Hypocalcemia, Hypopt, & Vit D Deficiency

Front 1

Ca homeostasis:

Back 1

THIS SLIDE IS KEY
Know PTH's various actions --> wants to increase serum CA !
-opposite effects for Ca/P reabsorption in kidney

Front 2

Factors that influence serum calcium:

Back 2

PTH
Vitamin D
Phosphorus
Calcium via effect on calcium sensing receptors
Parathyroid gland [via CaSR] --> PTH secretion
Loop of Henle [via CaSR] --> Renal calcium excretion

Front 3

CaSR control of PTH release:

Back 3

when Ca goes up, PTH goes down
there's a set point

Front 4

What effects does the CaSR have in the PT glands and in the kidney?

Back 4

Front 5

Describe the regulation of Ca:

Back 5

Front 6

Causes of hypocalcemia:

Back 6

3 biggies

Front 7

Describe Disorders of the Parathyroid Gland:

Back 7

*Abnormal parathyroid gland development (no PTH)
Genetic disorders --> X-linked or autosomal recessive
Complex congenital syndromes --> DiGeorge Syndrome

*Destruction of the parathyroid gland (no PTH)
Surgery --> Most common etiology
Autoimmune
Radiation to neck
Infiltrative disease --> Granulomas, Hemochromatosis, Wilson’s disease, Metastatic cancer
Infection --> HIV

Front 8

Hungry Bone Syndrome:

Back 8

*Usually occurs in conditions with an increased rate of bone resorption such as hyperparathyroidism

*Parathyroidectomy abruptly decreases PTH mediated bone resorption disrupting the equilibrium between OB-mediated bone formation and OC-mediated bone resorption

*Results in uptake of calcium, phosphate, and magnesium into bone

*Low serum calcium, phosphorus and magnesium levels, but PTH can be low, normal or high.

Front 9

Autoimmune PT disease:

Back 9

*Permanent - Immune mediated destruction of the parathyroid gland
-Isolated
-Polyglandular autoimmune syndrome type 1:
*Chronic mucocutaneous candidiasis --> childhood
*Hypoparathyroidism --> few years later
*Primary adrenal insufficiency --> adolescence

*Transient - Activating antibody to the calcium sensing receptor that decreases PTH secretion
-Not destructive and can remit spontaneously
-Isolated or autoimmune polyglandular syndrome

Front 10

Disorders of Parathyroid Hormone--Production or Secretion:

Back 10

*Abnormal PTH synthesis:
Autosomal dominant or recessive
Mutation in the signal peptide sequence of preproPTH that impairs processing to PTH

*Activating mutations of calcium sensing receptor:
Autosomal dominant or sporadic
Decreases set point of CaSR --> PTH is not released at calcium levels that normally trigger PTH release

*Activating antibodies to calcium sensing receptor:
Isolated or polyglandular autoimmune syndrome

Front 11

Back 11

*leads to a decrease in PTH secretion and synthesis.

Front 12

Back 12

*Ca set point changes. Shifts to the left.
*PTH secretion isn't triggered until Ca levels fall much lower than usual.

Front 13

Parathyroid Hormone Resistance Type 1a:

Back 13

*Type 1a = Mutation in the GNAS1 gene
-GNAS1 is a gene encoding the alpha sub unit of the G protein coupled to the PTH receptor

-Mutation results in an inability of PTH to activate adenyl cyclase when PTH binds to its receptor

**-MATERNAL transmission required for expression:
-PTH resistance at the RENAL TUBULES leads to HYPERphosphatemia, HYPOcalcemia and hyperparathyroidism --> OSTEITIS FIBROSA. Individuals have diminished urinary cyclic AMP response.
-Albright’s hereditary osteodystrophy (AHO)– round facies, short stature, short fourth metacarpal bones, obesity, subcutaneous calcifications, and developmental delay.

