Calcium and Phosphate Regulation (1 + 2) Flashcards
1
Q
What are calcium and phosphorus important for in the body?
A
proper mineralization of the skeleton and dentition
2
Q
Calcium is critical to which cellular functions?
A
- cell division/cell adhesion
- plasma membrane integrity
- 2nd messenger in signal transduction
- muscle contractility
- neuronal excitability
- bloot clotting
- skeletal development
- bone, dentin, and enamel mineralization
3
Q
What are the 3 major sites of calcium in our bodies?
A
- bone calcium 99%
- calcium in blood and extracellular fluid
- intracellular calcium
4
Q
[Ca10(PO4)6(OH)2] is the chemical formula for ____.
A
hydroxyapatite crystals
5
Q
_____ serves as the main reservoir of calcium to maintain blood ionized calcium within a normal range.
A
Bone hydroxyapatite
6
Q
What is the normal range for total serum calcium?
A
2.1-2.6 mM
7
Q
What is the biologically active fraction of calcium available to cells? Ionized, bound to albumin, or complexed with citrate or phosphate ions?
A
ionized
8
Q
What is the normal range for ionized calcium?
A
1.1-1.35 mM
9
Q
Calcium bound to ____ is pH dependent.
A
albumin
10
Q
Recommended daily calcium intake requirements increase with age and peak at what age before decreasing again?
A
puberty (9-18)
11
Q
Are the same amounts of calcium in our body absorbed and excreted?
A
YES - about 200mg absorbed by gut and 200mg excreted in urine
12
Q
How much calcium does our body store?
A
1 kg
13
Q
Are the same amounts of calcium released from bone and deposited into bone per day?
A
YES - normal bone turnover
14
Q
Our cells maintain ___ intracellular calcium concentrations in the cytosol.
A
low
15
Q
Is the intracellular or extracellular concentration of calcium higher?
A
extracellular concentration (10,000X higher)
16
Q
Why is the maintenance of a steep calcium gradient important? What regulates this mechanism?
A
because the intracellular calcium fluxes regulate cell function; gradient achieved by Ca2+ pumps in plasma membrane
17
Q
What cellular functions is phosphorus critical to?
A
- membrane composition (phospholipids)
- intracellular signaling
- nucleotide structure
- skeletal development
- bone, dentin and enamel mineralization
- chondrocyte differentiation
18
Q
How is phosphorus critical in intracellular signaling?
A
because phosphorylation is a critical signaling component
19
Q
How is phosphorus present in solution?
A
as free phosphate ions = inorganic phosphate
HPO4^2- and H2PO4-
20
Q
The majority of body phosphate is present in ____.
A
hydroxyapatite of the bones and teeth
21
Q
Is calcium or phosphorus absorbed more efficiently into the gut?
A
phosphorus
22
Q
Is dietary deficiency in phosphorus common?
A
NO
23
Q
What is the average adult serum phosphorus concentration?
A
0.8-1.5 mM
24
Q
____ is an important buffer to maintain physiological pH.
A
Phosphate
25
Do serum phosphate levels or serum calcium levels vary more? Which is not as tightly regulated?
phosphorus
26
What are the main organ systems involved with calcium and phosphorus homeostasis?
- gut
- parathyroids
- kidneys
- skeleton
27
The ____ secrete hormones to regulate Ca2+ and phosphorus uptake and release into the other associated organs.
parathyroids
28
Do the parathyroids primarily manage calcium being released or absorbed into the bone or organs?
absorption mainly
29
The ______ is the amount of Ca2+/Pi ingested in food equal to the sum of amount lost in feces and urine.
Net Zero Calcium/Phosphate Balance
30
What is the 3-step process of calcium uptake?
