Regulation of Ca and PO4 Metabolism Flashcards
Describe the distribution of Ca in the body
ECF - .1%
Plasma - .5% or less
ICF - 1%
Bones and teeth - 99%
What is the biologically active form of Ca? What percentage does this Ca make of the total amount of Ca in the body?
Free, ionized Ca - 50%
Protein-bound - 40%
Complexed to anions - 10%
What is the normal Ca levels for adult pts?
in the 9’s mg/dl
What are the symptoms and signs for hypocalcemia?
Symptoms: hyperreflexia, spontaneous twitching, muscle cramp, tingling and numbness
Chvostek sign: twitching of facial mm when facial n tapped
Trousseau sign: carpopedal spasm upton inflation of blood pressure cuff
What are the symptoms of hypercalcemia?
Decreased QT intervals, constipation, lack of appetite, polyuria, polydipsia, muscle weakness, hyporeflexia, lethargy, coma
How does hypocalcemia influence membrane excitability?
Reduces activation threshold for Na channels-> easier to evoke AP Increase membrane excitability Spontaneous AP: hypocalcemia tetany Tingling and numbness on sensory neurons Mm twitches on motorneurons and m
How does hypercalcemia influence membrane excitability?
Nervous system becomes depressed and reflex responses are slowed
Decrease excitability
How can the forms of Ca in the plasma be altered?
- change plasma protein concentration: Increase protein = increase total Ca concentration (no change in Ca ionized)
- Changes in [anion]: Increase PO4, decrease ionized [Ca]
- acid-base abnormalities: more H+, increase free ionized [Ca]
How does acidemia cause increase in free ionized Ca?
H+ outcompetes for spots on albumin, thus less Ca is bound to albumin
What levels of Ca often accompanies alkalemia?
hypocalcemia
Calcium homeostasis is tightly regulated and involves the coordinated actions of what?
3 organ systems: bone, kidney and intestine
3 hormones: PTH, Calcitonin, Vit D
During homeostasis, describe bone remodeling
no net gain or loss of Ca
new bone is formed (deposited)
old bone is resorbed
To maintain Ca balance, how much Ca must the kidneys excrete?
same amount of Ca that is absorbed by GI tract
What hormones promote increase in extracellular Ca levels? Where do they act?
Vit D: in intestines to absorb
Vit D and PTH: on bone to resorb
PTH: on kidneys to reabsorb
Describe the relationship of Phosphate with Ca
Critical for biological processes
Component of ATP, second messenger molecules, DNA, RNA, and Phospholipids
Intracellular anion
Involved in activation and deactivation of enzymes
Buffer in bone, serum, and urine
Describe the distribution of Pi in the body
Bone - 85%
plasma - less than 1% (85%: ionized, 10% protein bound, 6% complexed to cations)
ICF - 15%
What is extracellular concentration of Pi regulated by?
same hormones that regulate Ca concentration
*Extracellular [Pi] inversely related to that of Ca
What secretes PTH?
Chief cells of parathyroid glands that are posterior on the thyroid
What happens to levels of Ca stored as the body ages?
There are decreases in amount of Ca absorbed from dietary intake, and in dietary intake of Ca
Existing bone cells reabsorbed by the body faster than new bone is made
Aging contributes to osteopenia or osteoporosis
describe the structure and synthesis of PTH
Peptide hormone - single-chain with 84 a.a.
Synthesized on ribosomes as preproPTH: 115 aa
cleaved to proPTH: 90 aa
Transported to golgi and cleaved to form PTH
Packaged
What is the stimulus for PTH secretion?
low plasma Ca
*increase in EC [Ca] inhibits PTH synthesis and secretion thru Gq and Gi pathways
What does chronic hypercalcemia cause?
Decrease in synthesis and storage of PTH
Increase breakdown of stored PTH and release of inactive PTH fragment into circulation
What does chronic hypocalemia cause?
increase in synthesis and storage of PTH, hyperplasia of parathyroid glands (secondary hyperparathyroidism)
What role does Mg have on PTH?
parallel but less significant effects on PTH secretion
In alcoholism, hypoMg inhibits PTH synthesis, storage and secretion
What are the actions of PTH on bone, kidney and intestine?
Bone resorption
Kidney: decrease reabsorption of Pi, increase Ca reabsorption, Increase urinary cAMP
Intestine: Ca absorption via vit D
How does Vit D promote mineralization of new bone?
Increase both Ca and Pi plasma concentrations
Increase Ca x Pi product to promote mineralization
What is the main circulating form of Vit D?
