Normal total serum calcium (Ca+2)concentration is 8.8-10.4 mg/dl, and this is equivalent to 4.4-5.2 mEq/l or 2.2-2.6 mmol/l[1]. To convert from mmol/l to mEq/l, multiply by +2, which is the valence of calcium. To convert from mmol/l to mg/dl, multiply by 40 (the atomic weight of Ca+2) and divide by 10 (i.e., multiply by 4).The normal value for ionized Ca+2 is about half of total serum Ca+2, 4.4-5.2 mg/dl, 2.2-2.6 mEq/l, or 1.10-1.30 mmol/l.Serum Ca+2 exists in three forms: ionized (free; 48%), protein-bound (mostly to albumin and less to globulins; 45%), and complexed (bound to citrate, oxalate, carbonate, and phosphate; 7%), as shown in Figure _1_. Both ionized and complexed Ca+2 are diffusible (ultrafilterable by the kidney), while protein-bound Ca+2 is not[2].
Intracellular Ca+2 is bound to calmodulin and other Ca+2-binding proteins.Hypoalbuminemia will lead to hypocalcemia due to a decrease in protein-bound Ca+2. To correct for hypoalbuminemia, the following formula is used:
Corrected total serum Ca+2(mg/dl) = measured serum Ca+2(mg/dl) + 0.8 (4.0 - serum albumin g/dl).
For example, if serum Ca+2 is 7.8 mg/dl and serum albumin is 2.5 g/dl, corrected serum Ca+2= 7.8 + 0.8 (4.0 - 2.5) = 9.0 mg/dl; therefore, total serum Ca+2 is normal in this case and does not require replacement. Similarly, an increase in albumin by 1.0 g/dl will lead to a 0.8 mg/dl increase in total serum Ca+2. This equation is not always accurate, especially in patients with stage 3-5 chronic kidney disease (CKD)[3]. Ionized Ca+2 should be checked whenever feasible to ascertain the diagnosis of hypocalcemia or hypercalcemia.
The human body contains about 1,000-1,300 g of Ca+2, making Ca+2 the fifth most abundant element in the body[1]. About 99.3% of total body Ca+2 is in the bone (skeleton) and teeth, 0.6% is in soft tissues, and 0.1% resides in the extracellular fluid (ECF), including 0.03% in plasma[4]. Intracellular Ca+2 concentration is very low (about 100 nM), yet it is essential for several critical functions such as signal transduction, nerve conduction, muscle contraction, and blood coagulation.Ca+2 in the skeleton is complexed with phosphorus mainly as hydroxyapatite, which gives the bone its mechanical characteristics.It is important to know that only 1% of Ca+2 in the bone can immediately equilibrate with extracellular Ca+2.
Hypercalcemia is fairly common with a prevalence of approximately 1-4% in the general population and 0.17-3% in hospitalized populations [4]. Hypocalcemia is significantly more prevalent in hospitalized patients (10-18%). In those hospitalized in the intensive care unit, the prevalence of hypocalcemia can be as high as 70-80%[4]. It is important to also recognize that the prevalence of hypomagnesemia in the intensive care setting is as high as 65%, which contributes to the high prevalence of hypocalcemia in this patient population.
The average daily intake of Ca+2 is about 1,000 mg, of which 400 mg is absorbed in the small intestine. About 200 mg is excreted with intestinal secretions. Therefore, net absorption is 200 mg (about 20%); the remaining 800 mg is excreted in the stool[2]. About 500 mg of Ca+2 are exchanged daily between the bone and the ECF. Of the 10,000 mg of Ca+2 filtered through the kidneys, 9,800 mg (98%) are reabsorbed by the renal tubules, and approximately 200 mg are excreted, which equals the net amount absorbed in the small intestine (Figure _2_).
In the small intestine,Ca+2 is absorbed both paracellularly (passive absorption through tight junctions) and transcellularly (active absorption). Paracellular absorption dominates when Ca+2 intake is high, while transcellular absorption dominates when Ca+2 intake is low[1].Active absorption of Ca+2 is under the control of calcitriol [1,25(OH)2 D]. Transcellular Ca+2 absorption occurs via two epithelial Ca+2 channels that belong to the transient receptor potential (TRP) superfamily and specifically to the vanilloid subfamily (TRPV)[5]. These two channels are transient receptor potential vanilloid 5 (TRPV5; pronounced trip V5) and TRPV6. Free Ca+2 exits the cell via the sodium-calcium (Na+-Ca+2) exchanger.
