca resorption).

Question 32

What’s the biggest concern with over prescribing prednisone (glucocorticoids) for bone treatment?

Answer 32

Demineralization of bone. Note that it is prescribed for a variety of reasons (inflammations and such)

Question 33

How do glucocorticoids affect bones?

Answer 33

1. They inhibit osteoblast viability and osteocytes, stimulating bone mineralization.
2. Directly stimulates osteoclast viability, which stimulates osteoclast function and causes bone resorption (more mineralization)
3. It directly increases RANL:osteoprotegerin ratio. keep in mind that RANKL promotes osteoclast productivity.
4. GLucocorticoids DIRECTLY kill Type II muscle fibers, which lowers skeletal muscle mass and inhibits body’s load bearing activity.
5. Glucocorticoids stimulates stomatostatin, which kills GH gene expression, killing off all the effects of GH (like GH releases and protein anabolism)
6. Glucocorticoids kill off IGF1, which is needed in order for GH to work.
7. Glucocorticoids promote myostatin synth, which kills skeletal muscle mass.
8. Glucocorticoids promote proteoLYTIC factors and signaling, which kills protein anabolism and leads to lowered skeletal muscle mass
9. Glucocorticoids kills all Ca absorption from duodenum (gut) and kills Ca reabsorption from the distal tubule of kidney.
10. Glucocorticoids kill GnRH pulse generator and FSH, LH secretion, overall inhibiting gonadal steroidogenesis (so, no more estrogen), and killing bone mineral density

Question 34

Describe the progression of female development and menopause throughout their life.

Answer 34

1. Normal FSH and reproductive throughout teens till early 40s.
2. From mid to early 50s women undergo menopausal transition, where they skip cycles and may have amenorrhea. FSH goes up, E2 starts to fall.
3. 50s and beyond, women have their last menstral period. FSH is mad high, E2 is effectively low.

Question 35

What is FSH responsible for doing? Describe the relationship between E2 and bone.

Answer 35

Chronically elevated FSH (menopausal women) promotes osteoclast differentiation, which creates osteoclasts and fosters bone demineralization. In general, osteoblast mineralization creates osteoblasts, which foster mineralization. Osteoblasts still promote RANKL production and osteoprotegerin (which kills RANKL…negative feedback)

Question 36

How do you help menopausal women with bone issues?

Answer 36

Give E2, which promotes osteoblast differentiation and osteroprotegerin (which kills RANKL). You can also give bisphosphates, which kills osteoclast activity and causes osteoclast apoptosis.

Question 37

Difference between primary and secondary osteoporosis.

Answer 37

Primary: Age-related
Secondary: Caused by Glucocorticoids, Hypogonadism (lacking E2), alcohol abuse, and smoking.

Question 38

Describe the testicular steroidgenesis pathway.

Answer 38

17alppha-OHP4 becomes ANDROSTENEDIONE through conversionn by CYP17. ANDROSTENEDIONE can be converted to estrone with CYP19 or to testosterone with 17beta-HSD. Estrone becomes E2 with help of 1-HSD enzyme. The E2 then binds to E receptor on bone. Testosterone binds to bone through androgen receptors. Testosterone can be converted to E2 with CYP19.

Question 39

What is a nontraditional potential pathway for E2 production?

Answer 39

Androgens are aromatized into testosterone through bone and fat. The formed E2 then binds to E receptors on bone.

Question 40

In primary hyperparathyroidism, what is the problem? What are signs of this disease?

Answer 40

Parathyroid is overactive, reabsorbs too much Ca. Not subjective to negative feedback. Signs include:

1. High (or normal…like, high normal. Which is questionable because PTH is normally supposed to be at lower end) PTH
2. Modest hyperclacemia
3. Low-Normal phosphorus
4. High-normal amounts of calcitriol
5. 24 hr urine calcium will be high or normal
6. There would be hyperphosphaturia, but it’s never measured
7. Bone mineral density would be low, usually the caortical bone is affected the most.
8. Patient would likely have osteopenia, osteoporosis, and increased alk phosphatase
9. Severe hypercalcemia would lead to decreased QT intervals (arrhythmia)

Question 41

What would bring patient to clinic because of hypercalcemia due to primary hyperparathyroidism?

