What are the 3 main bone minerals?
- Hormones involved?
- Organs involved?
- Aka 1,25 dihydroxycholecalciferol
How is serum calcium distributed (what forms)
- Albumin (most)
- Ionized (free)
What form(s) of Ca is/are monitored and regulated by the body?
ONLY ionized Ca!
How are ionized Ca levels affected by acid-base status?
Acidosis -> Ca displaced form albumin -> increased ionized Ca
(alkalosis decreases iCa)
Serum Ca levels must be corrected for what?
Plasma protein changes
- Excess production/loss of protein (liver or kidney disease)
Corrected serum Ca for albumin: Serum Ca* + 0.8 (4 - albumin**)
*Serum Ca in mg/dL
**Albumin in g/dL
Correct the serum Ca for albumin of 2.5 and Serum Ca of 8.2
Corrected Ca = Serum Ca + 0.8 (4 - albumin)
Corrected Ca = 8.2 + 0.8 (4-2.5)
Corrected Ca = 9.4
What are the effects of PTH?
Increase serum Ca
- Increase bone resorption
- Increases renal production of calcitriol
- Increase renal Ca reabsorption
Decrease serum PO4
- Increases PO4 excretion
What are the effects of calcitonin?
- Secreted by what cells/organ
Lower serum Ca (not very significant role)
- Produced by parafollicular cells (C-cells) of thyroid
Describe the parathyroid glands
- 5% have more, 5% have fewer
Found posterior to thyroid or in upper mediastinum
Describe the Ca sensing receptor?
- Expressed by what cells
- Mechanism (in parathyroid)
- Expressed by: parathyroid, kidney, bone marrow, osteoclasts, breast, C-cells, stomach gatrin cells
- GPCR (7 TM segments)
- Ca binds receptor when levels are high
- Stimulates PLC-beta -> IP3 -> high cytosolic Ca
- Blocks secretion of PTH from parathyroid
What stimulates PTH secretion?
- Low Calcium
- High Phosphate
Describe Vitamin D synthesis
- D3 generated in the skin (UV-B rays)
- Diet (cholecalciferol/ergocolciferol)
- Animals: fish oils, eggs, fortified milk/cereal
- Plants (Vit D2- ergo)
- D3 and D2 need to be metabolized into active hormones; this is regulated by PTH (1a-OHase activity)
- Active Vit D works on intestine and bone
What are effects of active Vitamin D?
Increase Ca AND PO4 in ECF
- Increase gut uptake of Ca and phosphate
- Increase osteoblast activity to increase matrix protein synthesis
- Increase osteoclast activity (via OB release of OAFs) to increase Ca release
- Increase renal reabsorption of Ca and phosphate
What can cause hypercalcemia?
- Primary hyperparathyroidism (#1)
- Malignancy (#2)
- Small cell carcinoma (mostly squamous!)
- Renal cell carcinoma
- Multiple myeloma
- Familial Hypercalcemic Hypocalcuria (AD)
- Excess Vitamin A/D
- Milk of magnesia (tums)
- Infection (TB, coccidio, histo)
- Renal failure (3' hyperparathyroidism)
- Padget's of bone (in conjunction w/ immobilization)
What drugs may cause hyeprcalcemia?
What are the most common causes of primary hyperparathryoidism?
1. Adenoma (90%)
- Autonomous secretion of PTH by parathyroid adenoma
2. Hyperplasia (7%)
- Typically occurs in hereditary syndromes (MEN1 and MEN2a have component of this)
3. Carcinoma (3%)
What will you see in labs with primary hyperparathryoidism?
- High PTH
- High Ca
- Low phosphorus
What are the clinical manifestations of 1' hyperparathryoidism?
- Height loss
- Osteitis fibrosa cystica
What is Osteitis Fiborosa Cystica
- Associated with what conditions
- Associated with severe 1/2' hyperparathyroidism
- Increased numbers of osteoclasts and fibroblasts
- Accumulation of “hemosiderin” in tumor gives them the name “brown tumors”
- Subperiosteal resorption
- Bone cysts
- Severe hypercalcemia
- Bone pain
- Surgical resection of parathyroid tumor
- Causes rapid reversal of clinical findings!
What is seen here?
Resorption of distal phalanx (symptom of 1' hyperparathyroidism?)
What is seen here?
Bone cysts in primary hyperparathyroidism
What is secondary hyperparathyroidism
- Renal insufficiency:
- Hypocalcemia (due to decreased 1,25(OH)Vita D production)
- Intestinal malabsorption
- Hypocalcemia (from Vit D deficiency)
- High PTH
- Low Ca
- High (renal) or low (malabsorption) phosphorus
What are consequences of 2' HPT?
Osteitis fibrosa cystica
- Sub-periosteal resorption of bone
What is teritary hyperparathyroidism?
- Autonomous PTH secretion
- PTH gland hyperplasia
- High Ca
- Variable phosphorus
- High PTH
- Calcimimetic (bind CaSR and suppress PTH)
How is malignancy related to hypercalcemia (mechanisms, 4)?
- PTH related protein (PTHrP) that mimics PTH (amino terminus binds normal PTH receptor)
- Osteoclast activating factors (i.e. cytokines)
- Osteolytic bone lesions (myeloma, breast carcinoma)
- Ectopic production of calcitriol (lymphoma)
What tumors produce PTHrP
- Mechanism of action
- Lab values
- Squamous cell carcinomas (lung, esoph, H/N, skin, cervix)
- Renal, bladder
Lymphoma due to HTLV-1
Action: mimics PTH
- Low PTH
- High C
- Low PO4
What is the effect of an inactivating mutation of the CaSR?
