Hypocalcemia and hypercalcemia

1. What is calcium homeostasis?

Calcium homeostasis refers to the regulation of the calcium concentration in the extracellular fluid. Normal serum calcium concentration varies between laboratories, but is usually 8.5 to 10.5 mg/dL (2.1 to 2.6 mmol/L) and it represents the sum of the three circulating fractions: 45% protein bound (albumin ∼80%, globulins ∼20%), 15% complexed to anions (citrate, bicarbonate, lactate, phosphate), and 40% free, or ionized. The ionized calcium is the physiologically active form, which is recognized by the calcium-sensing receptor (CaSR). The main hormonal regulators of ionized calcium are parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D (1,25D).

2. Which are the units of measurements for serum calcium and what is the conversion between them?

Serum calcium is expressed in conventional units, as mg/dL, in SI (Système International) units, as mmoles/L, and sometimes as mEq/L. Calcium has a molecular weight of 40 and its valence is 2. Therefore:

• Calcium (mg/dL) × 0.25 = Ca (mmol/L)

• Calcium (mg/dL) × 0.5 = Ca (mEq/L)

• Calcium (mEq/L) × 0.5 = Ca (mmol/L)

3. Describe the normal calcium balance.

Calcium balance represents the net difference between calcium intake and output in the body in steady state. This balance is positive during skeletal growth in children, zero in adults, and negative in the elderly. In a healthy adult on an average Western diet of 1000 mg elemental calcium per day, the net intestinal calcium absorption is ∼200 mg; bone mineral accretion (∼500 mg) equals bone resorption (∼500 mg). The kidneys, under hormonal control, will excrete ∼200 mg calcium in the final urine, rendering a neutral calcium balance. Calcium homeostasis and balance become altered in advanced chronic kidney disease (CKD). A positive calcium balance has been demonstrated in patients with CKD stage 3 and 4 placed either on a 2000 mg calcium diet or on 1500 mg calcium carbonate supplements. Thus calcium supplementation in this population should be used with caution, to avoid calcium overload.

4. What causes spurious hypocalcemia?

Total serum calcium is routinely measured with colorimetric assays. The commonly used arsenazo–III reagent complexes with certain gadolinium compounds (like gadodiamide and gadoversetamide), blocking the detection of calcium. The artifact can be as large as 6 mg/dL and persists until the gadolinium is excreted from the body. The ionized calcium is unchanged in this situation and can confirm the spurious hypocalcemia.

5. What causes pseudohypocalcemia?

Unlike true hypocalcemia (low ionized calcium), pseudohypocalcemia is defined as a normal ionized calcium, with low total serum calcium. This usually occurs in conditions associated with low serum albumin (malnutrition, nephrotic syndrome, cirrhosis, etc.). In general, the concentration of calcium falls by 0.8 mg/dL for every 1 g/dL decrease in serum albumin concentration. One of the formulas to correct serum calcium for low albumin, derived from studies in cirrhotic patients with low albumin, is:

A study of CKD patients not yet on dialysis showed that total calcium and albumin-corrected calcium failed to identify true hypocalcemia or hypercalcemia in 20% of the patients. Directly measuring the ionized calcium is preferred in this population.

6. How does the acid-base status affect the ionized calcium?

Serum pH is inversely related to the ionized calcium. An increase in pH causes an increased binding of calcium to albumin, resulting in a drop in ionized calcium, while the opposite occurs when the pH drops. Total calcium remains unchanged in these situations. In patients with CKD with metabolic acidosis, measurement of total calcium underestimates the ionized calcium.

7. What are some common causes of hypocalcemia?

Here is a list of the various causes; each is discussed in more detail in further questions:

• Hypoparathyroidism: genetic and acquired (post-surgical)

• PTH resistance (pseudohypoparathyroidism)

• Vitamin D deficiency or resistance

• Kidney disease

• Hypomagnesemia

• Hyperphosphatemia

• Hungry bone syndrome

• Medications

• Human immunodeficiency virus

• Acute pancreatitis

• Sepsis and critical illness

8. What are some causes of hypoparathyroidism?

Idiopathic hypoparathyroidism may be the result of the absence of parathyroid glands, brachial dysembriogenesis (DiGeorge syndrome), or polyglandular autoimmune disorder. Acquired forms can result from surgery, neck irradiation, or infiltrative diseases like hemochromatosis, amyloidosis, and thalassemia. The most common cause is hypomagnesemia.

9. What is pseudohypoparathyroidism?

In contrast to hypoparathyroidism, in which the synthesis or secretion of PTH is impaired or absent, in pseudohypoparathyroidism, target tissues are unresponsiveness to the actions of PTH. Chronic hypocalcemia in this disorder leads to hyperplastic parathyroid glands and increased levels of PTH.

10. Briefly discuss the vitamin D–related causes of hypocalcemia.

• Vitamin D deficiency: associated with inadequate exposure to ultraviolet light, poor dietary intake, or malabsorption. Also, vitamin D deficiency may occur in patients with nephrotic syndrome as a result of losses of vitamin D–binding protein in the urine.

• Abnormalities of vitamin D metabolism: either reduced hydroxylation of vitamin D to 25-hydroxyvitamin D (25D) in chronic liver diseases or reduced hydroxylation of 25D to 1,25D in kidney failure or vitamin D–dependent rickets type I (deficiency of 1α-hydroxylase).

• Resistance to the actions of vitamin D: vitamin D–dependent rickets type II (molecular defects in the vitamin D receptor).

11. What factors contribute to hypocalcemia in CKD?

• Hyperphosphatemia

• Decreased levels of 1,25D

  • Decreased kidney mass as kidney disease progresses

  • Accumulation of bone-derived hormone fibroblast growth factor 23 (FGF-23). FGF-23 reduces the activity of the 1-hydroxylase enzyme in the kidney.

• Skeletal resistance to the calcemic action of PTH.