Where is calcium stored?
Mitochondria and ER
What is “pump-leak” transport?
Ca2+ leaks into cytosolic compartment and is pumped into storage sites in organelles
How is calcium stored in serum?
- Ionized (50%)
- Protein-bound (40%) - 9/10 of this is bound to albumin, rest to globulins
- Complexed to serum constituents (10%) - like citrate and phosphate
Why are patients with acute respiratory alkalosis prone to seizures?
Low ionized calcium in ECF (increased binding to proteins) and therefore increased permeability to sodium ions
Normal calcium range in plasma:
8.5-10 mg/dL
Where does Vitamin D3 synthesis occur?
Keratinocytes in skin (stimulated by PTH)
The active metabolite is 1,25-dihydroxy-D
Skin/diet –> liver –> kidney –> bone/intestine
What is the point of regulation in Vitamin D synthesis?
1alpha-hydroxylase (mitochondrial P450 enzyme in kidney)
PTH stimulates this
Order of best calcium absorption (and phosphate)?
Duodenum > jejunum > ileum
Dependent on vitamin D
What type of activation regulates PTH?
G-protein (phospholipase C and IP3); decrease in cAMP
Overall action of PTH:
Increase plasma Ca2+, decrease plasma phosphate
- bone resorption
- kidney reabsorption (distal tubule)
- inhibit phosphate reabsorption
- stimulate 1,25-(OH)2-D synthesis (Vitamin D activity)
Normal plasma phosphate?
3-4.5 mg/dL
Parathyroid chief cells have a…
Calcium sensing receptor (CaSR)
Regulate ionized calcium via PTH secretion (low levels will stimulate PTH)
What produces calcitonin?
Parafollicular cells of thyroid (NEURAL CREST DERIVED - rest of thyroid is endoderm)
- Inhibit osteoclast resorption and promote renal excretion of calcium
Calcitonin acts via ______
Increased cAMP concentrations in bone and kidney (inhibit osteoclast; also inhibit urinary excretion of calcium/phosphate)
- Probably not necessary for survival, but can be used to treat hypercalcemia
List some bone formation stimulants:
- GH
- Insulin-like GF
- Insulin
- Estrogen
- Androgens
- Vitamin D
- Calcitonin
** Inhibitor is cortisol
Bone reabsorption stimulators:
- PTH
- Cortisol
- Thyroid hormone
- Prostaglandins
- IL-1, IL-6, TNF-alpha and beta
Bone reabsorption inhibitors:
- Estrogen, androgen
- Calcitonin
- gamma-interferon
- NO
- Transforming GF beta
What is a cause of Pseudohypoparathyroidism?
End organ PTH resistance (PTH high, but no response, so calcium is low)
- Classic sign is “knuckle knuckle dimple dimple” on metacarpals
- Short, obese, variable mental retardation, Elfin faces, enamel hypoplasia
What is an important cause of hypercalcemia of malignancy?
Parathyroid hormone related protein (PTHrP)
- Can activate PTH receptor
- May be important in lactation
- Associated with a few cancers (can be secreted by them)
What does vitamin D deficiency lead to in children?
Rickets (prior to closure of growth plates)
Sufficient osteoid, poor mineralization
- Osteomalacia occurs at any age
Consequences of primary hyperparathyroidism? Treatment?
Caused by adenoma, hyperplasia, carcinoma
- Nephrolithiasis / nephrocalcinosis
- CNS disturbances (depression, seizures)
- Constipation, peptic ulcer disease, acute pancreatitis
- Osteitis fibrosa cystica
Surgical excision or Cinacalcet (Sensipar)
Primary hyperparathyroidism labs…
PTH, calcium, phosphate, urinary cyclic AMP, alkaline phosphatase
Increased PTH Increased calcium Decreased phosphate Increased urinary cyclic AMP Increased alkaline phosphatase
What is secondary hyperparathyroidism?
Excess PTH in response to problem outside of glands - chronic renal failure or after gastric bypass surgery
Describe the process of secondary hyperparathyroidism in RENAL INSUFFICIENCY
- Decreased kidney phosphate excretion
- Increased phosphate binds calcium
- PTH released (free calcium lower)
- More bone resorption
