Calcium Balance and Mineral Metabolism Flashcards
What is the primary role of PTH ?
PTH raises blood calcium levels
Where are CaSR located and what action does it have at those tissues?
parathryoid: regulates PTH secretion
kidney: regulates calcium excretion
By what mechanisms is PTH stimulated/suppressed?
PTH is stimulated by low Ca and high phosphate (phosphate binds free calcium and increases activation of vitamin D)
PTH is suppressed by high active vitamin D
What are PTH’s action at the kidney?
increase Ca reabsorption at the distal nephron
inhibits phosphate reabsorption proximally (decreases cotransporters in proximal tubule)
PTH increases transcription of 1a-hydroxylase (activates vitamin D)
What are PTH’s actions at the bone?
PTH acts via receptors on osteoblasts and in this way increases function of osteoblasts and osteoclasts
increase osteoclast activity leads to release of calcium and phosphate from bone into the blood
What is PTH-related protein?
structurally similar to PTH and not completely understood- if levels are high it can mimic excess PTH
What is the action of calcitonin in humans?
in other animals it is used to decrease calcium levels but has no appreciable activity in humans; salmon calcitonin is more active in humans and is used pharmacologically
What are the steps in vitamin D synthesis?
sunlight forms cholecalciferol (D3) from 7-dehydrocholesterol
liver can take D3 or D2 (from food or supplements) and make it into 25 hydroxyvitamin D3 (storage form)
from storage form, kidney makes 1,25 dihydroxyvitamin D3 which is the active form
Which is the best compound to measure to estimate vitamin D status?
25-OH vit D is the predominant form and is unregulated so levels reflect total vitamin D entering the system
What enzyme is responsible for vitamin D activation?
25(OH)D is hydroxylated by 1a-hydroxylase to 1,25-D
both 25-D and 1,25-D circulate bound to protein, but 25-D is more tightly bound, leading to a longer half-life (weeks v. hours)
How is the activity of 1a-hydroxylase regulated?
induced by PTH, and low phosphate
inhibited by calcium and FGF-23
What are the actions of vitamin D activity?
stimulates calcium and phosphate absorption in the GI tract
decrease transcription of PTH at parathyroid
maintains adequate minerals for bone health and stimulates FGF-23 production
What is the action of FGF-23?
phosphate wasting in the kidney
suppression of 1a-hydroxylase activity
stimulated by 1,25D, calcium and phosphate
diseases of excess FGF-23 have low phosphate, poor bone mineralization and low 1,25D levels (osteomalacia)
How do you determine between abnormal parathyroid function or external factors causing calcium imbalance?
measure PTH level
What are causes and mechanisms of primary hyperparathyroidism?
causes: single or multiple adenomas, diffuse hyperplasia, parathyroid carcinoma is rare; monoclonal expansions can carry mutation in growth regulating gene
mechanisms: action of excess PTH to increased calcium resorption from the bone, increased calcium retention at the kidney and activation of vitamin D increasing GI calcium absorption
How doe the set point of PTH regulation by Ca change with primary hyperparathyroidism?
increase in set point of suppression of PTH by Ca
adenomas will also show a relative non-suppressibility
thought to be due to both increased cell mass and decreased numbers of CaSR on the surface of tumor cells
What are features of the “classic” presentation of primary HPT?
bones: generalized demineralization, brown tumors and fractures
stones: nephrolithiasis and nephrocalcinosis
GI: nausea, vomiting, constipation
Psych: confusion, memory difficulties, difficulty concentrating
today is usually an asymptomatic finding on routine labs, treated with removal of involved gland
What is the mechanism of Familial Hypocalciuric Hypercalcemia? What would you see in Ca levels?
loss of function mutation in CaSR so CaSR is less sensitive to calcium (benign)
mildly high Ca and high PTH, ***low urinary Ca levels
In cases of hypercalcemia in patients with appropriate parathryoid function, what would expect for levels of PTH?
gland appropriate suppresses PTH to low levels- this includes causes like increased calcium absorption, calcium release from bone and impaired calcium excretion
Name 3 mechanisms of hypercalcemia of malignancy.
invasion/destruction of bone by tumor
production of PTHrP by tumor
production of vitamin D by tumor
Name other diseases or medications that can lead to hypercalcemia.
vitamin D intoxication (rare)
sarcoidosis/granulomatous disease (unregulated 1a-hydroxylase)
hyperthyroidism (via bone breakdown)
milk-alkali syndrome: hypercalcemia, renal failure and metabolic alkalosis due to milk and Na-bicarb
prolonged immobilization: elevated bone resorption
What are common symptoms of hypocalcemia?
primarily symptoms of neuromuscular irritability: premolar or digital paresthesias, muscle cramping, tetany, seizures
Define primary hypoparathyroidism and causes due to parathyroid dysfunction.
primary hypoparathryodism: low Ca and low or inappropriately normal PTH
causes: absence or destruction of parathyroid: DeGeorge’s syndrome, post-surgical, autoimmune
impaired PTH secretion from intact glands: low magnesium, activating mutations of CaSR
Describe the condition Autosomal Dominant Hypocalcemia.
mechanism: CaSR has a gain of function mutation (acts as if there is more calcium then there is) and inappropriately suppresses PTH secretion (low Ca and low PTH seen)
causes urinary calcium loses even with serum calcium levels are low
Describe the phenotype of Albright’s Hereditary Osteodystrophy?
AHO: short stature, round face, short 4th metacarpal, obesity
What is pseudohypoparathyroidism? (mechanism)
a disorder of resistance to PTH- action at the kidney causing low serum Ca and very high PTH due to a mutation in the Gsa component of PTH receptor signaling
type 1a: both PTH resistance and AHO
pseudo-pseudohypoparathryodism: just AHO but normal PTH
How is genetic imprinting important in PHP?
renal responsiveness requires presence of maternal Gsa
an abnormal gene from mom leases to PTH resistance and AHO
an abnormal gene from dad leads to normal gene function in the kidney but AHO
(women can inherit the gene from their father and not have PHP and imprint the gene, giving it to their children -who will be affected)