In what condition(s) is this seen?
(Calcium sensing receptor)
- Inactivating mutation -> failure of activation by calcium
- Ca levels falsely perceived as low
- PTH is still released (hyperparathyroidism)
This occurs in Familial Hypocalciuric Hypercalcemia
Describe Familial Hypocalciuric Hypercalcemia
- Distinct from 1' hyperparathryoidism
- 1' hyperparathryoidism typically has normal/high urine Ca, while it is low in FHH (FEca under 1%)
- Autosomal dominant; heterozygous mutation (overall disease manifestation is less severe)
- Increased "set point" for Ca-regulated PTH secretion (PTH released even when Ca not that low; CaSR is inactivated and PTH continues to be secreted even when Ca is high)
- Symptoms: mild, asymptomatic, found incidentally on labs (PTH normal/high but serum Ca is not low)
- FHx of hypercalcemia
- No treatment needed
What are signs/symptoms of hyperalcemia?
Bones, stones, moans, and groans
- Bones: osteoporosis, fractures, osteitis fibrosa cystica, brown tumor of jaw, bone pain/arthralgias
- Stones: nephrolithiasis, renal failure
- Moans (abdominal): nausea, constipation, peptic ulcer disease, acute pancreatitis
- Groans (psychiatric): altered mental status, lethargy, coma, psychosis, decreased concentration, depression
- Band keratopathy (corneal calcification)
- HTN, cardiac arrhythmia, shortened QT interval
What is acute management of hypercalcemia?
1. Hydrate aggressively with IV saline
2. Loop diuretic (furosemide) after* adequate hydration
3. Decrease bone resorption
- Bisphosphonates IV (pamidronate/zoledronate once)
- Later onset (2-3d), but longer sustained duration of action
- Calcitonin (4 to 8 IU/kg sc q12h)
- Earlier onset (1/2-1d), but short duration of action (2-3d)
4. Glucocorticoids when indicated
- Vit D intoxication, granulomatous diseases or hematologic malignancies mediated by Vit D
5. Gallium nitrate or plicamycin
- For refractory hyperCa
- Beware of toxicities (renal, bone marrow, hepatic)
6. Dialysis (against low Ca bath)
Is QT long or short in hypercalcemia?
Short QT (Long QT in hypocalcemia)
What are indications for surgery in 1' hyperparathryoidism?
- Nephrocalcinosis, nephrolithiasis, osteitis fibrosa cystica
- Altered mental status
- Corrected serum Ca > 1 mg/dL above normal
- Renal: Decreased Creatinine Clearance (CrCl under 60%)
- 24 hr urinary calcium > 400 mg, increased stone risk or presence of nephrolithiasis or nephrocalcinosis by radiograph, ultrasound, or CT
- Skeletal: T-score
What are major/minor causes of hypocalcemia?
- Vitamin D deficiency
- Exhaustion of skeletal Ca stores with repeated pregnancies
- Hypoparathryoidism (surgical, idiopathic)
- Pseudo-hypoparathyroidism-PTH resistance
- “Hungry bones” following surgery for primary hyperparathyroidism
- Activating mutation of CaSR**
- Mg++ deficiency (severe)
- Pancreatitis (chelation effect)
Rickets and osteomalacia may result from what?
What is rickets? Osteomalacia?
Rickets occurs in kids and osteomalacia in adults
- Impaired mineralization of new bone matrix (osteoid)
- Surfaces of cortex and trabeculae have thickened layer of unmineralized osteoid
- Disorganized bone susceptible to deformity/fracture
- Inadequate exposure to sunlight
- Sunscreen (SPF 8)
- Decreased dietary intake
- Liver/kidney disease
- Genetic defects in Vit D receptor (resistance)
What is seen in nutritional rickets (example)?
- Cupping and fraying of distal metaphysis of radius and ulna
- Gen varum (bowing of legs)
What is seen here?
- Seen in hypocalcemia
Difference between Vitamin D:
- Deficiency (under 20)
- Insufficiency (under 30)
What are clinical features of Osteomalacia?
- Low serum calcium or phosphorus, or both
- Key point: Low calcium X phosphorus product
- Elevated level of serum alkaline phosphatase
- Bone pain
- Proximal muscle weakness
- Pseudofractures (“Looser’s Zone” or Milkman’s fractures):
- Indicative of severe osteomalacia
- Weak site predisposed to traumatic fracture
What is seen here?
Looser's zone (pseudofractures)
- Seen in osteomalacia
What are signs and symptoms of hypocalcemia?
Symptoms (Ca under 7 mg/dL)
- Perioral, tongue and extremity paresthesias
- Facial spasms
- Muscle cramps (back, legs)
- Carpopedal spasm
- Chvostek's sign
- Trousseau's sign
- Prolonged QT interval
What is Chvostek's sign?
Neuromuscular irritability seen in hypocalcemia
- Tap the facial nerve in front of the ear (below the zygomatic arch)
- Positive sign is contraction of the ipsilateral facial muscles
What is Trousseau's sign?
Seen in hypocalcemia
- Inflate BP cuff above systolic (10 mmHg) and hold; results in:
- Carpal spasm
- Muscular contraction at wrist and MCP joints
- Hyperextension at fingers
- Flexion of thumb
How to treat acute/severe hypocalcemia?
1. Calcium - PO ("elemental")
- IV infusion
2. Normalize Mg
- Will allow for normal PTH secretion
- Especially useful if hypoparathryoid
4. Thiazide diuretic
- Increases renal reabsorption of Ca
- Include amiloride to avoid hypokalemia