Week 4: Hypocalcemia

Question 1

Causes of hypocalcemia

Answer 1

Low serum albumin-most common
Chronic renal failure
Magnesium deficiency
Hypoparathyroidism
Pseudohypoparathyroidism
Osteomalacia due to Vitamin D deficiency
Hungry bone syndrome
Acute hemorrhagic/edematous pancreatitis
Hyperphosphatemia

Question 2

Low serum albumin causing hypocalcemia

Answer 2

• Must correct the serum Ca: (4-measured albumin) x0.8 +serumCa=corrected
• if corrected serum calcium is normal, evaluation is over
• Causes of low serum albumin: malnutrition, liver cirrhosis, nephrotic syndrome
• level of ionized Ca is normal but total Ca is low

Question 3

Hypocalcemia due to chronic renal failure

Answer 3

• reduction of phosphate clearance->hyperphosphatemia
• decreased production of 1,25(OH)2VitD leads to decreased Ca absorption in the gut
• skeletal resistance to PTH
• elevated serum BUN and Cr
• with decreasing GFR, PTH levels rise due to decreased levels of activated Vit D, hyperphophatemia and hypocalcemia
• high phosphorus stimulates PTH
• phophorus also complexes with Ca–>decreases Ca levels–>doesn’t bind to CaSR and releases inhibition on PTH release
• P also stimulates FGF 23 (normally inhibits PTH) but in hyperparathyroidism, this function is not effective

Question 4

Magnesium Metabolism

Answer 4

• normal distribution: extracellular Mg is only 1% of total body. Rest is in skeleton and soft tissue
• Need optimally 400 mg/day, 30-50% absorbed in gut
• kidneys: mostly reabsorbed in PCT (15-20%) and TALH (65-75%)
• problems with magnesium deficiency usually due to gut or kidney issues

Question 5

physiological role of magnesium deficiency

Answer 5

• enzyme substrate formation (e.g. kinases, ATPase, GTPMg)
• direct enzyme activation
• influence membrane properties: nerve conduction, calcium channel activity, potassium transport

Question 6

Causes of Magnesium deficiency: GI

Answer 6

• low dietary intake
• malabsorption syndromes (celiacs)
• extensive bowel resection
• bariatric surgery
• acute and chronic diarrhea
• Intestinal and biliary fistulas
• Protein calorie malnutrition
• Acute hemorrhagic/edematous pancreatitis
• Primary intestinal Mg malabsorption (mutation in TRPM6, a magnesium channel)

Question 7

Causes of magnesium deficiency: Renal

Answer 7

• alcohol
• osmotic diuresis: diabetes
• diuretics
• hypercalcemia: nephrogenic Di
• chronic IV therapy (Na)
• metabolic acidosis
• drugs for transplant patients
• PPIs
• chronic renal disease
• cardiac glycosides
• genetic defects such as gitleman’s

Question 8

Mechanism of magnesium deficiency as cause of hypocalcemia

Answer 8

1. Impaired PTH secretion
   - PTH is inappropriately normal or low in Mg deficiency
   - In normal individuals, high serum Mg will inhibit PTH secretion
   - in Mg deficiency: Mg is important part of GTP part of G protein receptors. Without Mg, Ca sensing receptor doesn’t work and can’t detect low Ca levels. That’s why there are low/normal PTH even with low Mg.
2. there is skeletal and renal PTH resistance
3. Impaired formation of 1,25(OH)2 VitD
4. Resistance to Vitamin D

Question 9

Hypoparathyroidism as cause of hypocalcemia

Answer 9

• post surgical: 90%
• idiopathic (autoimmune): 10%
• congenital
• infiltrative disease
• radiation therapy
• activating mutation of the Ca sensing receptor: decreased set point and increased sensitivity to Ca

Question 10

Pseudohypoparathyroidism

Answer 10

• similar to hypoPTH with hypocalcemia and hyperphosphatemia. But has elevated PTH and end organ resistance to PTH
  1. Type 1a (alb rights hereditary osteodystrophy)
• inactivating mutation of GNAS1 gene with reduction of Gsa protein. hormones bind but don’t act. blunted response
• resistance to PTH, TSH, LH, FSH, glucagon
• short, mental retardation, shorted 4th metacarpal
  2. Type Ib: hormone resistance to PTH only
  3. Type Ic: resistance to multiple hormones, unknown mechanism
  4. Type II: renal resistance, no phosphaturic response to PTH

Question 11

Hypocalcemia: osteomalacia and rickets

Answer 11

• Vitamin D deficiency
• decreased Ca absorption through gut
• skeletal PTH resistance
• secondary hyperPTH

Question 12

Hungry Bone syndrome

Answer 12

• healing phase of hyperPTH. Bone trying to heal itself and can happen after parathyroid surgery
• prolonged drops in Ca levels
• Ca goes from serum to bone rapidly and there is rapid remineralization of bone
• also can occur in healing phase of hyperthyroidism, bone marrow neoplasia, Rx of Vit D deficiency, or in osteoclastic bone metastasis

Question 13

Hypocalcemia due to acute hemorrhagic and edematous pancreatitis

Answer 13

Multifactorial causes

• pancreatic lipase liberates FFA, and FFA chelate calcium (saponification)
• magnesium deficiency from alcohol
• excessive calcitonin secretion due to excessive glucagon secretion
• systemic protease inhibits PTH secretion or degrades circulating PTH

Question 14

Hyperphosphatemia as cause of hypocalcemia

Answer 14

• calcium and phosphate bind together in plasma
• high phosphate inhibits synthesis of 1,25(OH)2VitD
• high phosphate may be due to renal failure, cell lysis (rhabdomyolysis, admin of chemoRx agents), excessive PO4 administration, hypoPTH, pseudohypoPTH

Question 15

Symptoms and signs of hypocalcemia

Answer 15

1. Neuromuscular hyperexcitability
   - paresthesias, hyperreflexia
   - Trousseau’s sign and Chvostek’s sign
   - tetany
2. Neurological
   - seizures, depression, anxiety, irritability
   - papilledema
   - increased CSF pressure
3. Dermatologic
   - dry, scaly skin, brittle nails, monilia of nails
4. Opthalmologic
   - cataracts
5. Prolonged QT: can lead to arrhythmias
6. calcification of basal ganglia

Question 16

Neurological manifestations of Magnesium deficiency

Answer 16

• Positive Chvostek’s sign: spasm from tapping on facial nerve
• positive Trousseau’s sign: bp cuff to 20mmHg above systolic, note flexion of wrist, MP joint, extension of IP joint, adduction of digits. Carpopedal spasm
• seizures
• vertigo, ataxia, nystagmus, athletoid, chorioform movements
• muscle weakness, tremor, fasciculations, wasting
• psych: depression and psychosis

Question 17

Laboratory evaluation of hypocalcemia

Answer 17

1. serum albumin
2. serum PTH
   - low: hypoPTH, Mg deficiency
   - high: most other hypocalcemia states
3. Serum Mg
4. Serum phosphate
   - high or high normal in disorders of decreased PTH or peripheral resistance to PTH. high in uremia
5. X-rays
6. EKG
7. PTH stimulation test: not really used, can distinguish between pseudohypoPTH and hypoPTH

Question 18

Approach to treating hypocalcemia

Answer 18

1. neuro symptoms: give IV calcium
2. Mg deficiency: give Mg IV for 3-5 days or in mild cases, oral Mg
3. HypoPTH and pseudohypoPTH
   - oral calcium supplements everyday
   - Vit D orally
   - AlOH gel to bind PO4
   - hydrochlorothiazide to lower urinary Ca