25-OH-cholecalciferol
Describe the Vit D synthesis process
7-dehydrocholesterol -> cholecalciferol with UV light
Cholecalciferol from diet
->25-OH cholecalciferol in liver via 25-hydroxylase
Activated in renal proximal tubule via 1a-hydroxylase if [Ca] and [PO4] is low and PTH is high (Gs pathway for enzyme activation)
What is the active form of Vit D?
1,25 -(OH) cholecalciferol
What is the gene for 1a-hydroxylase?
CYP1a gene
Vit D is modified to what inactive form in the kidney? by what enzyme and its gene?
24,25 - (OH) cholecalciferol by 24 hydroxylase
Gene: CYP24 *promoted by increase levels of active Vit D
Where is the PTH receptor located in bone?
on osteoblasts
NOT osteoclasts
What are the short term actions of PTH on bone?
bone formation: via direct action on osteoblast
*basis for intermittent synthetic PTH administration in osteoporosis tx
What are the long-term actions of PTH on bone?
bone resorption: indirect action on osteoclasts mediated by cytokines released from osteoblast
What is M-CSF role in bone?
induce stem cells to differentiate into osteoclast precursors, mononuclear osteoclasts, and mature multinucleated osteoclasts
What is RANKL?
cell surface protein produced by osteoblasts, bone lining cells, and apoptotic osteocytes
Primary mediator of osteoclast formation
What is RANK?
cell surface protein receptor on osteoclasts and osteoclast precursors
What is OPG (Osteoprotegerin)?
soluble protein produced by osteoblasts; decoy receptor for RNAKL; inhibits RANKL/RANK interactions
PTH causes an _____ in RANKL, ______ OPG
increase
Decrease
Vit D causes an ____ in RANKL
increase
What are the actions of PTH on distal convoluted tubule?
complements increase in plasma [Ca]
Acts through Gs to form cAMP (urinary cAMP)
Protein kinase Phosphorylates and Inhibits Na/PO4 cotransporter (phosphaturia)
What are the actions of Vit D on the kidney?
Ca and Pi reabsorbtion
How does Vit D in the intestine promote absorption of Ca?
Promotes transcription of calbindin
Calbindin takes free Ca in cell and helps transport it via Ca ATPase and Ca/Na antiporter
What is the role of PTH on Ca and Pi homeostasis in the kidney?
stimulates 1a-hydroxylase activity
Stimulates Ca reabsorption by thick ascending limb of henle’s loop and distal tubule
Inhibits Pi reabsoption by proximal nephrons (NPT2a)
What is Vit D role in bone?
sensitizes osteoblasts to PTH
Regulates osteoid production and calcification
What is Vit D role in the kidney?
promotes Pi reabsorption by proximal nephrons
Minimal actions of Ca
What is Vit D role in parathyroid gland?
Directly inhibits PTH gene expression
Directly stimulates CaSR gene expression
Describe calcitonin’s actions on bone. What is the major stimulus ?
Inhibits bone resorption
Thus decreases blood Ca and Pi concentrations
*effect occurs ONLY at high circulating levels of the hormone
Decreases activity and # of osteoclasts via calcitonin receptors on osteoclasts
Major stimulus: increase in plasma [Ca]
What role does Calcitonin have on chronic (minute-to-minute) regulation of plasma [Ca}?
No role
Thyroidectomy: decreased calcitonin but no effect in Ca metabolism
Thyroid tumors: increase calcitonin but no effect in Ca metabolism
Does calcitonin have a role in the kidneys?
yes, reduces Ca uptake in kidneys
What does Estradiol-17 beta stimulate?
intestinal Ca absorption and renal tubular Ca reabsorption
What effect does estradiol-17b have on osteoblasts and osteoclasts function?
one of most potent regulators
Promotes survival of osteoblasts and apoptosis of osteoclasts
favors bone formation over resorption
What effect do adrenal glucocorticoids like cortisol, have on Ca levels?
promote bone resorption
Renal Ca wasting
Inhibit intestinal Ca absorption
all this = glucocorticoid-induced osteoporosis in pt taking it for anti-inflammatory and immunosuppressive symptoms
What occurs with primary hyperparathryoidism?
Adenoma of the parathyroid: increase PTH secretion
High Ca, high Vit D
Patients excrete excessive amounts of Pi, cAMP, and Ca (Ca-oxalate stones)
Stones, bones, and groans (hypercalciuria, increase bone resoprtion, constipation)
What is the usual treatment for primary hyperparathyroidism?
Parathyroidectomy
What is secondary hyperparathyroidism?
