11/15: Hormonal Control of Calcium and Phosphorus II Flashcards

1
Q

What is the main way that the Ca and Pi homeostasis can be disrupted?

A

Chronic kidney disease

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2
Q

How does chronic kidney disease affect Ca/Pi homeostasis?

A

impaired kidney function interferes with Ca2+ and Pi reabsorption

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3
Q

What is hypocalcemia?

A

Low serum calcium

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4
Q

What are serum calcium levels in hypocalcemia?

A

(low serum calcium)
< 8.5 mg/dL total calcium or
<4.4 mg/dL ionized calcium

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5
Q

What are causes of hypocalcemia?

A
  1. Inadequate PTH production (hypoparathyroidism)
  2. Syndromes with hypoparathyroidism
  3. PTH resistance
  4. Inadequate vitamin D
  5. Vitamin D resistance or synthesis defects
  6. Miscellaneous
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6
Q

What is hypoparathyroidism?

A

Hypocalcemia with serum PTH inappropriately low for hypocalcemic state

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7
Q

What is the most common cause of hypoparathyroidism?

A

autoimmune destruction of
parathyroids/loss of parathyroids due to thyroidectomy

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8
Q

What does the loss of PTh producing tissue cause?

A

hypocalcemia due to decreased Ca 2+ uptake in gut/kidney, decreased Ca2+ release from bone

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9
Q

What is a congenital disease with complete lack of parathyroids at birth?

A

Di George Syndrome

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10
Q

What mutations is hypoparathyroidism associated with?

A

Activating CaSR mutations

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11
Q

How does activating CaSR mutations cause hypoparathyroidism?

A

CaSR is hypersensitive to extracellular Ca2+ and suppresses PTH
production, even though even though Ca2+ levels are low (i.e.
parathyroid “misreads” Ca2+ levels as high and inappropriately
suppresses PTH)

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12
Q

A decrease in Ca2+ reabsorption in kidney (more excreted in urine) and decreases release from bone, uptake in gut, etc causes?

A

Low serum calcium

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13
Q

What is hypocalcemia due to?

A

Lack of responsiveness of target tissues to PTH

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14
Q

What mutations is hypocalcemia due to?

A

Mutations in G proteins important for PTH signaling

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15
Q

What is vitamin D deficiency due to?

A

Lack of sunlight
Malabsorption of vitamin D

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16
Q

What does lack of vitamin D inhibit?

A

Ca and Pi uptake in gut (due to
downregulation of calcium and phosphate transport proteins,
Calbindins, TRPV6, NaPi-IIb)

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17
Q

What does lack of vitamin D lead to in growing children?

A

Rickets

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18
Q

What is rickets?

A
  • Impaired bone mineralization/outward curvature of long bones (bowing)
  • Insufficiently mineralized vertebrae/curved spine
  • Disorganized growth plate/growth retardation
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19
Q

What does lack of vitamin D and phosphate lead to in adults?

A

Osteomalacia

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20
Q

What is failure of osteoid to fully calcify - soft bones?

A

Osteomalacia

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21
Q

What is VDDR type I (vit d-dependent rickets) due to a defect in?

A

Renal 25-OH-vit D-1-alpha-hydroxylase

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22
Q

What is VDDR type II due to a defect in?

A

Vit D receptor (VDR)

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23
Q

Which VDDR has very low 1,25(OH)2D3?

A

VDDR Type I

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24
Q

Which VDDR has high 1,25(OH)2D3?