1. Uptake
2. Transcellular transport of calcium
3. Extrusion
31
The ____ of calcium from the apical side of the cell occurs through ion channels of the TRP superfamily (transient receptor potential).
uptake
32
What facilitates the transcellular transport of calcium?
calcium binding proteins called calbindins
33
How is calcium uptake regulated?
by TRP ion channels
34
What facilitates the extrusion of calcium on the basal surface of cells?
membrane transport proteins (Ca2+ ATPases or Na+ dependent Ca2+ exchangers
35
How does calcium get across the cell?
via calbindins
36
____ receptor ion channels uptake calcium on the apical side of intestinal epithelial cells.
TRPV6
37
____ allows transcellular (through-the-cell) transport to the basal side of the cell.
Calbindin
38
What pumps calcium out of the basal surface of the cell?
Ca2+ATPase pumps
39
During ____ dietary calcium intake, passive calcium uptake by a paracellular (between cell) pathway can also occur.
high
40
How is phosphate taken up in the gut?
taken up into the cell by a phosphate transporter, such as NaPi-IIb
41
Where is the NaPi-IIb co-transporter located at in the body?
on the brush border of cells in the ileum
42
What type of transporter is the NaPi-IIb transporter?
Na+ dependent Pi co-transporter
43
Can phosphorus be taken up passively?
some, yes
44
Where are Ca2+ and Pi filtered in the kidney?
in the glomerulus
45
What happens to calcium and phosphorus, filtered in the kidney, in the kidney tubules?
99% of calcium and 85% of phosphorus are REABSORBED
46
What would happen if we lost the ability to resorb calcium and phosphate in the kidneys?
we would very quickly become deficient because we are simply not taking in enough dietary minerals to compensate for losses
47
Is the mechanism for calcium uptake in renal reabsorption the same as in the gut?
YES - almost identical, but the isoforms are different
1. Uptake
2. Transcellular transpor
3. Extrusion
48
Is the mechanism for phosphorus uptake in renal reabsorption the same as in the gut?
YES - but the co-transporters are NaPi-IIa and NaPi-IIc
49
In osteoclasts how is most of the calcium transported transcellularly?
it is transported through the cell via endocytosis into acidic vesicles, followed by exocytosis at the cell surface
50
Where does the process of calcium uptake, transcellular calcium transport, and calcium extrusion occur?
- gut
- kidneys
- osteoclasts
51
Many hormones involved in the regulation of calcium and phosphate homeostasis work by altering the expression of what?
key transporter molecules
52
Which hormones regulate calcium?
- parathyroid hormone (PTH)
- 1,25-dihydroxyvitaminD3 (calcitriol)
- calcitonin
53
Which hormones regulate phosphate?
- parathyroid hormone (PTH)
- 1,25-dihydroxyvitaminD3 (calcitriol)
- fibroblast growth factor-23 (FGF23)
54
Which hormones regulate both calcium and phosphate levels?
- parathyroid hormone (PTH)
| - 1,25-dihydroxyvitaminD3 (calcitriol)
55
Calcitonin is produced by the ____ glands.
thyroid
56
How does dentin matrix protein-1 (PHEX) have a role in phosphate regulation?
it regulates FGF23
57
Are calcium and phosphate released together during bone resorption?
YES - always
58
Can calcium and phosphate regulation be controlled independently?
YES - through actions of calcitonin and FGF23 (each control calcium and phosphate independently) AND the transport molecules for calcium and phosphate are different
59
What hormone is released when a low serum calcium is detected?
PTH from the parathyroids
60
What does PTH trigger?
- increased Ca2+ release from bone
- increased Ca2+ uptake in the gut
- increased Ca2+ reabsorption in the kidneys
61
What hormone is released when a high serum calcium is detected?
calcitonin from the thyroid AND parathyroid stops releasing PTH
62
What does halting of PTH secretion and release of calcitonin trigger?
- decreased Ca2+ release from bone
- decreased Ca2+ uptake in the gut
- decreased Ca2+ reabsorption in the kidneys
63
How do the parathyroids detect serum calcium levels?
via the calcium sensing receptor (CaSR) expressed in the parathyroid gland
64
If there is increased serum calcium, then CaSR signaling ____ and PTH secretion ____.
increases; decreases
65
If there is decreased serum calcium, then CaSR signaling ____ and PTH secretion ____.
decreases; increases
66
What is PTH's calcium regulatory activity confined to?
the first 34 amino acids (out of 84 total)
67
What is the receptor that binds PTH?
