HYPOCALCEMIA
July 8th, 2005
Tatyana Danilov, MD
Background: 40% of serum calcium is bound to albumin (ratio of 0.8 mg/dL calcium : 1 g/dL albumin). This
ratio can be affected by serum pH. Most common cause of a low serum calcium is low albumin (reduces
protein binding, but not biologically important ionized calcium).
Parathyroid Glands – 4 glands located immediately behind the thyroid gland with a macroscopic appearance
of dark brown fat, therefore difficult to locate and often accidentally removed (particularly in the past) during
thyroid resection. Removal of 2 glands generally has no effect on the serum calcium level. Removal of 3
glands generally causes transient hypoparathyroidism, though the fourth gland will hypertrophy and take
over the function. If all 4 glands are removed, the patient is left with hypoparathyroidism.
Parathyroid Hormone (PTH): glands made of chief cells and oxyphil cells, the former being the producers of
PTH. A) PTH has 2 separate effects on bone, via effects on osteoblasts. (Osteoclasts lack PTH receptors
and are activated by cytokines released by osteoblasts the latter being activated by PTH.):
1) Rapid : takes place in minutes, activates existing cells to absorb calcium and phosphate salts
from the bone.
2) Slow: takes days, activating the production of more osteoclasts, followed by greatly enhanced
osteoclastic reabsorption of bone itself.
B) PTH effects on Kidneys:
1) Increases tubular reabsorption of calcium (in ascending limb of Loop of Henle, distal tubules
and collecting ducts)
2) Decreases phosphate reabsorption – very strongly – important for patients with CRF
3) Increases magnesium reabsorption
4) Increases calcitriol (1,25(OH)2D) production (active form of Vitamin D)
NOTE: Without PTH’s effects on the kidney, the calcium leached from the bone would be lost.
C) PTH effect on the Intestines – moderated by 1,25(OH)2D
1) Enchances calcium absorption
2) Enhances phosphate absorption- less so than effect of phosphate excretion in kidney
Causes of Hypocalcemia:
- Can be divided into 2 causes - decreased entry or loss from circulation
- Chronic hypocalcemia does not occur without either abnormal PTH or decreased Vitamin D activity
I. Decreased Calcium Entry
A) Hypoparathyroidism– typically from surgery, radiation or infiltrative processes (iron in hemachromatosis,
copper in Wilson’s disease, or malignancy). Other causes include congenital absence of 3 rd and 4th brachial
pouches (DiGeorge syndrome), or in association with Type I polyglandular autoimmune syndrome,
hypomagnesemia (interferes with PTH secretion) or even hypermagnesemia (inhibits PTH secretion and
action).
B) Pseudohypoparathyroidism: constellation of hypocalcemia, hyperphosphatemia and an increased serum
PTH level + resistance to the action of PTH. Caused by a constellation of genetic defects. Type 1a
(Albright’s hereditary osteodystrophy) leads to a genetic deficiency of the G s protein that couples PTH-R to
adenylyl cyclase. These patients have brachydactyly (short metacarpals), obesity, round facies and short
stature. Pseudopseudohypoparathyroidism = osteodystrophy but normal calcium metabolism (no clinical
significance, but often can phenotypically see short metacarpals).
C) Vitamin D deficiency (see high PTH, hypophosphatemia, high alkphos)
1.
dietary insufficiency (confined elderly people at high risk)
2.
impaired synthesis in skin
3.
defective activation of 1,25(OH)2D in liver or kidney
4.
accelerated catabolism of Vitamin D by liver (seen in patients on phenytoin or
barbiturates)
Can lead to impaired bone mineralization if occurs over long-term  osteomalacia and rickets
When checking Vit D levels – best to check a calcidiol level b/c it provides a better estimate of Vit D stores.
Low calcidiol levels are seen in poor oral intake, poor gut absorption, nephritic syndrome and phenytoin
therapy. Low calcitriol levels are seen in renal insufficiency and Type 1 rickets (1-hydroxylase deficiency).
Type 2 Rickets is associated with a defect in the Vitamin D receptor and calcitriol levels are elevated.