Increase in PTH levels is secondary to low [Ca] in blood due to renal failure, vit D deficiency
What are the levels of PTH, Ca, Pi and Vit in renal failure pts?
And in Vit D deficient pt?
Renal: High PTH, Low Ca, High Pi, Low Vit D
Vit D: High PTH, Low Ca, Low Pi, Low Vit D
What are the causes of hypoparathyroidism?
thyroid surgery, parathyroid surgery, autoimmune or congenital (less common)
What are most symptoms of hypoparathyroidism associated with?
decrease Ca
Muscle spasm or cramping
Numbness, tingling, or burning (esp around mouth and fingers)
Seizures
Kids: poor teeth development and mental deficiency
What is the treatment for hypoparathyroidism?
oral Ca supplement and active form of Vit D
What are the levels of PTH, Ca, Pi, and Vit D in pt with hypoparathyroidism?
PTH low, Ca low, Pi high, Vit D low
What is Albright hereditary osteodystrophy (pseudohypoparathyroidism type 1a)?
Autosomal dominant disorder
Gs for PTH in bone and kidney defective
Hypocalcemia and hyperphosphatemia develop
Increase PTH levels
*Administration of exogenous PTH = no Phosphaturic response and no increase urinary cAMP
What is the phenotype of Pseudo Hypoparathyroidism?
PTH high, Ca Low, Pi high, Vit D low
Short, short neck, obesity, subcutaneous calcification, short metatarsals and carpals
What are the symptoms of hyperparathyroidism?
Kidney stones
Osteoporosis
GI disturbances, peptic ulcers, nausea, constipation
Muscle weakness, decreased m tone
Depression, lethargy, fatigue, mental confusion
Polyuria
High serum Ca concentration; low serum PO4 concentration in most cases
What are the symptoms of hypoparathyroidism?
Tetany, convulsions, paresthesias, muscle cramps
Decreased myocardial contractility
First-degree heart block
CNS problems - irritability and psychosis
Intestinal malabsorption
Low serum Ca; high serum PO4
How is hypercalcemic syndrome associated with malignancy?
The tumor cells (with TGFb stimulus) produce PTHrP
PTHrP is aa peptide with close homology in N-terminal to PTH
Binds to Type 1 PTH receptors to stimulate reabsorption of Ca, resorption of Ca and Pi excretion
How is malignancy/hypercalcemia similar to primary hyperparathyroidism?
Increase levels of: urinary Ca, Urinary Pi, Urinary cAMP, blood Ca
Decreased levels of blood Pi
How is humoral hypercalcemia of malignancy different from primary hyperparathryoidism?
Decreased bone formation
Decreased PTH levels
Decreased Vit D (in cancer, vit D levels normally suppressed)
What is the treatment for malignancy/hypercalcemia ?
Tx: furosemide (inhibits renal Ca reabsorption and increases Ca excretion)
Etidronate (inhibits bone resorption)
What is the pathophysiology of PTH in Familial hypocalciuric hypercalcemia?
Autosomal Dominant
Mutations that inactivate CaSR in parathyroid glands
Ca receptors in ascending limb of kidney
Results: decrease urinary Ca excretion, increase serum Ca
What is CaSR?
Ca receptor in the parathyroid that is connected to Gq and Gi that both inhbit PTH gene transcription and PTH secretion
In the kidney it uses the same pathway to inhibit transcription of CYP1a gene into 1a-hydroxylase
What are the levels of PTH, Ca, Pi and Vit D in FHH?
PTH: N/increase Serum Ca: increase Urine Ca: decrease Pi: N Vit D: N
What can impair Vit D metabolisM
Dietary deficiency
Vit D resistance: Absence of 1a-hydroxylase, mutations affecting vit D receptor
Describe Rickets
Congenital disorder
Pseudovitamin D-deficient rickets or vitamin D-dependent rickets type 1 (decrease in 1a-hydroxylase)
Vitamin D-dependent rickets type II - Decrease in vitamin D receptor
Insufficient amount of Ca and Pi available to mineralize growing bone
Growth failure and skeletal deformities
What is the treatment for rickets-osteomalacia?
Vit D2 (ergocalciferol) or D3 (cholecaciferol)
Ca
Sunlight
1,25-(OH)2 - D3: calcitriol
What is osteomalacia?
Happens in adults
New bone fails to mineralize
Bending and softening of weight-bearing bones
What is the treatment of osteoporosis - bones become brittle and fragile ?
Antiresorptive therapy with bisphosphonates, estrogen, SERMs (raloxifene, tamoxifen), Calcitonin, RANKL inhibitors (Denosumab)
Anabolic therapy: PTH
