Regulation of Calcium and Phosphate Metabolism Flashcards
1
Q
Percent distribution of calcium in:
ECF
Plasma
ICF
Bones and teeth
A
ECF = 0.1%
Plasma = 0.5%
ICF = 1%
Bones and teeth = 99%
2
Q
What forms of calcium exist in the blood?
A
Calcium exists in ionized form, bound to plasma proteins, or complexed in non-ionized form
Protein bound = 40%
Unfilterable = 60%
Of the unfilterable Ca, 10% is complexed to anions and 50% is ionized calcium
3
Q
T/F: changes in plasma protein concentration alter the total Ca concentration in the opposite direction
A
False: changes in plasma protein concentration alter the total Ca concentration in the same direction as protein concentration
4
Q
What are 3 ways of altering forms of Ca in the plasma?
A
Altering total Ca by changing plasma protein concentration (changes in same direction)
Altering ionized Ca by changing the fraction of Ca complexed with anions (changes anion concentration)
Altering ionized Ca by changing the fraction of Ca bound to proteins (albumin binds Ca and H)
5
Q
If plasma [Pi] increases, the fraction of Ca that is complexed ________, thereby _______ ionized [Ca]
A
Increases; decreasing
6
Q
How does plasma [Ca] change in conditions of acidemia vs. alkalemia?
A
Acidemia = high plasma [Ca] — high plasma [H], albumin binds more H, thereby increasing Ca
Alkalemia = low plasma [Ca] — low plasma [H], albumin binds more Ca, thereby decreasing Ca
7
Q
What effect does hypocalcemia have on neuromuscular excitability?
A
Increases it, because more Ca is inside the cells
May lead to hypocalcemic tetany/spasticity
8
Q
What effect does hypercalcemia have on neuromuscular excitability?
A
Depresses it; threshold shifts away from resting membrane potential
9
Q
What are the regulators of plasma levels of calcium, thus controlling neuromuscular excitability?
A
PTH
Calcitonin
Calcitriol
10
Q
Primary hyperparathyroidism and malignancy are clinical conditions related to _____levels of serum Ca
A
Elevated
11
Q
Hypoparathyroidism, renal disease, and vit D deficiency are clinical conditions related to ___ serum Ca
A
Low
12
Q
What are the 3 coordinated organ systems primarily involved in Ca homeostasis?
A
Bone
Kidney
Intestines
13
Q
What hormone is responsible for bone formation from body calcium pool
A
Calcitonin
14
Q
What hormones are responsible for bone resorption into body calcium pool?
A
PTH
Calcitriol
15
Q
What hormones inhibit Ca excretion from kidneys?
A
PTH
Calcitriol
Calcitonin
16
Q
What hormone is responsible for absorption of calcium from the GI tract into the body calcium pooL?
A
Calcitriol
17
Q
About 1500 mg of Ca is taken in daily via the diet. The majority of this is excreted where?
A
Stool = 1300 mg
[200 mg excreted in urine]
18
Q
Extracellular concentration of Pi is inversely correlated to that of _____.
A
Ca
19
Q
Where is the majority of our phosphate stored?
A
85% in bone
[14% in cells, less than 1% serum]
20
Q
What system primarily controls the fine tuning of phosphate levels?
A
Renal excretion
[renal tubular reabsorption is inhibited by PTH; reabsorption depends on transport maximum]
21
Q
What are the 4 classic regulators of phosphate metabolism?
A
Dietary
Calcitriol
PTH
Renal tubular
22
Q
Calcitriol regulation of phosphate metabolism
A
Calcitriol increases phosphorus resorption from bone and absorption from intestine
INCREASES Pi reabsorption in kidney
23
Q
PTH regulation of phosphate metabolism
A
Phosphorus resorption directly from bone, and indirectly activates intestinal absorption through stimulation of calcitriol production
24
Q
What endocrine factors directly or indirectly control NaPi cotransporter activity in the apical membrane?
A
PTH
Vitamin D
FGF23
25
What effect do insulin, GH, and thyroid hormone have on renal phosphate reabsorption?
Increase it
26
What effect do calcitonin, glucocorticoids, and ANP have on renal phosphate reabsorption?
Decrease it
27
What effect does a gain of function mutation have in FGFR3?
Achondroplasia
28
Endocrine FGF derived from bone, regulated by phosphate and vitamin D levels, which in turn regulate phosphate homeostasis
FGF23
29
3 renal effects of FGF 23
Directly downregulates NaPi transporters in kidney
Stimulates PTH to downregulate NaPi transporters in kidney
Decreases Calcitriol production in kidney
30
Where is PTH synthesized and secreted?
Chief cells of parathyroid gland
31
Low plasma (ionized) [Ca] has what effect on PTH secretion?
