Endocrine Ca And PO4 homeostasis

Question 1

To maintain homeostatic phosphate levels, the body uses phosphate as a _____ ______ buffer and to produce _____ and _____. It can also store phosphate in _______.

Answer 1

Fixed Acid buffer;
Produce ATP and cGMP;
Bone

Question 2

Normal serum calcium levels lie within the range of ____ to ____ mg/dL. A majority of total calcium in plasma is bound to ________ protein.

Answer 2

8.5-10.5 mg/dL;

Albumin protein

Question 3

In order to get an accurate gauge of calcium levels, we must have what binding protein? Why is this relevant when determining calcium abnormalities?

Answer 3

Albumin, 3.5-5.5 g/dL;

Abnormal calcium levels are meaningless without a reading of this binding protein

Question 4

What indirect effect does ACTH secretion have on bone?

Answer 4

ACTH stimulates secretion of cortisol from the adrenal cortex (Z.F.). Cortisol has an catabolic effect on muscle, fat and bone.

Question 5

How are each of the following regions of long bone affected in the presence of GH and Estradiol? (Trabecular bone, Cortical bone, Growth plate)

Answer 5

Trabecular bone undergoes chronic remodeling;
Cortical bone undergoes less remodeling but maintains the strength of bone;
The growth plate grows longitudinally until the end of puberty when it fuses.

Question 6

What role do osteoblasts play in the mineralization and demineralization of bone.

Answer 6

Osteoblasts secrete RANK-ligand that can upregulate osteoclast function. They can also produce osteoprotegerin which lowers the effects of RANKL enabling mineralization.

Question 7

The catabolism of hydroxyapatite will release ____, ____ and ____ from the bones into plasma.

Answer 7

Calcium, phosphate and hydroxide are free during demineralization.

Question 8

Describe the mechanism by which osteoclasts mediate bone resorption.

Answer 8

Osteoclast’s H+ ATPase pumps H+ into the lacuna of bone to lower pH and generate HCO3- in the process. They have pumps that take demineralized ions from bone into plasma.

Question 9

What are the 2 pathophysiologic conditions pertaining to rates of mineralization and resorption?

Answer 9

Osteopenia/Osteoporosis occurs when resorption rates exceed mineralization. Metastatic Calcification occurs when mineralization exceed resorption. The latter is associated with Hyperparathyroidism and can present with calcification at joints, vessels and heart valves.

Question 10

What roles do PTH and Calcitriol have on calcium and phosphate handling in the kidney?

Answer 10

PTH stimulates Calcitriol, which stimulates Ca++ reabsorption, and promotes PO4 excretion. At the distal nephron, Ca++ reabsorption is promoted by both PTH and calcitriol.

Question 11

Describe how high calcium levels down-regulates itself via a negative feedback loop.

Answer 11

High plasma calcium levels increases filtered load which activates Calcium Sensing Receptor (CaSR) in PCT. This has a similar function to macula densa, as this decreases 1-alpha hydroxylase (CYP27B1) resulting in less Calcitriol secreted. This whole process is a negative feedback loop.

Question 12

The net effect of PTH on bone remodeling is ____ and ____ dependent.

Answer 12

Dose and time dependent

Question 13

How does the short term effect of supplemental PTH compare to chronic effects? Can this be used as treatment for osteoporosis?

Answer 13

Short term effect of PTH causes bone mineralization (anabolism), but the chronic term causes bone resorption (catabolism) via osteoblasts’ regulation on osteoclasts. Intermittent, low doses of PTH1-34 has been shown to be effective against osteoporosis.

Question 14

Name at least 5 therapeutic agents that can be used to treat osteoporosis.

Answer 14

PTH1-34 (teriparatide), Estradiol-17, Vitamin D, Bisphosphonates and supplemental Calcitonin can be used to treat osteoporosis.

Question 15

What is the function of Calcitonin and where is it secreted from? Does it have any associated pathologies?