**-PATERNAL transmission:(Pseudopseudohypoparathyroidism)
Phenotype of AHO (paternal transmission) WITHOUT PTH resistance at the renal tubules (normal maternal allele)

Front 14

Back 14

a= short stature
b, c, d= note short fourth metacarpal

Front 15

Parathyroid Hormone Resistance Types 1b, 1c, and 2:

Back 15

*Type 1 b – Mutation in regulatory elements of GNAS1
-Maternally transmitted
-PTH resistance confined to the kidney and leads to hyperphosphatemia, hypocalcemia, hyperparathyroidism
-No phenotypic abnormality of AHO!!!!!!!!!

*Type 1c - Mutation affecting the coupling of G protein to its receptor. Phenotype similar to Type 1a.

*Type 2 – Defect not identified. No features of AHO. Normal urinary cyclic AMP response without PO4 excretion.

Front 16

Disorders of Magnesium:

Back 16

*Hypomagnesemia
-Results in PTH resistance and reduced secretion in more severe states
-Normal, low or high PTH levels
-Associated with malabsorption, alcoholism, cisplatin, aminoglycosides, diuretics, etc.

*Hypermagnesemia
-Suppresses PTH secretion
-Associated with Mg treatment in eclampsia

Front 17

Summary of evaluation of Hypocalcemia:

Back 17

1) Mg evaluation first

low Ca + low PO4 = hungry bone
PTH resistance = genetic

Front 18

Vitamin D Metabolism and Action:

Back 18

UV or diet --> D3
Liver --> 25OH
Kidney --> 1,25 OH2 --> biologic effects

Front 19

Vit D deficiency flowchart of consequences:

Back 19

Front 20

Discuss 4 causes of Vitamin D Deficiency:

Back 20

*Deficient intake or absorption
-Poor diet or malabsorption
-Inadequate sunlight exposure

*Defective 25-hydroxylation
-Liver disease
-Anticonvulsants: convert to inactive Vitamin D metabolite

*Defective 1-alpha 25-hydroxylation
-Hypoparathyroidism (no PTH action)
-Renal failure
-Enzyme defect (VDDR-1)

*Vitamin D receptor defect (VDDR- 2)

Front 21

Discuss Vitamin D Deficiency in Children:

Back 21

*Vitamin D Status
-Transferred from the mother prenatally (lasts 3-4 wks)
-Ingested or produced by the skin

*Nutritional vitamin D deficiency
-Occurs when growth rates and calcium needs are high
-Associated with breast feeding, inadequate sun, malabsorption
-Prevention and treatment:
-Fortified formula
-Vitamin D supplements esp. breastfeeding

Front 22

Discuss Vitamin D Deficiency in Adults:

Back 22

*Vitamin D status
-Maintained by adequate UV exposure and diet

*Nutritional Deficiency
-Reduced production; production declines with age
-Varies with season, latitude, and skin pigmentation
-Reduced intake (Recommend 800-1000 IU/day)
50% consume <137 IU/d
25% consume <65 IU/d

*Treatment
Sun exposure
Vitamin D intake via diet or supplements

Front 23

Discuss Vit D supplements: sites of metabolism--

Back 23

*most supplements have D3
*D2 requires a Rx
*BOTH require the liver and kidney function

*IF bad liver/kidney, must give Calcitriol

Front 24

Discuss Vit D supplements: 5 types--

Back 24

*Cholecalciferol/Vitamin D3
-Metabolism- needs to be hydroxylated hepatically and renally to calcitriol
-Consider as daily supplement and in treatment of vitamin D insufficiency

*Ergocalciferol/Vitamin D2
-Metabolism- needs to be hydroxylated hepatically and renally to calcitriol
-Consider in treatment of vitamin D insufficiency, rickets and osteomalacia

*Calcidiol (25-hydroxyvitamin D)
-Metabolism- needs to be 1-hydroxylated to be fully active
-Consider in treatment of vitamin D insufficiency, rickets and osteomalacia

*Dihydrotachysterol (1-hydroxyvitamin D)
-Metabolism- functional equivalent of 1-hydroxyvitamin D and only 25-hydroxylation in the liver is required to form the active drug.
-Consider in patients in whom renal 1-hydroxylation is impaired

*1,25-OHD: Calcitriol
-Consider in the management of hypocalcemia in patients with renal failure, hypoparathyroidism and pseudohypoparathyroidism

Front 25

Back 25

3 defects here; understand them.