PTH1R
68
PTHrP is a _____ receptor.
G-protein coupled receptor
69
PTH actions are mediated via the activation of what?
via activation of adenylate cyclase/cAMP production
70
What happens when CaSR signaling is shut off due to low serum calcium levels?
PTH is released
71
____ actually reduces phosphate reabsorption in the kidney and can lead to phosphaturia.
PTH
72
In the kidney, ____ stimulates the conversion of 25-hydroxyvitaminD3 to the active form, 1,25-dihydroxyvitaminD3 (calcitriol).
PTH
73
What is phosphaturia?
excess phosphate in the urine
74
What does 1,25-dihydroxyvitaminD3 induce the expression of in calcium homeostasis?
calbindins and other components of the calcium transport system (TRPV6, ATPases)
75
What does the induced expression of calbindins and other components of the calcium transport system by active vitamin D3 result in?
increased:
- Ca2+ uptake in the intestine
- Ca2+ reabsorption in the kidney tubules
- Ca2+ release into circulation from bone
76
____ stimulates the conversion to active vitamin D3, which then induces the expression of calbindins, TRPV6s and ATPases.
PTH
77
What does activated vitamin D3 induce the expression of in phosphate homeostasis?
it induces the expression of phosphate transporters NaPi-IIa and NaPi-IIc
78
What does the increased expression of phosphate transporters from activated vitamin D3 result in?
increased:
- Pi uptake in the intestine
- Pi reabsorption in the kidney tubules
- Pi release into circulation from bone
79
Is activated vitamin D3 a negative feedback loop inhibitor?
YES
80
What do the combined actions of PTH and 1,25(OH)2D3 (active vitamin D3) facilitate?
they increase serum calcium back to a normal range
81
Further production of ___ is inhibited when Ca2+ returns to normal and when active vitamin D3 is inhibited in a negative feedback mechanism.
PTH
82
What happens when the calcium serum level is high and the CaSR signaling is activated?
PTH secretion is reduced
83
What happens to vitamin D3 production when CaSR signaling is activated?
PTH secretion is reduced, which reduces the amount of active vitamin D3 produced in the kidneys
84
What proteins are targeted in modulating calcium serum levels?
calcium transporter proteins
85
What happens when calcitonin stimulates the calcitonin receptor (CTR) on osteoclasts?
osteoclasts retract their ruffled border and prevents release of calcium
86
What gland releases calcitonin?
thyroid gland
87
Does calcitonin oppose PTH's actions?
YES
88
Why is the calcitonin role now thought to be minor?
because patients with thyroid tumors or thyroidectomies do not have marked differences in their calcium homeostasis
89
What is FGF23's receptor in the kidney?
Klotho
90
When is the expression of FGF23 induced in bone?
when the serum phosphate levels are too high
91
In what cells is FGF23 primarily expressed in?
osteocytes (but also osteoblasts, lining cells, and osteoprogenitors)
92
What are the two key proteins that inhibit the expression of FGF23 in osteocytes?
- dentin matrix protein (DMP-1)
| - phosphate regulating endopeptidase homolog (PHEX)
93
What important action of FGF23 inactivates the protein?
when it is cleaved into smaller fragments of 12 and 20
94
____ and ____ are genes that inhibit FGF23.
DMP1; PHEX
95
____ are the major source of endocrine (circulating) FGF23 and are now known to majorly regulate phosphate homeostasis.
Osteocytes
96
What are FGF23's actions in the kidney?