Answer 15

Calcitonin is a calcium regulating hormone secreted from parafollicular C cells of the thyroid gland in response to high plasma calcium levels. It works by impairing tubular reabsorption of Ca++ and down-regulating osteoclast bone resorption. There are NO LONG-TERM PATHOLOGIES associated with its excess or deficiency.

Question 16

What is FGF-23 and what are it’s 3 functions in relation to parathyroid and kidney function?

Answer 16

Fibroblast Growth Factor-23 is a protein that is produced by osteocytes.

1. It has a negative feedback on PTH secretion.
2. It inhibits CYP27B1 enzyme thus reducing Calcitriol production.
3. It also promotes renal phosphate excretion (thus lowering plasma PO4 levels).

Question 17

Why would FGF23 block PTH secretion, if it also reduces phosphate levels?

Answer 17

FGF23 knocks down PTH, even though phosphate excretion is still promoted. This is most likely to prevent too much calcium reabsorption.

Question 18

Why might someone find low calcium levels and high phosphorous in the blood labs of someone with Lupus Nephritis? What is the secondary diagnosis?

Answer 18

This is a sign of Secondary Hyperparathyroidism. Low calcium levels are seen because the sick kidneys cannot reabsorb Ca++. This also reflects high phosphorous levels since the kidneys cannot functionally excrete phosphate.

Question 19

What DXA T-score indicates a bone-mineral disorder?

Answer 19

A Dual energy X-ray Absorptiometry (DXA) t-score lower than -1.0 to -2.5 indicates bone loss. If it’s even less than -2.5, this is indicative of osteoporosis.

Question 20

What is alkaline phosphatase indicative of?

Answer 20

Alkaline phosphatase is a marker for bone turnover. The high their value, the more demineralization is occurring.

Question 21

What effect would a bone-mineral disorder have on FGF-23?

Answer 21

FGF23 levels increase due to the high bone turnover. This will promote phosphate excretion and reduce bone resorption.

Question 22

What androgen (sex hormone) plays a major role for bone health in BOTH sexes?

Answer 22

Estrogen (E2) is important for bone health in both sexes. It increases with corresponding levels of GH.

Question 23

What effects do glucocorticoids, such as cortisol, have on the following? (Muscle mass, GH secretion, bone mineralization, androgen production)

Answer 23

Cortisol reduces skeletal muscle mass, inhibits GH secretion (via Somatostatin), reduces bone mineralization and reduces androgen production.

Question 24

List some overall effects of Cortisol in the body.

Answer 24

Reduction in androgen production, bone integrating, serum calcium levels and skeletal muscle mass. An increase in visceral fat deposits, BP and appetite.

Question 25

What are the expected effects on FSH and Estrogen levels in a middle-aged female that experienced her last menstrual cycle years ago?

Answer 25

Elevated FSH and low E2 after 1+ years of menopause.

Question 26

Describe the mechanism by which women at menopause are at an increased risk of developing osteoporosis.

Answer 26

Lower levels of Estradiol reduces osteoclast apoptosis and osteoprotegerin which normally inhibits RANKL. These changes lead to osteoclast differentiation that further progresses the demineralization process.

Question 27

What role does Bisphosphonates play in bone regulation?

Answer 27

Bisphosphonates stimulate osteoclast apoptosis and inhibits their activity of breaking down hydroxyapatite.

Question 28

What is the significance of peripheral aromatization of testosterone?

Answer 28

Testosterone in males can be “aromatized” in bone or fat to be converted into Estrone/E2 which plays a major role in bone maintenance. This E2 binds to estrogen receptor (ER) to elicit to assist in bone integrity.

Question 29

What 2 conditions can occur in men with normal testosterone levels to result in osteopenia?

Answer 29

CYP19 deficiency which aromatizes testosterone into E2 or a rare loss of function mutation in ER-alpha can result in osteopenia. In other words, low activating enzyme or loss in receptor function can do it.

