Disorders of Calcium Metabolism

Question 1

Main mechanism of hypercalcemia in primary hyperparathyroidism

Answer 1

• Primary HPT is the most common cause of hypercalcemia
• Overall effect of PTH is to ↑ serum Ca2+ , so excessive ↑ in PTH would cause hypercalcemia.
• Bone
  
  • ↑ serum Ca2+by stimulating osteoclast (bone breakdown) bone resorption
• Kidney
  
  • ↑ Ca2+ reabsorption in distal tubule
• GI tract → indirect by way of Vit. D
  
  • ↑ Ca2+ absorption (requires 1 day)

Question 2

Disorders that can lead to primary hyperparathyroidism

Answer 2

• Adenoma: (85% in one parathyroid gland);
• 4 gland hyperplasia: OOOO (15%);
• carcinoma: oo*o (<1%),
• sporadic 90% of time, familial 10% of time, familial usually hyperplasia (not carcinoma)

Question 3

Clinical features/labs in primary hyperparathyroidism

Answer 3

• Clinical features: 50% are asymptomatic and it is picked up on routine biochemical screen.
• Symptoms: related to acions of PTH
• Labs: ↑ PTH, ↓ Phosphate, ↑ Ca2+

Question 4

Tx of primary hyperparathyroidism

Answer 4

• surgery when indicated (primary HPTH can only be cured with surgery)
• if hyperplastic, remove 3 & ½ glands, put last ½ in neck strap or forearm muscle
• Calcimimetic drugs
• bisphosphonates (off label)

Question 5

Effects of untreated hyperparathyroidism @ bones & kidneys

Answer 5

• osteoporosis/osteopenia, kidney stones, gastrointestinal pain and psychiatric disturbances
  
  • ==> “bones, stones, groans and moans”
• Other clinical features: arthritis, muscle weakness, band keratopathy, hypertension and anemia.
• Occasionally ==> chondrocalcinosis and episodes of pseudogout.

Question 6

Main mechanism underlying hypercalcemia in hypercalcemia of malignancy

Answer 6

• Most tumors make PTH related peptide (PTH-RP) and several other factors (TGF, TNF, IL-1, IL-6, etc)
• PTH-RP is similar in structure to PTH and thus binds to PTH receptor and stimulates osteoclastic bone resorption, which ↑ serum Ca2+, which ↓ PTH.
• No phosphorus wasting

Question 7

Most common tumors ==> hypercalcemia

Answer 7

Most common tumor types:

Lung cancer (squamous most common)
Breast
Head and neck
Then kidney, bladder, pancreatic, ovarian, multiple myeloma, lymphoma

Question 8

Dx & Tx of hypercalcemia of malignancy

Answer 8

• Diagnosis: ↑ Ca2+, ↓ PTH, ↑ PTH-RP
  
  • don’t usually test for PTH-RP
• Treatment: Saline infusion, inhibit bone resorption (bisphosphonates, calcitonin, plicamycin), remove calcium with dialysis

Question 9

Tx of hypercalcemic adenoma vs. hyperplasia

Answer 9

• Adenoma → remove gland with adenoma (Note: other glands often atrophy)
• Hyperplasia → remove 3.5/4 glands
• Familial causes (including familial HPTH, MEN1, MEN2A) are almost always hyperplasia, not an adenoma

Question 10

Characteristics of familial hypocalciuric hypercalcemia

Answer 10

• Mutations in calcium sensor receptor (CaSR), located on parathyroid cells and renal tubule cells
• Diagnosis: ↑ Ca2+ (mild), ↑ PTH (mild), ↓ urinary Ca2+, family history in 1st degree relatives
• ↓ urine calcium/creatinine clearance ratio (<0.01)
• No treatment needed, avoid surgery

Question 11

Major causes of hypocalcemia

Answer 11

• Vitamin D deficiency
• Hypoparathyroidism
• Pseudohypoparathyroidism
• hypomagnesemia
• acute pancreatitis
• hypoproteinemia/hypoalbuminemia
• renal/liver disease

Question 12

Vit D deficiency: mechanisms of hypocalcemia

Answer 12

• acquied due to poor oral intake, inadequate sunlight exposure, malabsorption
• acquired 1,25 (OH)2 vitamin D disease due to renal disease, hypoparathyroidism
• Congenital 1-α hydroxylase deficiency (vit D dep rickets type 1)
• Congenital Vitamin D receptor deficiency (vit D dep rickets type 2)

Question 13

Pseudohypoparathyroidism: mechanism of hypocalcemia

Answer 13

• Rare genetic disorder that results from inherited inactivating mutation in PTH receptor pathway (Gs mediated)
• Resistant to PTH

Question 14

Hypomagnesemia, Acute Pancreatitis, Hypoproteinemia: mechanisms of hypocalcemia

Answer 14

• Hypomagnesemia - impairs PTH secretion and causes resistance to the peripheral actions of PTH
• Acute pancreatitis - precipition of calcium salts with products of intra-abdominal lipolysis
• Hypoproteinemia/ hypoalbuminemia - ↓ serum total Ca concentration but do not usually affect the serum ionized concentration and therefore no Sx of hypocalcemia

Question 15

Mechanism of hypocalcemia in hypoparathyroidism

Answer 15

• Usually the result of damage to or removal of parathryoid glands during thyroid, parathyroid or head & neck surgery
• Idiopathic hypoparathyroidism - autoimmune - may be a part of APS1 (Automimmune Polyendocrine Syndrome Type 1) - incl/ adrenal insufficiency, Hashimoto’s thyroiditis & chronic mucocutaneous candidiasis
• DiGeorge Syndrome