*Defect in 1-a-hydroxylase: think kidney problem, hypoparathyroidism, or genetic defects.

Front 26

How do we lose Ca from the circulation? 2

Back 26

Front 27

Discuss Extravascular Deposits of Calcium:

Back 27

*Hyperphosphatemia
-Renal failure
-Excess intake
-Tissue break down such as rhabdomyolysis and tumor lysis

*Acute pancreatitis-- Ca builds in pancreas

*Osteoblastic metastases -- breast and prostate cancers

*Hungry bone syndrome (after parathyroidectomy)

Front 28

Discuss Intravascular Complexing of Calcium:

Back 28

*Reduce ionized but not total calcium levels
-Chelators bind calcium
Citrate
Lactate
Foscarnet
EDTA
-Alkalosis increases calcium binding to albumin

Front 29

4 ways we can get Hypocalcemia:

Back 29

Disorders of Magnesium
Hypoparathyroidism
Vitamin D deficiency
Loss of calcium from the circulation

Front 30

Signs and Symptoms of hypocalcemia:

Back 30

*Nervous system-- Increased neuromuscular irritability (Tetany)
- Paresthesias
- Muscle twitching
- Seizures
- Larngospasm
- Bronchospasm
- Trousseau's and Chvostek's signs

*Cardiovascular: Long QT interval with arrhythmia

*Other
Mental status change
Papilledema
Cataracts

Front 31

Back 31

Signs of Hypocalcemia
CHOVSTEK's= irritability of VII
TROUSSEAU's= BP cuff inflation makes arm spasm
EKG shows long QT

Front 32

Calcium Assessment:

Back 32

*Total Calcium
Bound to protein (albumin) – 45%
Bound to anion (phosphate and citrate) – 15%
Free or ionized calcium – 40%

*Ionized (free) calcium is metabolically active

*Total calcium and albumin
**Total calcium falls 0.8mg/dL for every 1g/dL reduction in albumin**
-Calcium-albumin complex altered by pH
-Acidosis reducing binding
-Alkalosis enhancing binding
-Critically ill with shifts in pH measure ionized calcium

*MUST LOOK AT ALBUMIN*

Front 33

Other Studies to assess Ca if Ca is found to be low: 6

Back 33

Parathyroid hormone
Vitamin D 25
Vitamin D 1,25
Magnesium
Phosphorus
Renal and liver function

Front 34

Decision making chart to diagnose low Ca, looking at PTH and Mg:

Back 34

*these charts seem important*

Front 35

Low Ca assessment looking at Vit D

Back 35

Front 36

Treatment of Hypocalcemia:

Back 36

**Find and treat underlying cause**

*Calcium
Oral supplement
IV calcium gluconate or chloride if severe and symptomatic

*Phosphate replacement
Oral supplements

*IF Vitamin D deficient
1,25-OHD / Calcitriol
Rapid onset
Renal disease or hypoparathyroidism
Otherwise, consider other Vitamin D preparations

*Magnesium replacement
IV MgSO4 in acute setting

*Thiazide
Reabsorption of calcium in the distal tubule (a bonus treatment)

Front 37

Discuss Vitamin D Supplements:

Back 37

*Maintenance
Cholecalciferol (Vitamin D3)

*Vitamin D deficiency or insufficiency
Ergocalciferol (Vitamin D2)

*Renal failure or hypoparathyroidism
Dihydrotachysterol (1-hydroxyvitamin D)
Calcitriol (1,25-OHD)

*Liver disease
Calcidiol (25-hydroxyvitamin D)
Calcitriol (1,25-OHD)

Front 38

The Ca-Albumin formula:

Back 38

**Total calcium falls 0.8mg/dL for every 1g/dL reduction in albumin**

*Correction= every 1g drop in albumin (below 4g/dL), you add 0.8mg Ca to get the corrected Ca level.