Lecture 47- Calcium and Phosphate Homeostasis Part 2 Flashcards
how does chronic kidney disease affects calcium and phosphate homeostasis
impaired kidney function interferes with calcium and phosphate reabsorption
what is hypocalcemia defined as
total serum calcium concentration less than 8.5 mg/dL in the presence of normal plasma protein concentrations or a serum ionized calcium concentration less than 4.4 mg/dL
what are the symptoms of hypocalcemia
muscle cramping
increased neuromuscular excitability
muscle spasms
fatigue
cardiac dysfunction
depression, psychosis, seizures
what are causes of hypocalcema
-inadequate PTH production (hypoparathyroidism)
- PTH resistant
- inadequate vitamin D
- vitamin D resistance or sythesis defects
what is hypoparathyroidism
hypocalcemia with serum PTH inappropriately low for hypocalcemia state
what syndrome is most commonly associated with hypoparathyroidism
DiGeorge syndrome
what is the most common cause of hypoparathyroidism
autoimmune destruction of parathyroids/loss of parathyroids due to thyroidectomy
what happens in DiGeorge syndrom
congenital disease with complete lack of parathyroids at birth
what is the conventional treatment for hypoparathyroidism
mainly calcium and calcitriol supplementation
what do constitutively activating mutations in CaSR cause
autosomal dominant hypocalcemia
what happens in a constitutively activating mutation in CaSR
CaSR signals constitutively even though Ca2+ levels are low -> parathyroid misreads Ca2+ levels as high and inappropriately suppresses PTH
what is pseudohypoparathyroidism
hypocalcemia due to lack of responsiveness of target tissues to PTH
what is the level of serum PTH in pseduohypoparathyroidism and why
high because parathyroid gland keeps trying to respond to correct the low serum calcium
what is mutated in pseudohypoparathyroidism
mutations in G proteins in PTH signaling
which is a more common cause of hypocalcemia: vitamin D deficiency or hypoparathyroidism
vitamin D deficiency
how does the lack of vitamin D inhibit calcium and phosphate uptake in gut
downregulation of calcium and phosphate transport proteins, calbindins, TRPV6, NaPi-2b
what does vitamin D deficiency lead to in children? adults?
-children: rickets
-adults: osteomalacia
what type of disorder is VDDR type 1
autosomal recessive
what is the defect in VDDR type 1
renal 25-OH-vitmain D-1 alpha hydroxylase
what are the concentrations of Calcium, phosphate, PTH, and 1,25(OH)2D3 in VDDR1
calcium: low
phosphate: low
PTH: high
1,25(OH)2D3: very low
what type of disorder is VDDR type 2
autosomal recessive
what is the defect in VDDR type 2
vitamin D receptor
what are the concentrations of calcium, phosphate, PTH, and 1,25 (OH)2D3 in VDDR2
calcium: low
Phospahte: low
PTH: high
1,25(OH)2D3 : elevated
which form of VDDR has alopecia associated
type 2
what is hypercalcemia defined by
serum total calcium greater than 10.5 mg/dL or ionized calcium greater than 5.4 mg/dL
what are the symptoms of hypercalcemia
-fatigue
- electrocardiogram abnormalities
-nausea, vomitting, constipation
-anorexia
-abdominal pain
-hypercalciuria/kidney stone formation
-calcification of soft tissues
- hypercalcemia crisis occurs at greater the 2.5 ionized serum calcium
what are the causes of elevated PTH levels
-primary hyperparathyroidism
-familial hyperparathyroidism
- inactivating mutations of CaSR
what is the cause of elevated 1,25(OH)2D3
hypervitaminosis D
what is hypercalcemia of malignancy
due to tumor production of factor which stimulate bone resorption
how does severe dehydration cause hypercalcemia
will increase serum Calcium concentration without changing total blood calcium
what happens in primary hyperparathyroidism
usually 1 of 4 parathyroid glands makes too much PTH due to development of benign adenoma resulting in excessive PTH synthesis/secretion
what are the results of primary hyperparathyroidism
-hypercalcemia
- phosphate is low
-high bone turnover
-kidney stones
what is the treatment for primary hyperparathyroidism
parathyroidectomy
what is the familial primary hyperparathyroidism MEN1 due to
inactivation of tumor suppressor gene Menin
what is familial primary hyperparathyroidism MEN2 due to
gain of function mutation in RET protoocnogene
what do mutations in MEN result in
neoplastic tumors in several endocrine tissues including parathyroids
what type of disorder is familial primary hyperparathyroidism MEN1? MEN2
MEN1: recessive
MEN2: autosomal dominant
what will heterozygotes for inactive CaSR have
familial hypocalciuric hypercalcemia
what happens in familial hypocalciuric hypercalcemia
CaSR doesnt signal even though Ca2+ levels are high and PTH is inappropriately elevated. Pi is lower than normal