Ca+2 homeostasis is dependent on three processes: intestinal absorption, bone turnover (Ca+2 exchange with the bone), and renal reabsorption[1]. The hormonal regulators of these processes are the parathyroid hormone (PTH), calcitriol [1,25(OH)2 D], which is the most active form of vitamin D, and serum ionized Ca+2. The receptors for these hormonal regulators are the PTH receptor (PTHR), the vitamin D receptor (VDR), and the calcium-sensing receptor (CaSR) respectively[6].
The CaSR is a G protein-coupled receptor that regulates PTH secretion from the parathyroid glands. The CaSR senses extracellular ionized Ca+2. When serum Ca+2 is high, the CaSR is activated with a subsequent increase in renal Ca+2 excretion (calciuria) and inhibition of PTH secretion[7]. PTH inhibition decreases the release of Ca+2 from the bone and inhibits the synthesis of calcitriol.Inhibition of calcitriol synthesis also reduces mobilization of Ca+2 from bone and decreases active intestinal absorption of Ca+2. These effects will help in restoring Ca+2 towards normal levels [8].The opposite effect is seen when serum Ca+2 is low. The CaSR is inactivated with a subsequent decrease in renal Ca+2 excretion and an increase in PTH secretion. PTH stimulation increases the release of Ca+2 from the bone and enhances the synthesis of calcitriol. Calcitriol mobilizes Ca+2 from the bone and increases active Ca+2 absorption in the intestine. These effects will help in restoring Ca+2 towards normal levels [9]. The CaSR is also expressed in the basolateral membranes of the thick ascending limb (TAL) of the loop of Henle.
In the kidney, the proximal tubule (PT) reabsorbs 60-70% of filtered Ca+2, the TAL reabsorbs 20%, the distal convoluted tubule (DCT) reabsorbs 10%, and the collecting duct (CD) reabsorbs 5%[2]. Regulation of Ca+2 excretion in the kidney occurs at the terminal nephron. Ca+2 reabsorption in the PT is 85% via the paracellular route (passive)[10]. Active transport via the apical membrane (transcellular) is responsible for the remaining 15% and is enhanced by calcitonin and PTH.In the TAL, absorption is both paracellular and transcellular but mostly paracellular [11]. As in the PT, transcellular (active)Ca+2 transport in the TAL is enhanced by calcitonin and PTH.Claudin-16 interacts with claudin-19 (both are tight junction proteins) forming a cation-selective tight junction protein complex that enables paracellular Ca+2(and Mg+2) transport in the TAL (Figure _3_).
Claudin-14 blocks paracellular Ca+2 reabsorption in the TAL in response to increased serum Ca+2 level[12].Ca+2 reabsorption in the DCT is entirely active via the transcellular route through TRPV5 channels[13].Hormonal regulations of Ca+2 and phosphate are tightly linked, while there is no hormonal system that significantly controls Mg+2 metabolism[14]. Phosphate homeostasis is regulated by PTH, calcitriol, fibroblast growth factor 23 (FGF-23), and FGF/Klotho receptor complex[2]. FGF-23 is secreted from the bone in response to an increase in serum phosphate level. It results in phosphaturia and a decrease in calcitriol production with a subsequent decrease in intestinal phosphate (and Ca+2) absorption. Increased PTH secretion leads to phosphaturia. While both PTH and FGF-23 are phosphaturic, they have the opposite effect on calcitriol (FGF-23 decreases and PTH increases the renal production of calcitriol).