- decreases reabsorption of phosphate (down-regulates expression of phosphate transporters)
- decreases production of active vitamin D3
97
What is the overall effect of FGF23?
lowers serum phosphate
98
What is the main mechanism for rapid regulation of phosphate?
kidney reabsorption pathway
99
Where are NaPi-IIa and NaPi-IIc expressed?
in the proximal tubules of the kidneys
100
___ inhibits phosphate reabsorption via the inhibition of NaPi-IIa and NaPi-IIc transporters.
PTH
101
What happens to phosphate reabsorption in the kidney in the absence of PTH?
phosphate reabsorption is increased
102
In the kidney, PTH ___ calcium resorption and ___ phosphate resorption.
promotes; inhibits
103
____ is produced by osteocytes when serum phosphate is high, downregulating NaPi-IIa and NaPi-IIc transporters, and reducing phosphate reabsorption in the kidney.
FGF23
104
What does "reabsorption" mean?
release
105
Why does PTH have opposite effects on renal calcium and phosphate reabsorption?
it allows for differential regulation
106
What is the mechanism for regulating phosphate levels separately from calcium?
FGF23 is released by bone due to high Pi levels, so FGF23 will act to inhibit active vitamin D3 and decrease Pi reabsorption in the kidneys to decrease serum Pi
107
___ increases serum calcium and ___ serum phosphate.
PTH; decreases
108
1,25(OH)2D3 or calcitriol ___ serum calcium levels and ___ serum phosphate levels.
increases; increases
109
FGF23 ___ serum phosphate levels.
decreases
110
Is there independent regulation in calcium and phosphate homeostasis?
YES - some degree from different actions of calcitonin and FGF23
111
What are some different ways that calcium and phosphate homeostasis can be disrupted?
- dietary deficiency (Ca, Pi, vitamin D)
- mutations in receptor genes
- elevated or decreased PTH (from tumors, CaSR mutations, agenesis of parathyroids, loss of tissue due to thyroid surgery)
- insensitivity to PTH
- mutations in phosphate transporter molecules
- mutations in FGF23 or FGF23 regulators (DMP1, PHEX)
- chronic kidney disease
112
____ is the condition where blood calcium is below the normal range of 1.1-1.35 mM.
Hypocalcemia
113
What are some symptoms of hypocalcemia?
- muscle cramping
- increased neuromuscular excitability
- muscle spasms
- fatigue
- cardiac dysfunction
- depression, psychosis, seizures
114
What are some causes of hypocalcemia?
- inadequate PTH production
- syndromes with component of hypoparathyroidism
- PTH resistance
- inadequate vitamin D
- vitamin D resistance
115
Why might there be inadequate PTH production?
gene mutations, hypoparathyroidism, parathyroidectomy, CaSR mutations, radiation, tumors, autoimmunity
116
What is hypoparathyroidism?
hypocalcemia with serum PTH levels that are inappropriately low for their hypocalcemic state
117
What happens when PTH-producing tissue is lost?
- hypocalcemia due to decreased Ca2+ uptake in gut/kidneys
| - decreased Ca2+ release from bone
118
____ syndrome is a congenital disease with complete lack off parathyroids at birth.
DiGeorge
119
What is the treatment for hypoparathyroidism?
calcium and calcitriol supplementation (BUT it can increase the risk of kidney stones due to hypercalciuria)
120
Hypoparathyroidism associated with _____ mutations lead to continuous CaSR signaling even without high calcium levels.
activating CaSR
121
What happens when the parathyroids "misread" calcium levels as high and inappropriately suppress PTH?
- Ca2+ reabsorption is decreased in the kidney and decreases release of calcium from bone
- leads to low serum Ca2+
122
____ is hypocalcemia from a lack of responsiveness of target tissues to PTH, even though PTH is being produced normally.
Pseudohypoparathyroidism
123
In pseudohypoparathyroidism, serum PTH is ____ as the parathyroid glands keep trying to correct the low serum Ca2+ levels, to no avail.
high
124
_____ is insensitivity to PTH.
Pseudohypoparathyroidism
125
Lack of _____ inhibits Ca2+ and Pi uptake in the gut due to the down-regulation of calcium and phosphate transport proteins (calbindins, TRPV6, NaPi-IIb).
vitamin D
126
Vitamin D deficiency in children leads to ___.
rickets
127
Vitamin D deficiency in adults leads to ___.