Question 30

What effects would a primary Hyperparathyroidism have on PTH, Calcitriol, Bone density and alkaline phosphatase? What would someone experiencing this be at risk of developing?

Answer 30

Primary hyperPTH would present as high PTH levels, high Calcitriol, low bone mineral density and increased levels of alkaline phosphatase. An accompanying hypercalcemia would present as a shorted QT interval, increasing the risk of A-fib.

Question 31

List at least 4 symptoms that a patient with hypercalcemia may experience.

Answer 31

Lethargy, fatigue, neuromuscular weakness, cognitive impairment

Question 32

A thyroidectomy can potentially damage the _________ glands. This is indicated by __________ and __________ in blood lab results.

Answer 32

Damaged parathyroid glands;

Hypocalcemia and Hyperphosphatemia

Question 33

List at least 5 signs and symptoms associated with primary hypoparathyroidism (hypocalcemia).

Answer 33

Trousseau’s Sign: Carpal spasm in response to transient ischemia; Neuromuscular hyperexcitability; CNS Depression; Arrhythmia + Prolonged QT interval

Question 34

Describe the mechanism by which Hyperphosphatemia runs in Renal failure.

Answer 34

Sick kidneys do not respond to increasing levels of PTH, which triggers PO4 reabsorption and hinders Ca++ reabsorption. THis results in Hyperphosphatemia and the Hypocalcemia that overstimulates PTH secretion and bone demineralization.

Question 35

How does FGF-23 affect renal phosphate reabsorption, Calcitriol and CYP27B1?

Answer 35

FGF-23 decreases phosphate reabsorption, inhibits CYP27B1 enzyme and reduces Calcitriol levels.

Question 36

How does Estrogen (E2) differ from Cortisol in regards to Calcium mobilization of the bone?

Answer 36

E2 inhibits bone demineralization to obtain Ca++ whereas Cortisol promotes it.

Question 37

Why would supplemental estrogen (via hormone-replacement therapy) not be an advisable treatment strategy for a middle aged woman with a history of cancer in the family?

Answer 37

Although estrogen (E2) can stave off the effects of osteoporosis, it can stimulate neoplasms (tumors).

Question 38

How does Primary Hypoparathyroidism present after a parathyroidectomy under the following parameters? (Serum PTH, Ca++, PO4 and Calcitriol)

Answer 38

1 HypoPTH =

Decreased PTH, decreased Ca++, increased PO4, decreased Calcitriol

Question 39

How does Primary Hyperparathyroidism present from an PT adenoma under the following parameters? (Serum PTH, Ca++, PO4 and Calcitriol)

Answer 39

1 HyperPTH =

Increased PTH, increased Ca++, decreased PO4, increased Calcitriol

Question 40

How does Secondary Hyperparathyroidism present from a renal failure under the following parameters? (Serum PTH, Ca++, PO4 and Calcitriol)

Answer 40

2 HyperPTH (CKD) =
increased PTH, decreased Ca++, increased PO4, decreased Calcitriol

Question 41

How does Secondary Hyperparathyroidism present from Calcitriol deficiency under the following parameters? (Serum PTH, Ca++, PO4 and Calcitriol)

Answer 41

2 HyperPTH (Calcitriol def.) =
increased PTH, decreased Ca++ [cannot absorb from diet], decreased PO4 [PTH wins], decreased Calcitriol

Question 42

How does Secondary Hypoparathyroidism present from Calcitriol Excess under the following parameters? (Serum PTH, Ca++, PO4 and Calcitriol)

Answer 42

2 HypoPTH (Calcitriol XS) = decreased PTH, increased Ca++ [absorption from gut], increased PO4 [XS Calcitriol > PTH effects], increased Calcitriol

Question 43

Elevated levels of Calcitriol has a ______ -feedback effect on PTH secretion and a ______ -feedback effect on CaSR.

Answer 43

Calcitriol = negative-feedback on PTH;

Positive-feedback on CaSR