1. Disorders of Calcium Metabolism:
Hypercalcemia
Dr. BHUMIKA KATOCH
(F5)

2. Calcium and phosphorus Bone Vitamin D Parathyroid Hormone Calcitonin
REVIEW, Ca++ metabolism:
PTH, Vitamin D and Calcium homeostasis
Calcium and phosphorus
Bone
Vitamin D
Parathyroid Hormone
Calcitonin

3. Extracellular Calcium
Three definable fractions of calcium in serum:
Ionized calcium 50%
Protein-bound calcium 41%
90% bound to albumin
Calcium complexed to serum constituents 9%
Citrate and phosphate

4. Calcium turnover

5. Renal Excretion
The kidneys account for the bulk of regulated calcium excretion
Three distinct locations along the renal tubule are involved
The regulation of calcium excretion at each of the three renal sites is different

6. Renal Excretion Proximal convoluted tubule
Accounts for 70% of calcium reabsorption
Mainly paracellular pathway

7. Renal Excretion FHH, FBH (familial benign/hypocalciuric hypercalcemia)
Proximal convoluted tubule
Thick ascending limb of loop of Henle
20 % of calcium reabsorption
Calcium sensing receptor
(CaSR)
FHH, FBH (familial benign/hypocalciuric hypercalcemia)
Caskey F J , Pickett T M Nephrol. Dial. Transplant. 2005;20:

8. Renal Excretion Distal convoluted tubule PTH regulation
Proximal convoluted tubule
Thick ascending limb
Distal convoluted tubule
PTH regulation
8% of calcium reabsorption
20-8

9. Calcium and phosphorus Bone Vitamin D Parathyroid Hormone Calcitonin
PTH, Vitamin D and Calcium homeostasis
Calcium and phosphorus
Bone
Vitamin D
Parathyroid Hormone
Calcitonin
20-9

10. Calcium Regulation: Bone Exchange
Bone is dynamic and is constantly remodeled
Calcium is exchanged between blood and bone daily (roughly 400 mg/day); 10% of skeleton per year
Ongoing remodeling allows bone to store and release calcium as needed to help maintain homeostasis

11. Normal bone remodeling cycle

12. Hypercalcemia/hyperparathyroidism: clinical signs
GI:
Nausea, vomiting, abdominal pain
Constipation
Renal:
Polyuria, dehydration
Renal failure
Nephrolithiasis
Neurological
Fatigue
Confusion
Depression
Stupor, coma
Skeletal
Bone pain and tenderness
Spontaneous fracture (compression fx’s)

13. Hyperparathyroidism/Hypercalcemia – signs/symptoms
Neuromuscular
Muscle weakness, hypotonia
Cardiovascular
Hypertension
Short QT interval

15. Hypercalcemia: major causes
Primary hyperparathyroidism (PHPT)
Malignancy
Others

16. Hyperparathyroidism: causes
Primary
Adenoma (90%)
Multiple gland enlargement (10%)
MEN 1
MEN 2A
Familial hyperparathyroidism
Carcinoma (<1%)
Familial benign hypercalcemia (FBH)
Secondary (normo- or hypocalcemic)
Renal failure
Vitamin D deficiency

17. Primary hyperparathyroidism
Affects approximately 100,000 patients a year.
Prevalence: 0.1 to 0.3% of the general population.
More common in women (1:500) than in men (1:2000).
Patients with single adenoma (~90%): minimally invasive surgery
Sestamibi imaging ~90% sensitive, ~98% specific
Minimally invasive = incision length < 2.5 cm
Intraoperative PTH testing confirms biochemical cure

18. Malignant hypercalcemia: major causes
PTHrP - mediated
Breast carcinoma
Squamous carcinoma (lung, head & neck, esophagus)
Renal carcinoma
Cytokine/osteoclast activating factor - mediated
Myeloma (lymphoma, leukemia)
Tumor production of calcitriol
Lymphoma

19. Hypercalcemia: other causes
Drugs:
Vitamin D
Calcium carbonate (milk alkali syndrome)
Lithium
Thiazide diuretics
Vitamin A
Sarcoidosis, other granulomatous disorders
Hyperthyroidism

20. Hypercalcemia - Treatment
NS bolus to restore volume; then 100 – 200 ml/hr
Bisphosphonates (onset hrs)
Calcitonin 4 – 8 IU q6-8 hrs (onset immediate, resistance develops in hrs)
[Mg and K prn]

22. REGULATION OF RENAL 1α-HYDROXYLASE PRODUCTION
Stimulates
PTH
Low calcium
Low phosphate
Calcitonin
Inhibits
1,25(OH)2D3
High calcium
High phosphate

23. Summary: vitamin D action
Main action of 1,25-(OH)2-D is to stimulate absorption of Ca2+ (and phosphate) from the intestine.
also:
acts on osteoblasts to increase RANKL and thus activate osteoclasts to increase Ca++ resorbtion.
is necessary for proper bone formation.

24. Parathyroid Hormone

25. Calcium regulates PTH secretion via a CaSR

26. PTH and calcium+phosphate homeostasis

27. Calcitonin
Decreases plasma Ca2+ and phosphate concentrations, mainly by decreasing bone resorption.
Synthesized and secreted by the parafollicular cells (aka C cells) of the thyroid gland.
Release stimulated by hypercalcemia and inhibited by hypocalcemia
Slide credit: Dale Buchanan Hales Ph.D.

28. Calcitonin effects Calcitonin rapidly inhibits osteoclast activity
causes inhibition of osteoclast motility, alterations in cell morphology and osteoclast inactivation.
Kidneys
inhibits calcium reabsorption (increases excretion)
also increases phosphorus excretion
Role in calcium homeostasis unclear

29. Parathyroid hormone increase Ca++, decrease PO4 levels in blood
Effect on bones
Effect on gut
Effect on kidneys
Parathyroid hormone increase Ca++, decrease PO4 levels in blood
Promotes
resorption
Indirect effects via increase in calcitriol from 1-hydroxylation
Promotes Ca++ reabsorption and PO4 excretion, activates 1-hydroxylation
Calcitriol (vitamin D) Ca++, PO4 levels increase in blood
(RANKL→bone resportion)
Increases Ca++ and PO4 absorption
No direct effects
Calcitonin
Inhibits resorption
Promotes Ca++ and PO4 excretion

30. Hypocalcemia: clinical signs
Paresthesias
Tetany (carpopedal spasm)
Trousseau’s, Chvostek’s signs
Seizures
Chronic: cataracts, basal ganglia Ca

31. Trousseau’s sign

32. Hypocalcemia: causes Hypoparathyroidism
Surgical (thyroid, parathyroid surgery)
Autoimmune
Magnesium deficiency
PTH resistance (pseudohypoparathyroism)
Vitamin D deficiency
Vitamin D resistance
Other: renal failure, pancreatitis, tumor lysis