Stimulates it
32
What is the role of the calcium sensing receptor (CaSR) in regulating release of PTH and reabsorption of Ca in the nephron?
Increased ECF [Ca] inhibits PTH secretion, bc calcium activates Gq pathway leading to inhibition of PTH expression at gene level
Low ECF [Ca] stimulaltes PTH secretion — when Ca is not present, CaSR gene is upregulated so that more calcium can bind
33
Mutations in CaSR can cause what condition?
Familial hypocalciuric hypercalcemia (FHH)
34
Effect of chronic hypercalcemia on PTH levels
Decreases synthesis/storage PTH
Breaks down any stored PTH, releases inactive PTH fragments into circulation
35
Effect of chronic hypocalcemia on PTH levels
Increases synthesis/storage of PTH
Results in hyperplasia of parathyroid glands (aka secondary hyperparathyroidism)
36
What effect does magnesium have on PTH?
Same effects as calcium, but to a lesser extent (so typically decreases synthesis/storage of PTH)
Exception = severe hypomagnesemia may inhibit PTH synthesis, storage, and secretion
37
What three signaling molecules are responsible for the physiologic actions of PTH?
PKA
ionized [Ca]
PKC
38
Decreased plasma [Ca] —> _______ PTH secretion —> ______ bone resorption and ____ Ca and Pi in blood
Increased; increased; increased
39
Decreased plasma Ca —> _______ PTH secretion; _____ Pi reabsorption in kidney, ______ Ca reabsorption, and _____ urinary cAMP
Increased; Decreased; increased; increased
40
Decreased plasma Ca —> ______ PTH secretion —> ______ Ca absorption in intestine
Increased; increased
41
What effect does vitamin D have on plasma concentrations of calcium and phosphate via action from bone?
Increases both
42
What effect does vitamin D have on phosphate levels via action on kidney and intestine?
It can induce both FGF 23 and Klotho to increase urinary excretion of Pi and lower serum phosphate levels, but can also facilitate increased intestinal absorption of phosphate to increase serum phosphate levels
43
Vitamin D _____ calcium and phosphate products to promote mineralization of new bone
Increases
44
Various names for biologically active vitamin D
1,25-dihydroxycholecalciferol
1,25-hydroxy-vitamin D
1,25(OH)2D3
Calcitriol
45
What form of Vit D is inactive natural form made in the skin upon exposure to sunlight?
Vit D3 (cholecalciferol)
46
What form of vit D is supplement provided by plant sources that must be converted to active form in body?
Vit D2 (ergocalciferol)
47
What form of Vit D is inactive in body but commonly measured in lab tests?
25(OH)D = 25-hydroxy-VitaminD
48
Vitamin D3 is first metabolized in the _____ prior to reaching is final biologically active form in the ____
Liver; kidney
[the form made in the liver is the inactive one measured by lab tests]
49
The ________ enzyme in the _____ of the kidney is responsible for converting inactive vitamin D to active form
1-alpha hydroxylase (aka CYP1alpha); proximal tubule
50
What effect do the following have on 1-alpha-hydroxylase (responsible for active form of Vit D in kidney):
[Ca]
PTH
Phosphate
Low [Ca], high PTH, and low Pi stimulate 1 alpha hydroxylase
51
T/F: the main circulating form of Vit D is the biologically active form
False: main circulating form is lab test form = 25-OH-cholecalciferol
52
Renal 1-alpha-hydroxylase (aka CYP1-alpha) is tightly regulated.
What effect does active form of Vit D have on this enzyme?
Inhibits it via feedback loop; simultaneously activates CYP24 which promotes formation of inactive form of Vit D
53
Renal 1-alpha-hydroxylase (aka CYP1-alpha) is tightly regulated.
What effect does high calcium levels (via CaSR) have on this enzyme?
Inhibits it
54
Renal 1-alpha-hydroxylase (aka CYP1-alpha) is tightly regulated.
What effect does PTH have on this enzyme?
Stimulates it
55
_______ reabsorbs proteins from the tubular lumen that were filtered at the glomerulus, including the vitamin D binding protein (DBP), some of which was complexed to vit D in glomerular filtrate
Megalin
56
Does vitamin D have genomic or nongenomic effects?
Both -in the genomic response, vitamin D binds to the nuclear VDR
57
What cells associated with bone have PTH receptors?
Osteoblasts! [NOT osteoclasts]
58
Short- vs. Long-term actions of PTH on bone
Short term = bone formation (directly acts on osteoblasts)
Long term = bone resorption (indirectly acts on osteoclasts)
59
________ acts synergistically with PTH to stimulate osteoclast activity and bone resorption
Vitamin D
60
Agent involved in bone formation/resorption released by osteoblasts; induces stem cells to differentiate into osteoclast precursors, mononuclear osteoclasts, and mature multinucleated osteoclasts
M-CSF (macrophage colony-stimulating factor)
61
What is the receptor activator for NF-kB ligand and primary mediator of osteoclast formation?