osteomalacia
128
____ is the failure of osteoid to fully calcify due to low serum calcium and phosphate, which causes soft bones.
Osteomalacia
129
_____ is the flaring of the metaphysis and a growth plate that appears fuzzy on x-rays.
Metaphyseal cupping
130
_____ rickets is due to a lack of vitamin D; ____ rickets is due to mutations in vitamin D enzymes and receptors.
Vitamin D-deficient; vitamin D-dependent
131
_____ is due to a defect in renal 25-OH-vitamin D-1a-hydroxylase, causing very low 1,25(OH)2D3 levels.
VDDR Type I
132
____ is due to a defect in the vitamin D receptor, and causes elevated 1,25(OH)2D3 levels.
VDDR Type II
133
In ____, the patient has a mutation in the enzyme that produces the active form of vitamin D.
VDDR Type I
134
Both VDDR Type I and Type II have ___ serum Ca2+/Pi levels and ___ PTH levels.
low; high
135
____ is pseudovitamin D deficiency rickets.
VDDR Type I (body doesn't convert to active form)
136
____ is hereditary vitamin D resistant rickets.
VDDR Type II (receptor cannot detect vitamin D)
137
_____ is having high serum calcium levels.
Hypercalcemia
138
____ is when blood calcium concentration is higher than the normal range of 1.1-1.35 mM.
Hypercalcemia
139
What are the symptoms of hypercalcemia?
- fatigue
- electrocardiogram abnormalities
- nausea, vomiting, constipation
- anorexia
- abdominal pain
- hypercalciuria/kidney stones
- calcification of soft tissues
140
What are some causes of hypercalcemia?
- elevated PTH levels
- elevated 1,25(OH)2D3 levels
- malignancy
- severe dehydration
141
What can cause elevated PTH levels?
- hyperparathyroidism
- inactivating mutations of CaSR
- tumors
- hypophosphatemia
142
_____ is caused by PTH oversecretion, usually due to the development of a benign adenoma that results in excessive PTH synthesis.
Primary Hyperparathyroidism (PHPT)
143
In ____, PTH secretion is not adequately inhibited by the normal negative feedback response to elevated Ca2+.
primary hyperparathyroidism (PHPT)
144
Patients with ____ will have low phosphate levels, high bone turnover, and kidney stones.
primary hyperparathyroidism (PHPT)
145
Why is serum phosphate usually low in patients with PHPT?
there is decreased renal reabsorption of phosphate since PTH has the opposite effect on phosphate in the kidneys
146
Mutations in ____ and ____ result in neoplastic tumors in several endocrine tissues, including the parathyroids, which leads to excess PTH secretion.
MEN1; MEN2A
147
Familial primary hyperparathyroidism results in _____ from mutations in tumor suppressor and proto-oncogenes.
multiple endocrine neoplasia (MEN)
148
In _____ mutations of CaSR, CaSR doesn't signal even when calcium levels become very high, so PTH remains inappropriately elevated.
inactivating
149
If CaSR doesn't signal even when Ca2+ levels are high, how does the parathyroid respond?
the parathyroid misreads this inactivation as Ca2+ levels being too low, so PTH is inappropriately elevated
150
Inactivating mutations of CaSR results in ____ serum Ca2+ levels and _____ Pi.
elevated; lower than normal
151
Which mutation is more dangerous in inactivating mutations of CaSR? Heterozygous or homozygous?
homozygous - results in severe neonatal hyperparathyroidism
152
_____ can occur due to the presence of tumors that secrete factors that stimulate bone resorption, such as breast cancer or multiple myeloma.
Hypercalcemia
153
Why is hypercalcemia of malignancy dangerous?
because the large amounts of bone resorption occuring leads to massive amounts of calcium being released into the body
154
Tumors can secrete ____, which can mimic PTH actions and increase the amount of serum calcium.
PTHrP
155
In chronic renal failure, what hormone gets oversecreted in response to conditions of hypocalcemia or decreased 1,25(OH)2D3?