II. Loss from Circulation
Beth Israel Deaconess Medical Center Interns’ Report
Hyperphosphatemia – binds to calcium and leads to deposition in bones and other tissues. When
Calcium-Phosphate product is > 70 this becomes a worry. Metastatic calcification = precipitation of
calcium phosphate in tissues. Calciphylaxis = precipitation leading to tissue necrosis/ischemia
a. Renal insufficiency
b. Rhabdomyolysis
c. Tumor Lysis
B) Pancreatitis – calcium soaps form in the abdomen leading to hypocalcemia
C) Hungry Bone Syndrome – after parathyroidectomy for hyperparathyroidism
D) Chelation – via EDTA contained in blood transfusions, foscarnet or lactate
A)
Other causes:
Hypomagnesemia: causes PTH resistance, may also be seen with Cisplatin therapy
Metabolic Acidosis: changes free fraction of calcium  it is recommended that an ionized calcium be
checked periodically in patients with sepsis, lactic acidosis, severe burns, post-surgery.
Surgery: due to volume expansion, hypoalbuminemia, high citrate concentration after large blood
transfusions, some patients may have true temporary ionized hypocalcemia
Fluoride poisoning; Bisphosphonates (especially zoledronic acid); Calcimimetric drugs (Cinacalcet) used to
control secondary hyperparathyroidism of renal failure
Symptoms:
Pathognomonic clinical feature = tetany (neuronal hyperexcitability leading to muscle cramps, generalized
muscle spasm, laryngospasm, and eventually seizures). Degree of symptomatolgy is proportional to
duration of hypocalcemia (chronic versus acute).
Other symptoms = coarse, brittle hair with patch alopecia, coarse nails with transverse grooves, cataracts
and keratoconjunctivitis, hypotension and decrease cardiac output, steatorrhea (from impaired pancreatic
enzyme excretion), dementia (reversible 50% of time), anxiety, delirium, depression, movement disorders.
Evaluation:
Physical findings:
Heart failure, hypotension, papilledema, skin, hair and nail findings, CNS symptoms
Trousseau’s Sign: inflate sphygmomanometer to 20 mmHg greater than SBP and hold for 3
minutes. Watch for carpal spasm.
Chvostek’s Sign: tap on the patient’s facial nerve anterior to the parotid gland observing for
contraction of facial muscles. Note, can be positive in 10% of patients with normal serum calcium levels.
EKG Findings: Prolongation of ST and QT segments, due to prolongation of Phase 2. The QTc is rarely >
140% of normal and if it is, a U-Wave is likely included in the measurement. If hypocalcemia and
hyperkalemia coexist, can see prolongation of ST segment with “tented” T-waves.
Check serum ionized calcium, PTH, phosphate, alkaline phosphatase, magnesium, +/- amylase, calcidiol
and calcitriol levels. Ensure the PTH and calcium levels are checked simultaneously b/c PTH levels change
quickly and can be affected by treatment for the condition.
Treatment:
Mild Asymptomatic (ionized calcium >3.2 mg/dl): supplemental calcium usually enough
Acute Symptomatic: If symptomatically hypocalcemic, treat with intravenous calcium until
symptoms resolve and an oral regimen can be given. 1 ampule 10% Calcium Gluconate = 90 mg
elemental calcium, 1 amp 10% Calcium Chloride = 360 mg elemental calcium (requires central
venous access). Should also consider giving intravenous Magnesium (unless there is renal
failure!) since hypomagnesemia can cause refractory hypocalcemia. Interestingly, a normal serum
magnesium level may not reveal total body magnesium depletion, and the patient may still be
deficient. If magnesium is low, the hypocalcemia will be resistant to treatment until the magnesium
is repleted.
Chronic Treatment: Oral Calcium and Vitamin D repletion. Thiazide diuretics and sodium
restriction are occasionally used. Avoidance of hypercalciuria is preferable in patients with chronic
hypocalcemia on oral supplementation, so may only aim to keep serum calcium level 8-8.5 mg/dL.
Special Cases:
Autosomal Dominant Hypocalcemia: usually asymptomatic and require little or no treatment; raising the
patient’s calcium can lead to increased hypercalciuria and renal insufficiency
Renal Failure: oral phosphate binders to lower serum phosphate, calcium (but avoid calcium citrate), +/- vitD
Beth Israel Deaconess Medical Center Interns’ Report