what do homozygotes for inactive CaSR have
neonatal severe hyperparathyroidism- potenitally fatal and requires parathyroidectomy
what happens in hypercalcemia of malignancy
tumors secrete factors that stimulate bone resorption. some secrete PTHrP which mimics PTH actions leading to elevated serum calcium and bone degradation
what is secondary hyperparathyroidism
oversecretion of PTH in response to conditions of hypocalcemia and or decreased 1,25(OH2)D3, can also be caused by vitmain D malabsorption
what is the most common cause of secondary hyperparathyroidism
chronic renal failure
what is hypophosphatemia defined by
phosphate levels lower than normal range, lower than 2.5-4.5 mg/dL
what are the causes of hypophosphatemia
-decreased intestinal absorption of phosphate
-increased urinary excretion
-redistribution from extracellular fluid into cells/tissues
what causes decreased intestinal absoprtion of phosphate
-dietary vitamin D deficiency/low sun exposure
- vitamin D receptor defects/synthetic defects
-malabsorption of vitamin D
what is increased urinary secretion seen in
renal phosphate wasting disorders, primary and secondary hyperparathyroidism
what phosphate disorders are rickets/osteomalacia associated with
hypophosphatemia
what is the most common disorder of renal phosphate wasting
x-linked hypophosphatemic rickets
what are the features of XLH
growth retardation, rachitic/osteomalacic bone disease, dental abscesses, weak bones
what mutation is XLH due to
mutation in PHEX gene on X chromosome
what is the mechanism of XLH
-PHEX produced by osteoblasts, osteocytes, odontoblasts
-PHEX normally inhibits FGF23 production
-XLH mutations of PHEX lead to inappropriately elevated FGF23 production even though serum phosphate is low- mainly by osteocytes
-FGF23 reduced renal absorption of phosphates
what are the levels of Pi and 1,25(OH)2D3 in XLH
Pi is low
vitamin D is low
what is the treatment form XLH
-phosphate supplementation/ high dose calcitriol
-maybe surgical intervention to correct limb deformities
what is the mutation ADHR and what does it stand for
autosomal dominant hypophosphatemic rickets
- mutation in FGF23 that alters cleavage site so it cannot be proteolytically inactivated, FGF23 stays active longer
what is the mutation in ARHR and what does it stand for
mutations in DMP1 which is expressed by osteocytes leading to overproduction of FGF23
- autosomal recessive hypophosphatemic rickets
what is HHRH stand for and what is the mutation
hereditary hypophosphatemis rickets with hypercalciuria
-due to heterozygous or homozygous loss of function mutations in type 2 sodium phosphate cotransporter NaPi2c
what is the level of 1,24(OH)2D3 in HHRH
elevated
what is the treatment for HHRH
phosphate supplements alone
what is the common theme of genes associated with inherited hypophosphatemic rickets/osteomalacia
they all result in elevated FGF23
what is tumor induced osteomalacia (TIO)
acquired syndrome of renal phosphate wasting, factors secreted into circulation by tumors cause alternations in Pi metabolism that mimic hypophosphatemic rickets
what is hyperphosphatemia defined by
phosphate levels greater than 4.5 mg/dL or higher than 1.5 mM
what are the symptoms of acute hyperphosphatemia
-hypocalcemia
-suppresses 1 alpha hydroxylase activity in kidney lowering 1,25D3 levels, which further exacerbates hypocalcemia by reducing calcium uptake in gut/renal reabsorption
what are the symptoms of chornic hyperphosphatemia
-soft tissue calcification, renal failure, secondary hyperparathyroidism, renal osteodystrophy
-hyperphosphatemia from renal failure plays role in development of secondary hyperparathyroidism
what are the causes of hyperphsophatemia
-acute phosphate load
- decreased urinary excretion
-redistribution to extracellular space
-genetic causes of hyperphosphatemia (familial tumoral calcinosis)
what is the cause of acute phosphate load
phosphate containing laxatives/enema
what are the causes of decreased urinary excretion
renal insufficiency/failure
- secondary to hypoparathyroidism/pseudphypoparathyroisim
- vitamin D intoxiation
what does the treatment of hyperphosphatemia involve
administration of phosphate binding salts-calcium, magnesium, aluminum
- aluminin avoided in patients with renal failure
how do these diseases implicate dental care
-increased periodontitis in patients with hypophosphatemic rickets/osteomalacia
- some patients with vitamin D dependent ricks have thin enamel-> microscopic cracks harbor bacteria that cause cavities
- bisphosphonates cause BNJ
- poor muscle tone/muscle weakeness are common and seizures can occur