A

VDDR type II

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25
What are the diseases of hypocalcemia?
Pseudohypoparathyroidism Hypoparathyroidism Vitamin D Deficient Rickets Vitamin D Dependant Rickets
26
What are levels of hypercalcemia?
High serum calcium total calcium >10.5mg/dL (2.6mM) or ionized calcium >5.4mg/dL (1.3mM)
27
What are causes of hypercalcemia?
1. Elevated PTH levels 2. Elevated 1,25(OH)2D3 levels 3. Miscellaneous
28
How does hypercalcemia occur in relation to PTH?
PTH hypersecretion not adequately inhibited by normal negative feedback response to elevated Ca2+
29
What are inherited forms of familial primary hyperparathyroidism?
Multiple endocrine neoplasia (MEN) MEN1 MEN2A
30
What is due to inactivation of tumor suppressor gene Menin (gene name MEN, One copy of gene is mutated, but “second hit” needed for tumor formation?
MEN1
31
What is due to gain of function mutation in RET protooncogene?
MEN2A
32
What do heterozygotes for inactive CaSR have?
Familial hypocalciuric hypercalcemia (FHH)
33
What do homozygoyes for inactive CaSR have?
neonatal severe hyperparathyroidism (NSHPT)
34
How do inactivating mutations of CaSR occur?
CaSR doesn’t suppress PTH production even though Ca 2+ levels are high (i.e. parathyroid misreads Ca2+ levels as being low) therefore PTH is inappropriately elevated
35
How can hypercalcemia of malignancy occur?
Due to tumors secreting factors that stimulate bone resorption
36
What are diseases of hypercalcemia?
Primary Hyperparathyroidism Familial Primary Hyperparathyroidism Hypercalcemia of Malignancy
37
What is oversecretion of PTH in response to conditions of hypocalcemia and/or decreased 1,25(OH)2D3?
Secondary hyperparathyroidism
38
What is the common cause of secondary hyperparathyroidism?
Chronic renal failure
39
What are phosphate levels of hypophosphatemia?
Low serum phosphate <2.5-4.5 mg/dL
40
What are causes of hypophosphatemia?
1. Decreased intestinal absorption of phosphate 2. Increased urinary excretion 3. Redistribution from extracellular fluid into cells/tissues
41
What are the main diseases associated with hypophosphatemia?
Rickets/osteomalacia
42
What is x-linked hypophosphatemic rickets (XLH)?
Due to mutations in PHEX gene on X-chromosome
43
What is PHEX produced by?
Osteoblasts, osteocytes, odontoblasts
44
What does PHEX inhibit?
FGF23 production
45
What do XLH mutations of PHEX lead to?
Inappropriately elevated FGF23 production, even though serum phosphate is low (mainly by osteocytes)
46
What does FGF23 reduce?
renal reabsorption of phosphate (leads to renal phosphate wasting - i.e. more excreted in urine)
47
When FGF23 reduces renal absorption what does this cause?
Low serum Pi Phosphaturia Low 1,25(OH)2D3
48
What is a rare form of inherited hypophosphatemic rickets?
ADHR (Autosomal Dominant Hypophosphatemic Rickets)
49
What is ADHR due to mutations in?
FGF23
50
What happens in mutations in FGF23?
Alter cleavage site so it cannot be proteolytically inactivated – FGF23 stays active longer
51
What is recessively inherited hypophosphatemic rickets?
ARHR (Autosomal Recessive Hypophosphatemic Rickets)
52
What is ARHR due to mutations in?
Dmp1
53
What is Dmp1 expresed by?
osteocytes and negatively regulates FGF23
54
What does a mutation in Dmp1 lead to?
Overproduction of FGF23
55
What is hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to?
heterozygous or homozygous loss of function mutations in type II sodium phosphate cotransporter NaPiIIc
56
What three genetic conditions result in elevated FGF23?
XLH ADHR ARHR1
57
What genetic condition results in reduced function of Na+ dependent phosphate transporter?
HHRH
58
Acquired syndrome of renal phosphate wasting
Tumor Induced Osteomalacia (TIO)
59
How are TIO levels associated with FGF23?
levels go down with surgical resection of tumor – may require supplementation with phosphate and calcitriol
60
What does acute hyperphosphatemia suppress?
1 α-hydroxylase activity in kidney, lowering 1,25D 3 levels, which further exacerbates hypocalcemia by reducing Ca2+ uptake in gut/renal reabsorption
61
What are causes of Hyperphosphatemia?
Acute phosphate load Decreased urinary excretion Redistribution to extracellular space Genetic causes of hyperphosphatemia
62
What dental abnormalities do vit d-dependent rickets cause?
thin enamel, hypomineralization→ microscopic cracks harbor bacteria → frequent cavities
63
Patients with hypercalcemia of malignancy often treated with
High dose bisphosphonates