L85- Calcium and PTH Flashcards
How is serum ionized and total calcium influenced by Albumin and pH? Describe the trends
Albumin - binds Ca and is part of total Calcium measured
- low albumin state lowers the Total but not the ionized calcium
pH changes are like so:
- Alkaloses lowers ionized Ca and increases protein-bound calcium vs Acidosis rasises Ionized Calcium and lowers protein-bound calcium
CC: Hyperventilation causes respiratory alkalosis and reduces ionized calcium giving people the tingling sensation!
How do you measure ionized calcium? How do you estimate ionized calcium from total calcium?
Measuring ionized calcium is hard….samples taken careully and directly to freezer - finicky test and sucks to do…..SO INSTEAD….
Estimate Ionized Ca from Total Calcium and Albumin concentration!
CORRECTION FACTOR = (4-Albumin) x 0.8
Add correction factor to Total Calcium to get corrected calcium
*Corrected for low albumin
What are the most important organs and hormones in calcium regulation?
Organs - intestines, bones, kidneys
Hormones - PTH and Calcitriol
What is the relationship between PTH secretion and Calcium levels? What regulates this? Describe the relationship graphically.
Calcium sensing receptors on the Parathyroid cells act as the Calciostat and sense Ca in serum and either raise or lower PTH levels accordingly
More Calcium then PTH down
Less Calcium PTH up
(see graph picture)
Walk through the process of Vitamin D production and regulation.
1) 7-dehydrocholesterol in skin + UBV sunlight –> Vitamin D3
2) Vitamin D3 to the liver –> 25-OHD3
3) 25-OHD3 to the kidney –> 1,25OH-D3 aka Calcitriol which is the active form
Vitamin D2 from exogenous plant sources undergoes same 25 and 1-hydroxylation as D3
Regulation:
- 7-dehydrocholesterol in skin decreases w/ age so need more sun and Melanin absorbs UVB more so darker pigments need more sunlight
- 25-OD D is what you measure to Dx Vitamin D deficiency
- 1-Hydroxylation in kdiney regulated and INCREASED by PTH but that ability decreases w/ age and renal insufficiency
How does PTH act on it’s target organs?
Bone:
- Acute exposure stimulates bone formation by osteoblasts BUT prolonged exposure stimulates bone breakdown by osteoclasts (*can use synthetic PTH for osteoporosis)
GI Tract: no direct effect
Kidney
- PTH promotes Ca absorption and P excretion in the proximal tubule
- stimulates 1-hydroxylase production
What is the difference in renal effects from PTH vs 1,25D?
PTH tells kidney to lose P and hold onto Ca
1,25 D tells kidney to hold onto BOTH Ca and P!!!
What is the mechanism of different actions of PTH on bone cells? (RANK-RANKL expression pathway)
PTH binds receptors on OB acutely to stimulate them –> bone formation AND expression of RANKL cell surface receptors
then OC Precursors w/ RANK on their surface bind w/ RANKL and causes them to differentiate and activate into mature OC and get bone destruction
Vitamin D 1,25 actions on Target Organs?
Bone:
- stimulates bone breakdown at high levels and maintains serum Ca and P for bone formation
GI:
Ca and P absorption increased
PTH Glands:
- inhibits PTH release - feedback control!
What is Calcitonin? Actions? Where does it come from?
Calcitonin releaased and made by Thyroid C Cells
does NOT play a role in NORMAL physiology
pharmacologic doses inhibit bone resporption
What is PTHrP? What is the physiologic role and pathologic role?
Parathyroid Hormone Related Peptide (aa2-13) bids to the same receptor as PTH
Physiologic Role:
Made in Fetal parathyroid, cartilage, keratinocytes, placenta and in adult breast
Used for mobilization of Ca in pregnancy to make baby bones and for lactation
Pathologic Role:
causes Hypercalcemia in Solid tumors!!!!!!
Where is phosphorous found? REgulated by? Too much causes? relation to 1,25 D?
