01-30 Calcium Disorders

Question 1

To what is calcium bound in the serum? What percent is bound vs. free?

Answer 1

50% bound to albumin, 50% free

Question 2

Effect of chronic ∆s in albumin vs. acute ∆s in pH on Ca++ homeostasis?

Answer 2

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

Question 3

S/Sx of Hypocalcemia

Answer 3

• *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

Question 4

Chvostek Sign

Answer 4

“…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)

Question 5

Trousseau’s sign

Answer 5

“…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)

Question 6

S/Sx of Hypercalcemia

Answer 6

**generally: depressed CNS
**usually start w/ Ca’s > 12
—Fatigue
—Polyuria/dypsia
—GI complaints/constipation
—Neuro sx: lethargy → confusion → coma → death

Question 7

Calcium problems w/ blood transfusions

Answer 7

—citrate in the transfusion bag can bind Ca causing transient hypocalcemia

Question 8

Body’s reaction to low serum [Ca++]

Answer 8

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

Question 9

How do parathyroid glands sense [Ca++]?

Answer 9

GPCR
—Ca++ binds
—2nd messengers
—↑ intracellular [Ca++]
—Inhibits PTH secretion/transcription/gland prolif

Question 10

What effect would an inactivating mutation of the Calcium sensing protein in the Parathyroid have?

Answer 10

Parathyroid would “see” always low Ca++ and pump out tons of PTH → hypercalcemia

Question 11

[COSTANZA] Pathway of Vitamin D synth?

Answer 11

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

Question 12

[COSTANZA] Regulation of Vit D synth?

Answer 12

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)

Question 13

[COSTANZA] Vitamin D deficiency in kids?

Answer 13

causes rickets

Question 14

[COSTANZA] Vitamin D deficiency in adults?

Answer 14

leads to osteomalacia (soft bone from failure of new bone to mineralize → bending/softening of weight-bearing bones)

Question 15

[COSTANZA] What is Vitamin D resistance?

Answer 15

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

Question 16

How much Vitamin D are we making in Hanover in January? (per Dr. St. Germain?)

Answer 16

essentially none via our skin

Question 17

90% of pts w/ hypercalcemia have either:

Answer 17

#1: 1° hyperparathyroidism
—familial, sporadic, MEN1 or 2, FHH*

#2: malignancy
—causing either osteolysis of PTHrP synth

*FHH = familial hypocalciruic hypercalcemia

Question 18

Talk about the composition of the parathyroid glands.

Answer 18

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.

Question 19

What do we mean by 1° vs 2° hyperparathyroidism?

Answer 19

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++])

Question 20

What is the most common cause of 1°HP?

Answer 20

parathyroid adenoma causes 80-85% of 1° HP

Question 21

What happens to [PTH] after removal of a parathyroid adenoma?

Answer 21

immediate sharp decrease of at least 50% of the serum [PTH]

—measured with rapid-assay intraoperatively

Question 22

Histo of parathyroid adenoma?

Answer 22

ALWAYS
—↑ed endocrine cell mass

NOT ALWAYS
—little/no fat
—homogenous cell population
—cytologic atypia

Question 23

Path of 2°HP?
—Gross
—Micro
—Etiology/effect?

Answer 23

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

Question 24

Systemic complications of hyperparathyroidism

Answer 24

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

Question 25

Which cancers cause bone mets that are most likely to cause 2° hypercalcemia?

—Two categories
—Causes?
—% cases?
—MEDIATORS?
—Bone mets present?

Answer 25

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

Question 26

Which cancers are mostly likely to cause a paraneoplastic syndrome w/ secretion of PTHrP?

Answer 26

1. Lung - squamous cell carcinoma
2. Kidney - renal cell carcinoma
3. Ovary - small cell carcinoma

Question 27

How do granulmatous diseases (e.g. TB) cause hypercalcemia?

Answer 27

M0s prod excess 1,25(OH)2-D

—lymphomas by same mechanism

Question 28

Effect of thiazides on Ca++

Answer 28

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)

Question 29

Distinguish 1° HP vs. Malignancy
—Typical age group
—Time Course
—Ca Elevation
—Sx
—Kidney stones
—Occurence
—Mediator(s)
—Bone turnover
—Tx

Answer 29

[IMAGE q29 from slide 27)

Question 30

What are the indications for surgery in tx of 1°HP?

Answer 30

—Sx: GI, renal, kidney stones, neuro
—Age: < 50 y/o
—[Ca]: > 11.5
—Marked hypercalciuria
—Unexplained renal failure
—Osteoporosis

Question 31

How do cancer cells cause bone osteolysis and therefore hypercalcemia?

Answer 31

don’t eat them directly
—stimulate osteoclasts* and inhibit osteoblasts**

FYI:

• via RANKL
• *via dickkopf1