Answer 41

1. Lethargy
2. Fatigue
3. Neuromuscular weakness
4. Cognitive functions questionable
5. May not show any symptoms.

Question 42

What is PTHrP? (PTH-related Peptide)

Answer 42

It’s an ectopic PTH. Works exactly the same as PTH. Produced by cancers.

Question 43

What’s a cause of hypercalcemia?

Answer 43

Thiazide diuretic use (acts on NCC channel, and upon acting, Ca is spared and allowed to be reabsorbed in the distal tubules).

Question 44

Treatment for primary hyperparathyroidism. How would you recognize a non-primary disorder of hypercalcemia?

Answer 44

parathyroidectomy, calcitonin (mineralizes bone). In non-primary hypercalcemia, PTH would be low.

Question 45

What are causes of hypocelcemia due to primary hypoparathyroidism? What would labs show?

Answer 45

Thyroidectomy, parathyroidectomy, autoimmune, hereditary. Labs would show hypocalcemia and hyperphosphatemia.

Question 46

What are signs of hypocelcemia due to primary hypoparathyroidism

Answer 46

Trousseau’s sign: take bp cuff, max it out, leads to carpal spasm in response to transient ischemia.
Chovstec’s sign: Ipsilateral facial muscle spasm in response to tapping facial nerve.
Other symptoms include skeletal muscle cramping, and prolonged QT interval.

Question 47

Describe the pathway of the downfall of the kidneys in chronic kidney disease (Secondary Hyperparathydroism).

Answer 47

In chronic kidney disease, Vitamin D production adn Ca reabsorption is utterly wrecked. AS a result, you have hypocalcemia sine a lot of Ca is being dumpied in urine instead of being rebsorbed. Sick kidneys can’t respond to PTH, even though concetrations of Ca are below 9. As a result, parathyroid keeps secreting PTH. Even thought the kidneys cannot respond, the bones can. PTH still causes bones to resorpt PO4 and Ca. The result of this is hyperphosphatemia. Note that the increase in PO4 concentrations will yet again cause PTH to to be secreted since the job of PTH is to cause PO4 to be excreted and reabsorb Ca. As this cycle continues, bone is continuously being decriminalized, leading to osteoporosis. All the excess Ca is literally just being excreted or accumulating i joints and valves of the heart. Excreted Ca leads to hypocalcemia since Vitamin D is not being produced and nothing is happening to help reabsorb Ca from urine since the kidneys are wrecked.

Question 48

Is kidney failure associated with hypocalcemia or hyperphosphatemia?

Answer 48

Both. Reason: Kidneys can’t respond to PTH, so can’t make calcitriol, reabsorb Ca, or excrete PO4.

Question 49

What are two unique consequences of a parathyroid adenoma leading to unchallenged PTH?

Answer 49

1. The hypercalcemia would increase the Ca in glomerular filtrate, saturating Ca reabsorptive capacity, affecting CaSR. CaSr resposds by killing AQP and NKCC channels, and simaltensously leading to nephrogenic DI.
2. The unchallenged PTH kills PO4 reabsorption and leads to hyperphosphaturia, which leads to hypercalciuria. The end result is renal lithiasis (kidney stones)

Question 50

Describe the myocyte plateau potential.

Answer 50

4. Resting
5. Na influx. seen as spike.
6. Peak of spike seen in 0. Transient K efflux
7. Plateu, Ca influx and K efflux
8. Downward phase. K efflux

Question 51

What happens in the plateau phase in periods of hyper vs hypocalcemia?

Answer 51

Hypercalcemia: Shortened QT interval, seen as shortened plateau phase
Hypocalcemia: Prolonged QT interval, seen as lengthened plateau phase.

Question 52

Explain the pathway of hyperphospatemia

Answer 52

A sick kidney (GFR less than 30) is unaffected by PTH. This means PO4 is reabsorbed, leading to hyperphosphatemia. This also means Ca is not reabsorbed, leading to hypocalcemia, which constantly summons PTH and ultimately leads to bone demineralization (which furthers the hyperphosphatemia)

Question 53

How does increased pO4 absorption in GI affect plasma Ca?

Answer 53

The increased plasma PO4 form the GI acts as negative feedback for plasma Ca, literally working to reduce plasma Ca.