PTH is the main regulator of renal Ca+2 reabsorption. A decrease in serum ionized Ca+2(hypocalcemia) inactivates the CaSR in the parathyroid glands and subsequently stimulates PTH secretion. PTH and calcitriol enhance renal Ca+2 reabsorption in the DCT via the transcellular (active) route[13]. Moreover, PTH stimulates bone resorption by the osteoclasts and increases the secretion of calcitriol, which in turn stimulates intestinal Ca+2 and phosphate absorption by activating the VDR. Conversely, hypercalcemia decreases PTH secretion by activating the CaSR and the above actions are reversed. The hormonal response keeps serum Ca+2 in a narrow physiologic range[1]. Therefore, the function of the CaSR in the parathyroid glands is to change PTH secretion depending on serum ionized Ca+2 level.Both Mg+2 and Ca+2 bind to the CaSR in the parathyroid glands and the kidney; however, each has a distinct binding site. Mg+2 plays a role in PTH modulation by acting on the CaSR [15,16]. PTH secretion is stimulated in acute hypomagnesemia and suppressed in hypermagnesemia. It is important to note that profound hypomagnesemia suppresses (rather than stimulates) PTH secretion and increases PTH resistance in the bone leading to hypocalcemia[9,10].
Calcitriol is the most active form of vitamin D and is produced by tubular renal cells.25-hydroxyvitamin D [25(OH)D] is produced in the liver and is converted to calcitriol by 1α-hydroxylase[3,8,17].Calcitriol enhances intestinal Ca+2 and phosphate absorption in addition to renal Ca+2 reabsorption in the DCT.
Volume expansion increases urine Na+and Cl-excretion and subsequently decreases renal Ca+2 absorption and the reverse is true in volume contraction.In metabolic alkalosis, bound hydrogen ions dissociate from albumin, which increases the fraction of albumin available for ionized Ca+2 binding[2]. Therefore, metabolic alkalosis leads to hypocalcemia. Acute and chronic metabolic acidosis leads to hypercalcemia because hydrogen is buffered in the bone with subsequent release of Ca+2 and calcinuria. Ionized Ca+2 changes by 0.12 mg/dl for each 0.1 change in pH.Inhibition of the sodium-potassium chloride cotransporter 2 (NKCC2) in the loop of Henle by loop diuretics enhances Ca+2 excretion in the urine[8]. Thiazide diuretics are associated with hypercalcemia and hypocalciuria due to enhanced Ca+2 reabsorption in the PT (following Na+ and water reabsorption due to volume contraction) and in the DCT (Table _1_).
Hypercalcemia increases calcitonin production by the C cells in the thyroid gland. Calcitonin inhibits bone resorption by the osteoclasts and increases renal Ca+2 and phosphate excretion[18].Hypercalcemia activates CaSR in the basolateral membrane of the TAL. CaSR inhibits the renal outer medullary potassium channel (ROMK), which in turn inhibits K+recycling in the TAL; subsequently, the activity of the NKCC2 is decreased, which lowers the positive transepithelial voltage. The final outcome of this sequence of events is a decrease in paracellular transport of Na+, Mg+2,and Ca+2(increased urinary excretion of Na+, Mg+2,and Ca+2)[2]. This explains why severe hypercalcemia leads to volume depletion and why normal saline (and not loop diuretics that lead to further volume depletion) is the first step in the management of severe hypercalcemia.
Hypocalcemia is defined as serum Ca+2 of<8.8 mg/dl (2.2 mmol/l or 4.4 mEq/l). Hypocalcemia is easily diagnosed because Ca+2 is included in routine chemistry panels. As in hypercalcemia,Ca+2 should be corrected in case of hypoalbuminemia or hyperalbuminemia. It is preferable to obtain ionized Ca+2 to ascertain the diagnosis, especially in critically ill patients in whom pH variation changes Ca+2 binding to albumin[19]. As mentioned above, metabolic alkalosis increases Ca+2 binding to albumin and decreases ionized Ca+2.Hypocalcemia stimulates PTH release, which increases renal production of calcitriol; both hormones increase serum Ca+2 by the mechanism mentioned above.
Hypocalcemia is more common than hypercalcemia in hospitalized patients. PTH can be low, normal, or high.Hypocalcemia due to PTH deficiency is associated with low or low normal PTH and hyperphosphatemia, while other causes are associated with high PTH. Vitamin D deficiency, acute pancreatitis, hungry bone syndrome, and Mg+2 deficiency cause hypocalcemia with normal or low serum phosphate[8]. The hungry bone syndrome is seen post parathyroidectomy in patients with severe primary hyperparathyroidism. The most common causes of hypocalcemia are listed in Table _2_.