RANKL - cell surface protein produced by osteoblasts, bone lining cells, and apoptotic osteocytes
62
Cell surface protein receptor on osteoclasts and osteoclast precursors
RANK
[RANK:RANKL interaction —> increased osteoclast formation]
63
Soluble protein produced by osteoblasts; decoy receptor for RANKL; inhibits RANKL/RANK interaction
OPG
[when osteoclast activity is sufficient, OPG is synthesized by osteoblasts with net effect of reduced osteoclast formation/activity]
64
PTH _____ RANKL and _____ OPG
Increases; decreases
65
Vitamin D _____ RANKL as a long term effect on osteoblasts
Increases
66
3 actions of PTH on kidney
Inhibits Pi reabsorption in proximal tubule (by inhibiting NPT resulting in phosphaturia)
Stimulates reabsorption of Ca in distal tubule
Stimulates 1-alpha hydroxylase, favoring vit D formation
67
Vitamin D acts on kidney to _____ Ca and Pi reabsorption
Stimulate
68
Vitamin D induces synthesis of IC calcium-binding protein ______, which buffers intracellular calcium
Vitamin D also induces the ______ that exports calcium across the basolateral membrane
Calbindin-9k
Ca2+-ATPase
69
Where is calcitonin released from?
Thyroid gland
70
Calcitonin ______ serum calcium and phosphate levels by _____ bone resorption (requires high doses to elicit this effect)
Lowers; inhibiting
71
What cells of the thyroid expess CaSR in order to regulate secretion of Calcitonin?
Parafollicular C cells
[CaSR senses elevated EC Ca which stimulates synthesis and secretion of calcitonin]
72
What effect does calcitonin have on osteoclasts and thus overall bone density?
Decreases activity and number of osteoclasts —> eventually increasing bone density
73
What effect does calcitonin have on renal handling of Ca and Pi?
Promotes renal excretion of Ca and Pi
74
How would a thyroidectomy vs. thyroid tumor affect calcitonin levels and Ca metabolism overall?
Thyroidectomy decreases calcitonin
Thyroid tumor increases calcitonin
NEITHER affects Ca metabolism overall
75
______________ results from a parathyroid problem resulting in hypersecretion of PTH; typically d/t adenoma, hyperplasia, or cancer
Primary hyperparathyroidism
76
Primary hyperparathyroidism results in _________ and ________ due to bone demineralization, increased GI Ca absorption (mediated by Vit D), and increased renal Ca reabsorption
Hypercalcemia; hypophosphatemia
77
With primary hyperparathyroidism, there is excessive excretion of ____, ____, and _____
Pi, cAMP, and Ca
78
Stones, bones, and groans refers to what condition?
Primary hyperparathyroidism
Hypercalciuria = Ca-oxalate stones
Increased bone resorption
Constipation
79
Typical tx for primary hyperparathyroidism
Parathyroidectomy
80
What is secondary hyperparathyroidism?
Increased PTH levels secondary to low blood Ca (low blood Ca can be caused by renal failure, vit D def, etc.)
81
Primary causes of hypoparathyroidism
Thyroid surgery
Parathyroid surgery
Autoimmune or congenital disease
82
Hypoparathyroidism results in _____ and ______, and most symptoms are associated with _____
Hypocalcemia; hyperphosphatemia; low Ca
[symptoms = tetany, convulsions, parasthesias, muscle cramps, poor tooth development]
83
Tx for hypoparathyroidism
Oral Ca and vitamin D supplements
84
Inherited autosomal dominant disorder in which tissues are PTH-resistant due to problem with PTH receptor (defective cAMP-mediated signal transduction)
Pseudohypoparathyroidism type Ia (albright hereditary osteodystrophy [AHO])
85
Pseudohypoparathyroidism type Ia ______ PTH secretion and low serum calcium levels; hypocalcemia and _____ develop
Increases; hyperphosphatemia
86
T/F: Administrations of exogenous PTH fails to provoke a phosphate diuresis, an increase in serum Ca, and an increase in urinary cAMP in those with pseudohypoparathyroidism type Ia
True
87
Phenotype of pseudohypoparathyroidism type Ia
```
Short stature
Short neck
Obesity
Subcutaneous calcification
Shortened metatarsals and metacarpals
```
88
General symptoms of hyperparathyroidism in terms of serum calcium concentration and serum phosphate levels
High serum calcium concentration
Low serum phosphate concentration
[also associated kidney stones, osteoporosis, Gi disturbances, muscle weakness, depression, confusion, polyuria]
89
General symptoms of hypoparathyroidism in terms of serum calcium concentration and serum phosphate levels
Low serum calcium concentration
High serum phosphate concentration
[also tetany, convuslions, decreased heart contractility, irritability, psychosis, GI malabsorption]
90
Humoral hypercalcemia of malignancy involves elevated _______, which is produced by tumors with close homology of N terminal domain to PTH
PTHrP (binds and activates same receptor as PTH)
91
Humoral hypercalcemia of malignancy produces a profile similar to what other condition?
