Download Calcium and phosphorus

Disorders of Calcium Metabolism:
Hypercalcemia
Dr. BHUMIKA KATOCH
(F5)
REVIEW, Ca++ metabolism:
PTH, Vitamin D and Calcium homeostasis
1.
Calcium and phosphorus
2.
Bone
Vitamin D
Parathyroid Hormone
Calcitonin
3.
4.
5.
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
Calcium turnover
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
Renal Excretion
• Proximal
convoluted tubule
– Accounts for 70% of
calcium reabsorption
– Mainly paracellular
pathway
Renal Excretion
• 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;20:1752-1755
Renal Excretion
• Proximal convoluted tubule
• Thick ascending limb
• Distal convoluted
tubule
– PTH regulation
– 8% of calcium
reabsorption
20-8
PTH, Vitamin D and Calcium homeostasis
1.
Calcium and phosphorus
2.
Bone
3.
Vitamin D
Parathyroid Hormone
Calcitonin
4.
5.
20-9
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
Normal bone remodeling cycle


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)
Hyperparathyroidism/Hypercalcemia
– signs/symptoms

Neuromuscular
◦ Muscle weakness, hypotonia

Cardiovascular
◦ Hypertension
◦ Short QT interval



Primary hyperparathyroidism (PHPT)
Malignancy
Others

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
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

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

Drugs:
◦
◦
◦
◦
◦


Vitamin D
Calcium carbonate (milk alkali syndrome)
Lithium
Thiazide diuretics
Vitamin A
Sarcoidosis, other granulomatous disorders
Hyperthyroidism
Hypercalcemia - Treatment
– NS bolus to restore volume; then 100 – 200 ml/hr
– Bisphosphonates (onset 24-48 hrs)
– Calcitonin 4 – 8 IU q6-8 hrs (onset immediate,
resistance develops in 24-48 hrs)
– [Mg and K prn]
REGULATION OF RENAL 1α-HYDROXYLASE PRODUCTION
Stimulates
Inhibits
PTH
Low calcium
Low phosphate
Calcitonin
1,25(OH)2D3
High calcium
High phosphate
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.
Parathyroid Hormone
Calcium
regulates
PTH
secretion
via a CaSR
PTH and calcium+phosphate homeostasis
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.
Calcitonin effects
• Calcitonin rapidly inhibits osteoclast activity
o causes inhibition of osteoclast motility, alterations in
cell morphology and osteoclast inactivation.
• Kidneys
o inhibits calcium reabsorption (increases excretion)
o also increases phosphorus excretion
• Role in calcium homeostasis unclear
Hormone
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 1hydroxylation
Promotes Ca++
reabsorption and
PO4 excretion,
activates 1hydroxylation
Calcitriol
(RANKL→bone
(vitamin D)
Ca++, PO4 levels resportion)
increase in
blood
Increases Ca++
and PO4
absorption
No direct effects
Calcitonin
No direct effects
Promotes Ca++
and PO4
excretion
Inhibits
resorption
Hypocalcemia:
clinical signs
•
•
•
•
•
Paresthesias
Tetany (carpopedal spasm)
Trousseau’s, Chvostek’s signs
Seizures
Chronic: cataracts, basal ganglia Ca
Trousseau’s sign
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