Calcium Balance and Mineral Metabolism

Question 1

What is the primary role of PTH ?

Answer 1

PTH raises blood calcium levels

Question 2

Where are CaSR located and what action does it have at those tissues?

Answer 2

parathryoid: regulates PTH secretion
kidney: regulates calcium excretion

Question 3

By what mechanisms is PTH stimulated/suppressed?

Answer 3

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

Question 4

What are PTH’s action at the kidney?

Answer 4

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)

Question 5

What are PTH’s actions at the bone?

Answer 5

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

Question 6

What is PTH-related protein?

Answer 6

structurally similar to PTH and not completely understood- if levels are high it can mimic excess PTH

Question 7

What is the action of calcitonin in humans?

Answer 7

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

Question 8

What are the steps in vitamin D synthesis?

Answer 8

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

Question 9

Which is the best compound to measure to estimate vitamin D status?

Answer 9

25-OH vit D is the predominant form and is unregulated so levels reflect total vitamin D entering the system

Question 10

What enzyme is responsible for vitamin D activation?

Answer 10

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)

Question 11

How is the activity of 1a-hydroxylase regulated?

Answer 11

induced by PTH, and low phosphate

inhibited by calcium and FGF-23

Question 12

What are the actions of vitamin D activity?

Answer 12

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

Question 13

What is the action of FGF-23?

Answer 13

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)

Question 14

How do you determine between abnormal parathyroid function or external factors causing calcium imbalance?

Answer 14

measure PTH level

Question 15

What are causes and mechanisms of primary hyperparathyroidism?

Answer 15

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

Question 16

How doe the set point of PTH regulation by Ca change with primary hyperparathyroidism?

Answer 16

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

Question 17

What are features of the “classic” presentation of primary HPT?

Answer 17

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

Question 18

What is the mechanism of Familial Hypocalciuric Hypercalcemia? What would you see in Ca levels?

Answer 18

loss of function mutation in CaSR so CaSR is less sensitive to calcium (benign)
mildly high Ca and high PTH, ***low urinary Ca levels

Question 19

In cases of hypercalcemia in patients with appropriate parathryoid function, what would expect for levels of PTH?

Answer 19

gland appropriate suppresses PTH to low levels- this includes causes like increased calcium absorption, calcium release from bone and impaired calcium excretion

Question 20

Name 3 mechanisms of hypercalcemia of malignancy.

Answer 20

invasion/destruction of bone by tumor
production of PTHrP by tumor
production of vitamin D by tumor

Question 21

Name other diseases or medications that can lead to hypercalcemia.

Answer 21

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

Question 22

What are common symptoms of hypocalcemia?

Answer 22

primarily symptoms of neuromuscular irritability: premolar or digital paresthesias, muscle cramping, tetany, seizures

Question 23

Define primary hypoparathyroidism and causes due to parathyroid dysfunction.

Answer 23

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

Question 24

Describe the condition Autosomal Dominant Hypocalcemia.

Answer 24

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

Question 25

Describe the phenotype of Albright’s Hereditary Osteodystrophy?

Answer 25

AHO: short stature, round face, short 4th metacarpal, obesity

Question 26

What is pseudohypoparathyroidism? (mechanism)

Answer 26

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

Question 27

How is genetic imprinting important in PHP?

Answer 27

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)