PTH
156
In ______, kidneys cannot produce much 1,25(OH)2D3, which normally inhibits PTH, and this results in calcium phosphate forming and removal of Ca2+ from circulation.
chronic renal failure
157
What is associated with chronic renal failure?
hypocalcemia
158
____ is when phosphate levels are lower than the normal range of 0.8-1.5 mM.
Hypophosphatemia
159
Who is typically affected by hypophosphatemia?
hospitalized patients, alcoholics, and patients with severe sepsis
160
What are some causes of hypophosphatemia?
- decreased intestinal absorption of phosphate
- increased urinary excretion
- redistribution from extracellular fluid into cells and tissues
161
What may cause the decreased intestinal absorption of phosphate in hypophosphatemia?
- vitamin D deficiency
- vitamin D receptor defects
- gut diseases that cause malabsorption
- nutritional deficiencies
- antacids with aluminum or magnesium
162
What may be the causes of increased urinary excretion of phosphate in hypophosphatemia?
- renal phosphate wasting disorders
- primary/secondary HPT
- mutations in FGF23
- Mutations in NaPi-IIc
163
What may be some causes of cellular redistribution of phosphate in hypophosphatemia?
- hungry bone syndrome (after parathyroidectomy)
- refeeding syndrome (after starvation)
- treatment for ketoacidosis
164
_____ is the most common disorder of renal phosphate wasting and is due to mutations in the PHEX gene.
X-linked Hypophosphatemic Rickets (XLH)
165
How does the PHEX mutation cause XLH rickets?
normally, PHEX acts to inhibit FGF23; XLH mutations of PHEX lead to inappropriately elevated FGF23 production, even though serum phosphate is low; when FGF23 levels are high, phosphate gets excreted in urine
166
How is XLH treated?
phosphate supplementation and high dose calcitriol
167
Autosomal dominant hypophosphatemic rickets (ADHR) is due to mutations in ____ that do not allow it to be inactivated.
FGF23
168
Autosomal recessive hypophosphatemic rickets (ARHR) is due to mutations in ____ that leads to the overproduction of FGF23.
DMP1
169
In ARHR, the mutation to DMP1 causes the overproduction of FGF23, which then ____.
facilitates the overexcretion of phosphate
170
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is due to loss-of-function mutations in the _____ gene.
NaPi-IIc (type II sodium phosphate co-transporter)
171
HHRH is clinically similar to patients with XLH, but HHRH patients have elevated levels of ____.
vitamin D3
172
What is the main culprit of diseases related to hypophosphatemia?
elevated FGF23 (+ a transporter regulated by FGF23)
173
What is tumor-induced osteomalacia (TIO)?
acquired syndrome where factors (FGF23) are secreted into the circulation by tumors that cause alterations in phosphate metabolism
174
____ is when phosphate levels are greater than the normal range of 0.8-1.5 mM.
Hyperphosphatemia
175
What are some symptoms of acute (short term) hyperphosphatemia?
- hypocalcemia (muscle tetany)
| - suppression of alpha-hydroxylase activity in kidney
176
What are some symptom of chronic hyperphosphatemia?
- soft tissue calcification
- rental failure
- secondary hyperparathyroidism
- renal osteodystrophy
177
What do the symptoms of hyperphosphatemia stem from?
calcium homeostasis being affected by phosphate levels
178
What are some causes of hyperphosphatemia?
- using laxatives with phosphate
- renal failure
- ketoacidosis
- severe systemic infection
- inactivating mutations to FGF23 or Klotho receptor
179
What happens when there is an inactivating mutation to FGF23 or its receptor, Klotho?
FGF23 is not able to facilitate phosphate excretion, so the body retains too much phosphate
180
What is the treatment for hyperphosphatemia?
administration of binding salts, such as calcium, magnesium, and aluminum
181
Why should dentists care about disorders of calcium and phosphate?
Patients may have:
- undermineralization
- short stature (adjustments for patient care need to be made)
- periodontitis
- higher incidence of caries
- treatment with bisphosphonates can cause BONJ