Question 16

Clinical and lab features of hypoparathyroidism

Answer 16

• Labs: ↓ Ca2+, ↑ Phosphate, ↓ serum PTH
• Symptoms:
  
  • parasthesias, muscle cramps, muscle weakness
  • Chvostek’s sign - facial wink when tapping facial nerve
  • acute; Trousseau’s sign - carpopedal spasm when a sphygmomanometer is maintained above systolic BP for 2 minutes
  • acute; mucocutaneous candidiasis (APS-1)

Question 17

Characteristics of modes of presentation of osteoporosis

Answer 17

• Fragility fractures occur with minimal or no trauma. Minimial fall is falling from standing height or less.
• If have fragility fracture you can diagnose osteoporosis
• Common fractures: vertebral, hip, wrist
• Overall 1.5 million fragility fracture/yr
• Risk factors = Previous fracture, age, falls, low bone mass

Question 18

Prevalence/causes of osteoporosis in men & women

Answer 18

• Advanced age and female gender are non-modifiable risk factors for osteoporosis.
• Estrogen deficiency following menopause or oophorectomy is correlated with a rapid reduction in bone mineral density in women.
• A decrease in testosterone levels has a comparable (but less pronounced) effect on bone mineral density in men.
• Fracture risk for a given bone density increases with age.

Question 19

Impact of osteporotic factures on health and economy

Answer 19

• osteoporosis ==> ~1.5 million bone fractures/yr ==> $17 billion/yr health care costs
• ~25% of women > 50yo develop osteoporosis
• ~25% of older persons w/hip fracture die within first year from fracture-related complications

Question 20

Abnormal vs. normal bone formation

Answer 20

• Normal bone formation
  
  • Resorption = formation
  • Osteoclast action = osteoblast action
  • Bone mass remains stable
• Abnormal bone formation:
  
  • Resorption > formation
  • Osteoclast action > osteoblast action
  • Bone mass is lost

Question 21

Characterisitcs of normal bone remodeling

Answer 21

• Accomplished by 3 cell types: osteoclasts, osteoblasts and osteocytes.
• Osteoclasts are multinucleated giant cells that attach to bone surfaces
  
  • secrete acid and proteolytic enzymes that dissolve underlying bone ==> resorption pit
• Osteoblasts secrete osteoid (bone specific collagen) ==>
  
  • mineralized with calcium and phosphate crystals (hydroxyapatite), refilling the resorption pit with new bone.
• Osteocytes reside in the bone matrix and function as mechanoreceptors
  
  • sense areas of mechanical stress in bone
  • orchestrating the rate and sites of bone remodeling by sending signals to osteoclasts and osteoblasts.

Question 22

Osteoporosis definition

Answer 22

Osteoporosis is defined as impaired bone strength that predisposes to the development of fragility fractures. Fragility fractures are bone fractures that occur with low trauma. eg. a fall from a standing height or less.

Question 23

Non-modifiable risk factors for osteoporosis

Answer 23

• Age
• Gender
• Race
• Early menopause
• Family history

Question 24

Modifiable risk factors for osteoporosis

Answer 24

• Low Ca2+ intake
• Low vitamin D intake
• Cigarette smoking
• Excess alcohol >2/day
• Excess caffeine >2/day
• Medications
• Estrogen deficiency
• Sedentary lifestyle

Question 25

Osteomalacia definition

Answer 25

• Defined as impaired bone mineralization resulting in soft, weak bones in adults.
• Symptoms and signs:
• Pain
• Deformities
• Fractures
• Psuedofractures → demineralization along arteries (Milkman’s fractures + Loser’s fractures)

Question 26

Causes of Osteomalacia

Answer 26

• Acquired Vitamin D Deficiency
  
  • Poor oral intake
  • Malabsorption
  • Inadequate sunlight exposure
• Acquired 1,25 (OH)2 Vitamin D Deficiency
  
  • Renal disease
  • Hypoparathyroidism
• Acquired Hypophosphatemia
  
  • Poor oral intake
  • Renal phosphate wasting

Question 27

Clinic features of Paget disease

Answer 27

• Idiopathic bone condition characterized by excessive + unregulated bone resorption + formation.
• Clinical features of Paget’s disease include bone pain, deformity, fractures, osteoarthritis, hypervascular bone, and a predisposition to the development of acetabular protrusion and osteogenic sarcoma.
• Most commonly affected bones are the pelvis, skull, vertebrae, femur, tibia and fibula.
• Neurologic complications:
  
  • Deafness due to involvement of the ossicles or compression of the 8th nerve,
  • May compress other cranial nerves or spinal cord

Question 28

Course of Paget Disease

Answer 28

1. Development of focal areas of aggressive, unregulated osteoclastic bone resorption by large, multinucleated osteoclasts. (5-10 years)
2. Mixed osteoclastic/osteoblastic phase during which osteoblastic bone formation becomes secondarily activated and focal areas of aggressive, unregulated bone formation develop. (5-10years)
3. Burned out phase: excessive bone resorption tapers off but focal areas of high bone formation remain active. (indefinite)

Question 29

Patholog of osteoporosis vs. osteomalacia vs. paget’s

Answer 29

• Osteoporosis
  
  • Fragility fractures.
  • T-score is ≤ -2.5
• Osteomalacia
  
  • true fractures + pseudofractures, also
• Paget’s Disease
  
  • Areas of intense radionuclide uptake on bone scanning.
  • focal osteolytic areas (resorption fronts, “blade of grass” sign), osteosclerotic areas ,adjacent to lytic areas; focal expansion of bone size.