Primary hyperparathyroidism
[increased urinary Ca, increased urinary Pi, increased cAMP, hypercalcemia, hypophosphatemia]
92
How does humoral hypercalcemia of malignancy differ from primary hyperparathyroidism?
Decreased bone formation
Decreased PTH levels
Decreased vitamin D (in cancer, vitamin D levels are normally suppresed)
93
Tx for humoral hypercalcemia of malignancy
Furosemide (inhibits renal Ca reabsorption = increases excretion), and etidronate (inhibitor of bone resorption)
94
What are some conditions resulting in impaired vitamin D metabolism?
Dietary deficiency
Vitamin D resistance
GI disorders, chronic renal failure, and Pi depletion affecting metabolism
95
Pathophys associated with vitamin D in children vs. adults
Rickets in children (insufficient Ca and Pi available)
Osteomalacia in adults (new bone fails to mineralize)
96
What are the 2 types of rickets?
Pseudovitamin D-deficient rickets or vitamin D dependent rickets type I (characterized by decreased levels in 1-alpha-hydroxylase)
Pseudovitamin D-deficient rickets or vitamin D-dependent rickets type II (decreased activity of VDR)
97
Tx for rickets or osteomalacia
Vitamin D2 or D3 supplemens
Ca2++
Sunlight
Calcitriol
98
2 major risk factors for osteoporosis
Female gender
Age
99
Which of the following is characterized by an increase in PTH, increase in Ca, decrease in Pi, and increase in Vit D?
A. Primary hyperparathyroidism
B. Secondary hyperparathyroidism due to renal failure
C. Secondary hyperparathyroidism due to vitamin D deficiency
D. Hypoparathyroidism
E. Pseudohypoparathyroidism type Ia
F. Humoral hypercalcemia of malignancy
A. Primary hyperparathyroidism
100
Which of the following is characterized by a decrease in PTH, decrease in Ca, increase in Pi, and decrease in Vit D?
A. Primary hyperparathyroidism
B. Secondary hyperparathyroidism due to renal failure
C. Secondary hyperparathyroidism due to vitamin D deficiency
D. Hypoparathyroidism
E. Pseudohypoparathyroidism type Ia
F. Humoral hypercalcemia of malignancy
D. Hypoparathyroidism
101
Which of the following is characterized by an increase in PTH, decrease in Ca, increase in Pi, and decrease in Vit D?
A. Primary hyperparathyroidism
B. Secondary hyperparathyroidism due to renal failure
C. Secondary hyperparathyroidism due to vitamin D deficiency
D. Hypoparathyroidism
E. Pseudohypoparathyroidism type Ia
F. Humoral hypercalcemia of malignancy
E. Pseudohypoparathyroidism type Ia
102
Which of the following is characterized by increased PTH, decreased Ca, decreased Pi, and decreased Vit D?
A. Primary hyperparathyroidism
B. Secondary hyperparathyroidism due to renal failure
C. Secondary hyperparathyroidism due to vitamin D deficiency
D. Hypoparathyroidism
E. Pseudohypoparathyroidism type Ia
F. Humoral hypercalcemia of malignancy
C. Secondary hyperparathyroidism due to vitamin D deficiency
103
Which of the following is characterized by decreased PTH, increased Ca, decreased Pi, and decreased Vit D?
A. Primary hyperparathyroidism
B. Secondary hyperparathyroidism due to renal failure
C. Secondary hyperparathyroidism due to vitamin D deficiency
D. Hypoparathyroidism
E. Pseudohypoparathyroidism type Ia
F. Humoral hypercalcemia of malignancy
F. Humoral hypercalcemia of malignancy
104
Which of the following is characterized by increased PTH, decreased Ca, increased Pi, and decreased Vit D?
A. Primary hyperparathyroidism
B. Secondary hyperparathyroidism due to renal failure
C. Secondary hyperparathyroidism due to vitamin D deficiency
D. Hypoparathyroidism
E. Pseudohypoparathyroidism type Ia
F. Humoral hypercalcemia of malignancy
B. Secondary hyperparathyroidism due to renal failure
