Lecture 46 Calcium and Phosphate Regulation Part 2 Flashcards
1
Q
How does chronic kidney disease affect Ca2+/Pi homeostasis?
A
- because impaired kidney function interferes with Ca2+ and Pi reabsorption
2
Q
Hypocalcemia
A
- blood calcium concentration below 1.1-1.35 mM ionized calcium
3
Q
What are the symptoms of hypocalcemia?
A
- muscle cramping
- increased neuromuscular excitability
- muscle spasms
- fatigue
- cardiac dysfunction
- depression, pyschosis, seizures
4
Q
Causes of hypocalcemia
A
- inadequate PTH production
- sydromes with component of hypoparathyroidism
- PTH resistance
- Inadequate vit D
- Vit D resistance
5
Q
What are the most common causes of hypoparathyroidism?
A
- autoimmune destruction of parathryoids/loss of parathyroids due to throidectomy
6
Q
What is hypoparathyroidism?
A
- it is hypocalcemia with serum PTH inappropriately low for hypocalcemic state (not secreting enough PTH)
7
Q
What happens with hypoparathyroidism?
A
- loss of PTH producing tissue leads to hypocalcemia due to decreased Ca2+ uptake in gut/kidney and decreased Ca2+ released from bone
8
Q
What is Di George syndrome?
A
- congenital disease with complete lack of parathyroids at birth
9
Q
What is the treatment for hypoparathyroidism?
A
- no approved hormonal treatment
- mainly calcium and calcitriol supplementation but this can increase the risk of kidney stones due to hypercalciuria
10
Q
What happens with hypoparathyroidism associated with activating CaSR mutations?
A
- CaSR signals constitutively even though Ca2+ levels are low (supresses PTH when it shouldnt)
- leads to decreased Ca2+ reabsorption in kidney (more excreted in urine) and decreases release from bone, uptake in gut, etc –> leads to low Ca2+ serum levels
11
Q
_________ is too much calcium in the urine and can cause kidney stones, can worsen if Ca2+ supplementation is used for treatment of hypoparathyroidism
A
- hypercalciuria
12
Q
________ is hypocalcemia not due to lack ofPTH but due to lack of responsiveness of target tissues to PTH
A
- pseudohypoparathyroidism
13
Q
What happens with pseudohypoparathyroidism?
A
- serum PTH is high as parathryoid gland keeps trying to respond to correct the low serum Ca2+ levels
- happens from mutations in G proteins important for PTH signaling
14
Q
What does lack of vitamin D inhibit?
A
- Ca2+ and Pi uptake in gut
due to downregulation of calcium and phosphate transport proetins, calbindins, TRPV6, NaPi-IIb
15
Q
What does vit D deficiency lead to in growing children?
A
- rickets
16
Q
What does vit D deficiency lead to in adults?
A
- osteomalacia
(failure of osteoid to fully calcify - soft bones) - (due to low serum calcium and phosphate)
17
Q
Is vit D deficiency more common cause of hypocalcemia or hyoparathyroidism?
A
- hypocalcemia
18
Q
What is VDDR type I?
A
- its a vitamin D deficiency where there is a defect in the enzyme that converts vit D to active form
19
Q
VDDR type I results in:
A
- AR inheritence
- defect in renal 25-OH-vit D 1 a hydroxylase
- low serum Ca2+, Pi
- high PTH
- low 1,25 (OH)2D3
20
Q
What is VDDR typeII?
A
- receptor for vit D doesnt work
21
Q
VDDR type II symptoms:
A
- AR inheritance
- defect in Vit D receptor
- several mutations identified
- low serum Ca2+ Pi
- high PTH
- alopecia
- elevated 1,25 OHD3 (because it cant be used)
22
Q
______ is a blood calcium concentration higher than normal range (>1.1-1.35 mM ionized)
A
- hypercalcium
23
Q
Symptoms of hypercalcium
A
- fatigue
- electrocardiogram abnormalities
- nausea, vomiting, constipation
- anorexia
- abdominal pain
- hypercalciuria/kidney stone formation
- calcification of soft tissues
24
Q
Causes of hypercalcium?
A
- elevated PTH levels
- ## elevated 1,25 OHD3 levels
25
What is primary hyperparathyroidism?
- oversectretion of PTH
- one of 4 PT glands makes too much PTH due to tumor
- also can be caused by hypercalcemia
- removal is a treatment
26
What is Men1?
- inherited form of hyperparathryoidism
- due to inactivation of tumor supressor gene menin (one copy of gene is mutatied but second hit needed for tumor formation
27
What is Men2?
- due to gain of function mutation in RET protoncogene
- AD inheritence
- milder than Men1
28
Inactivating mutations of CaSR
- heterozygoes have FHH
(CaSR doesnt signal even tho Ca signals are high)
- elevated Ca and lower Pi
- asymptomatic
- heterzyogtes have neonatal severe hyperparathyroidism and requires removal of parathyroid gland
29
Can hypercalcemia occur from tumors?
- yes the tumors will secrete bone resorption and causes bone degradation and elevated serum calcium
- can be life threatening
30
What is secondary hyperparathyroidism?
- oversecretion of PTH in response to conditions of hypocalcemia and or decreased 1,25(OH)2D3
31
What is the most common cause of 2nd hyperparathyroidism?
- chronic renal failure
32
Chronic renal failure Kidneys cant produce much 1,25OH2D3 which does what?
- normally inhibits PTH and do not excrete PI adequately resulting in insoluble calcium phosphate forming and removal of Ca2+ from circulation
33
Phosphate levels lower than
- hypophosphatemia
34
What causes X-linked hypophosphatemic rickets?
- mutations in phex gene
| - x linked dominant
35
XLH mutations of PHEX lead to inappropriately ______ production even though serum phosphate is low
- elevated FGF23
| PHEX no longer inhibits FGF23
36
What does FGF23 do?
- reduces renal reabsorption of phosphate (leads to renal phosphate wasting. ie more excreted in urine)
37
What are the features of X linked hyophoshatemic rickets?
- growth retardation, rachitic/osteomalacic bone disease, dental abscesses, weak bones
- most common disorder of renal phosphate wasting
38
What are the causes of hypophasphatemia?
- decreased intesinal absorption of phosphate
- increased urinary excretion
- redistribution from extracellular fluid into cells/tissues
39
what is the treatment for XLH?
- phosphate supplementation/high dose calcitrol
- response to treatment depends on age of patient at time of intiation
- may require surgical intervention to correct limb deformaties
-
40
ADHR
- rare form of inherited hypophoshatemic rickets -symptoms similar to XLH
41
What causes ADHR?
- mutations in FGF23 that alter its cleavage site so it cant be inactivated
42
What is ARHR?
- recessively inherited hypoposphatemic rickets, symptoms similar to XLH
43
What caues ARHR?
- mutations in Dmp1
| - results in overproduction of FGF23
44
Dmp1 expressed by ______ and negatively regulates FGF23
- osteocytes
45
What is Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH)
- rare inherited form of hypophasphatemic rickets
- due to heterozygous or homozygous loss of function mutations in type II Na phosphate cotransporter NaPiIIC
-
46
HHRH is similar to XLH but has elevated what?
- levels of 1,25OH2D3
47
How do you treat HHRH?
- phosphate supplements alone
48
What is common about hypophasphatemic rickets?
- 3 forms result in elevated FgF23
| - the other one is due to reduced function of Na+ dependent phosphate transporter which is regulated by FGF23