Phosphorous is a major component of Hydroxyapatite and cell membranes and ATP etc
Too much phosphorous can cause Vascular Calcification and therefore is tightly controlled
PTH and FGF23 (made by Osteocytes) stimulated by increased P and leads to Phosphaturia
*PTH stimulates 125D and FGF23 inhibits it!
What is the most common cause of Outpatient Hypercalcemia?
Primary Hyperparathyroidism
What are the causes of Primary Hyperparathyroidism?
85% Single adenoma
10% hyperplasia - sporadic or MEN1/2, or hereditary jaw tumor hyperparathyroidism sundrome
5% Ectopic - neck/mediastinum
1% cancer
Signs and Symptoms of Hyperparathyroidism?
Range from none to life-threatening depending on Degree of elevation of Ionized CA (>12 mg/dl; normal 8.5-10.5)
Bones - osteoporosis and fracture and pain
Stones - polyuria, azotemia, stones
Moans - NM weakness, fatigue and joint pain
Groans - GI constipation, anorexia, vomiting
Psychological Overtones - CNS - depression to obtundation
Other - e_ye Band Keratopathy_
NARROW QT –> how people die from cancer from high PTrP
What causes Autosomal Dominant Primary Hyperparathyroidism? What are the different types/forms of disease (MEN)? Which one causes Hypercalcemia?
Multiple Endocrine Neuromas!!!
MEN1: Parathyroid, Pituitary, Pancreas
- Increased Calcium!!!!!!
- Menin gene inactivation (tumor suppressor)
MEN2a: C Cells, Adrenal, Parathyroid
- Thyroid tumor
- ret gene activation (proto-oncogene)
MEN2b: C cells, Adrenal, Nerves, Parathyroid
- Thyroid tumor
- Ret gene activation
What are markers / how do you diagnose Primary Hyperparathyroidism? What else can also be associated with this?
Elevated Serum Ca
Elevated or inappropriately normal iPTH (should be suppressed)
Elevated or normal Urine Calcium (not low)
Associated:
- elevated Calcitriol
- low normal/low serum phosphorous
- Mild hyperchloremic Metabolic Acidosis
How do you treat Primary Hyperparathyroidism? Surgical or Medical?
Asymptomatic - observation
Symptomatic = Surgery w/ Sestamibi scan
if US+ - minimally invasive
if US- then 4 gland exploration
If poor surgical candidate treat medically w/ Cinacalcet which is Calcium Sensing Receptor Antagonist and tells Parathyroid gland to not release PTH
What is Familial Hypocalciuric Hypercalcemia?
AD mutation that’s rare
Inactivating mutation on the Calcium sensing receptor so always thinks not enough Ca/PTH and so keeps releasing PTH
Shifts PTH / Ca Curve to the Right
Kidney effects - Uca low and increase reabsorption of Ca
Diagnosed by low Ca/Cr clearance ratio
does NOT require treatment
What are potential causes of non-PTH mediated hypercalcemia? What lab values would you see?
Here, PTH suppressed in response to High Calcium indicating normal Parathyroid feedback response
3 types of causes:
1) 1,25 OH D mediated: Vitamin D intoxication, Granulomatous diseases, Lymphomas
2) PTHrP Mediated - Cancer
3) Other - Milk Alkali syndrome or Multiple Myeloma
Describe releationship between bone mass and strength and age. How can you get Osteoporosis?
Bone Mass is proportional to bone strength and fracture risk
Peak Bone mass in early 20s (F) and mid 20s (M)
>80% controlled by genes
(SEE GRAPH)
Osteoporosis - from failure to attain normal Peak bone mass or from bone loss or both!
What is Renal Osteodystrophy? Who gets it and why?
What are the types?
Present in ALL pts w/ CKD by the time that they reach dialysis due to 1) Phosphate Retention 2) Excess PTH and 3) reduced Production of 1,25 OH-D
(SEE PICTURE)
Types Include:
Hyperparathyroid Bone Disease - Osteitis Fibrosa cYstica - HIGH PTH!!!!
Adynamic Bone disease - lower than expected PTH
Mixed - Osteomalacia and Hyperparathyroid
