01-30 Calcium Disorders Flashcards
To what is calcium bound in the serum? What percent is bound vs. free?
50% bound to albumin, 50% free
Effect of chronic ∆s in albumin vs. acute ∆s in pH on Ca++ homeostasis?
chronic ∆s in [albumin] → ↓ total Ca but nl Ca++
acute ∆s in pH → ∆ binding affinity of alb for Ca++
—alkalosis ↑ affinity for Ca++ causing acute hypocalcemia of ionized Ca → sx of hyperventilation, e.g.
**Usually lab is for total Ca++, but from ICU you can order ionized albumin
S/Sx of Hypocalcemia
- *S/Sx based on excitation of CNS
- *Nl Ca++ is ~9
MILD (Ca of 7-8) or SLOW —fatigue —anx/irritable —numb/paresthesias (circumoral/extremities) —muscle cramps —carpopedal spasm
SEVERE (Ca < 6) or Very ACUTE
—Tetany
—Seizures
—Signs: Chvestok & Trousseau
Chvostek Sign
“…twitching of facial muscles in response to tapping over the area of the facial nerve.”
—”Chvostek’s sign is neither sensitive nor specific for hypocalcemia, since it is absent in about one third of patients with hypocalcemia and is present in approximately 10% of persons with normal calcium levels.”
(N Engl J Med 2012; 367:e15)
Trousseau’s sign
“…carpopedal spasm that results from ischemia, such as that induced by pressure applied to the upper arm from an inflated sphygmomanometer cuff”
—”Trousseau’s sign […] is more sensitive and specific; it is present in 94% of patients with hypocalcemia and in only 1% of persons with normal calcium levels”
(N Engl J Med 2012; 367:e15)
S/Sx of Hypercalcemia
**generally: depressed CNS
**usually start w/ Ca’s > 12
—Fatigue
—Polyuria/dypsia
—GI complaints/constipation
—Neuro sx: lethargy → confusion → coma → death
Calcium problems w/ blood transfusions
—citrate in the transfusion bag can bind Ca causing transient hypocalcemia
Body’s reaction to low serum [Ca++]
A. Low serum [Ca++] induces PTH release B. PTH has 4 actions —1. ↑ Ca++ & PO4 resorption from BONE —2. ↑ Ca++ & PO4 resorption from INTESTINES —3. ↑ 1,25(OH)2-D production in KIDNEY —4. ↑ PO4 wasting into urine at KIDNEYS
BOTTOM LINE: ↑ serum [Ca++] & no net ∆ in PO4
**if serum [Ca++] is too high, the opposite of the above occurs
How do parathyroid glands sense [Ca++]?
GPCR —Ca++ binds —2nd messengers —↑ intracellular [Ca++] —Inhibits PTH secretion/transcription/gland prolif
What effect would an inactivating mutation of the Calcium sensing protein in the Parathyroid have?
Parathyroid would “see” always low Ca++ and pump out tons of PTH → hypercalcemia
[COSTANZA] Pathway of Vitamin D synth?
SKIN:
—7-dehydrocholesterol + UV →
—cholecalciferol (also from DIET)
LIVER:
—cholecalciferol → 25(OH)cholecalciferol
KIDNEY
—25(OH)cholecalciferol to either
—Active: 1,25(OH)2-D via 1α-hydroxylase
—Inactive: 24,25(OH)2-D
[COSTANZA] Regulation of Vit D synth?
reg’d via renal 1α-hydroxylase
converts:
25(OH)cholecalciferol → 1,25(OH)2-chol… (active)
—stim’d by: ↑ PTH & ↓ [PO4] & [Ca]
If inactive, 25(OH)-D is stored as 24,25(OH)2-D (inactive)
[COSTANZA] Vitamin D deficiency in kids?
causes rickets
[COSTANZA] Vitamin D deficiency in adults?
leads to osteomalacia (soft bone from failure of new bone to mineralize → bending/softening of weight-bearing bones)
[COSTANZA] What is Vitamin D resistance?
Inability to convert Vit D to active form:
25(OH)-D —1α-hydroxylase→ 1,25(OH)2-D
Can be due to:
—chronic renal failure (most commonly)
—congenital absence of 1α-hydroxylase
How much Vitamin D are we making in Hanover in January? (per Dr. St. Germain?)
essentially none via our skin
90% of pts w/ hypercalcemia have either:
#1: 1° hyperparathyroidism —familial, sporadic, MEN1 or 2, FHH*
#2: malignancy —causing either osteolysis of PTHrP synth
*FHH = familial hypocalciruic hypercalcemia
Talk about the composition of the parathyroid glands.
Both fat and endocrine tissue
—weight increases w/ growth during childhood
—again in old age w/ fat increase
Can use % fat (which varies according to age, sex and race) to determine whether gland appears malignant or not.
What do we mean by 1° vs 2° hyperparathyroidism?
This is a functional definition i.e.
—1°implies the gland is autonomous and is itself the cause of ↑ PTH production
—2° implies the gland is responding to a change in calcium homeostasis (e.g. ↑ [Ca++])
What is the most common cause of 1°HP?
parathyroid adenoma causes 80-85% of 1° HP
What happens to [PTH] after removal of a parathyroid adenoma?
immediate sharp decrease of at least 50% of the serum [PTH]
—measured with rapid-assay intraoperatively
Histo of parathyroid adenoma?
ALWAYS
—↑ed endocrine cell mass
NOT ALWAYS
—little/no fat
—homogenous cell population
—cytologic atypia
Path of 2°HP?
—Gross
—Micro
—Etiology/effect?
GROSS
—all 4 are enlarged
MICRO
—hyperplasia
ETIOLOGY/EFFECT
—↑ PTH in response to hypoCa or hyperPO4
—most commonly a response to chronic renal failure
—can lead (rarely) to autonomous function 3° hyperparathyroidism in hyperplasia
Systemic complications of hyperparathyroidism
NOTE: b/c we often catch this condition early nowadays w/ routine lab work, these are rarely seen
—renal (calcium) stones
—non-homogenous reabsorption of bone on xray
Which cancers cause bone mets that are most likely to cause 2° hypercalcemia?
—Two categories —Causes? —% cases? —MEDIATORS? —Bone mets present?
LOCAL OSTEOLYTIC (20% of cases) —CAUSES: breast* carcinoma, MM, lymphoma —METS: present —MEDIATOR: Rank-L, TNFα, IL-6, MIPs, PTHrP (breast) \_\_\_\_\_\_
HUMORAL-MEDIATED (80% of cases)
—CAUSES: squamous CC, renal CC, breast*, bladder, endocrine, ovarian
—METS: absent
—MEDIATOR: PTHrP → urinary cAMP ↑, renal Ca absorption ↑, [1,25] ↓ (b/c PTH will be low)
**in both: osteoclasts activated and osteoblasts inactivated
—[PTH] low in both
Which cancers are mostly likely to cause a paraneoplastic syndrome w/ secretion of PTHrP?
- Lung - squamous cell carcinoma
- Kidney - renal cell carcinoma
- Ovary - small cell carcinoma
How do granulmatous diseases (e.g. TB) cause hypercalcemia?
M0s prod excess 1,25(OH)2-D
—lymphomas by same mechanism
Effect of thiazides on Ca++
Generally speaking, Ca++ follows Na+ in the kidney
—Thiazides, however, are Ca++ sparing
—may reveal a subclinical hyperparathyroidism (i.e. normal patients will not typically develop hypercalcemia with thiazide Rx)
Distinguish 1° HP vs. Malignancy —Typical age group —Time Course —Ca Elevation —Sx —Kidney stones —Occurence —Mediator(s) —Bone turnover —Tx
[IMAGE q29 from slide 27)
What are the indications for surgery in tx of 1°HP?
—Sx: GI, renal, kidney stones, neuro —Age: < 50 y/o —[Ca]: > 11.5 —Marked hypercalciuria —Unexplained renal failure —Osteoporosis
How do cancer cells cause bone osteolysis and therefore hypercalcemia?
don’t eat them directly
—stimulate osteoclasts* and inhibit osteoblasts**
FYI:
- via RANKL
- *via dickkopf1
