Serum calcium levels are tightly controlled within a narrow range, usually 8.5–10.5 mg/dL (2.1–2.6 mmol/L). However, the serum calcium level is a poor reflection of overall total body calcium, as serum levels are only 0.1–0.2% of extracellular calcium, which in turn is only 1% of total body calcium. The remainder of total body calcium is stored in bone. Ionized calcium, generally 40% of total serum calcium level is physiologically active, while the non-ionized calcium is bound to albumin or anions such as citrate, bicarbonate and phosphorus. In the presence of hypoalbuminemia, there is a relative increase in the ionized calcium relative to the total calcium, thus total serum calcium may underestimate the physiologically active (ionized) serum calcium. A commonly utilized formula for estimating the ionized calcium from total calcium is to add 0.8 mg/dl for every 1 mg decrease in serum albumin below 4 mg/dl.
Serum levels of ionized calcium are maintained in the normal range by inducing increases in the secretion of PTH (). PTH acts to increase bone resorption, increase renal calcium reabsorption, and increases the conversion of 25(OH)D to 1,25(OH)2
D in the kidney, thereby increasing gastrointestinal calcium absorption. Individuals with normal kidney function have protection against calcium overload by virtue of their ability to increase renal excretion of calcium and reduce intestinal absorption of calcium by actions of PTH and 1,25(OH)2
D. Calcium absorption across the intestinal epithelium occurs in both a vitamin D dependent mechanism, and a vitamin D independent or passive, concentration dependent pathway. In the kidney, the majority (60–70%) of calcium is reabsorbed passively in the proximal tubule driven by a gradient that is generated by sodium and water reabsorption. In the thick ascending limb, another 10% of calcium is reabsorbed via paracellular transport. Finally, at the distal convoluted tubule, the connecting tubule, and the initial portion of the cortical collecting duct another 10% of calcium reabsorption occurs. It is also primarily through these latter distal segments of the kidney where the regulation of urinary calcium excretion occurs24
. As detailed below, the treatment of hypercalcemia includes volume expansion to reduce the salt driven proximal reabsorption and loop diuretics which block the paracellular thick ascending limb transport.
Figure 1 Normal homeostatic response to hypocalcemia. In the presence of hypocalcemia, parathyroid hormone (PTH) secretion is increased. PTH acts on three target organs. PTH works level at the intestine indirectly by first increasing the 1-α-hydroxalase (more ...)
Inorganic phosphorus is critical for numerous normal physiologic functions including skeletal development, mineral metabolism, energy transfer through mitochondrial metabolism, cell membrane phospholipid content and function, cell signaling, and even platelet aggregation. Because of its importance, normal homeostasis maintains serum concentrations between 2.5 to 4.5 mg/dl (0.81 to 1.45mmol/L). The terms phosphorus and phosphate are often used interchangeably, but the term phosphate actually means the inorganic freely available form (HPO4 −2 to H2PO4 −1). However, most laboratories report this measurable, inorganic component as phosphorus. For simplicity we will refer to this measurable component as phosphorus for the remainder of this chapter.
Total adult body stores of phosphorus is approximately 700 g, of which 85% is contained in bone in the form of hydroxyapatite [(Ca)10(PO4)6(OH)2]. Of the remaining, 14% is intracellular, and only 1% is extracellular. Of this extracellular phosphorus, 70% is organic and contained within phospholipids, and 30% is inorganic, 15% is protein bound, and the remaining 85% is either complexed with sodium, magnesium, or calcium or circulates as the free monohydrogen or dihydrogen forms. It is this latter 0.15% of total body phosphorus (15% of extracellular phosphorus) that is freely circulating and measured. At pH of 7.4, it is in a ratio of about 4:1 HPO4 −2 to H2PO4 −1. For that reason, phosphorus is usually expressed in mmol rather than meq/L. Thus, similar to calcium, serum measurements only reflect a minor fraction of total body phosphorus, and therefore do not consistently reflect total body stores.
The recommended daily allowance (RDA) for phosphorus is 800 mg/day but the average American diet ingests approximately 1000–1400 mg phosphorus per day. Approximately 2/3 of the ingested phosphorus is excreted in the urine, and the remaining 1/3 in stool and this phosphorus excretion is highly dependent on kidney function. Many pre-packaged, fast food, and dark (cola) beverages contain extra phosphorus as preservative and thus it is difficult to accurately predict dietary intake based on the food type alone. In general, foods high in protein and dairy products contain the most phosphorus, whereas fruits and vegetables contain the least. Animal or synthetic protein has more bioavailable phosphorus than soy or grain based protein. Between 60 and 70% of dietary phosphorus is absorbed by the gastrointestinal tract, in all intestinal segments. Phosphorus absorption is dependent on both passive transport related to the concentration in the intestinal lumen (i.e. increased after a meal) and active transport stimulated by calcitriol42
. Medications or foods that bind phosphorus (antacids, phosphate binders, calcium) can decrease the net amount of phosphorus absorbed by decreasing the free phosphate for absorption. In the kidney, approximately 70–80% of the filtered load of phosphorus is reabsorbed in the proximal tubule which serves as the primary regulated site of the kidney. The remaining approximately 20–30% is reabsorbed in the distal tubule14
When serum phosphorus levels decrease, there is a stimulation of the 1-alpha hydroxylase enzyme in the kidneys, thereby increasing conversion of calcidiol to calcitriol which in turn increases intestinal phosphorus absorption. There is also a reduction in urinary phosphorus excretion. In the presence of hyperphosphatemia, there is a rapid increase in urinary excretion of phosphorus mediated by the serum phosphorus level, PTH, and most likely FGF2337
. There is a rapid response of the kidneys to excrete urinary phosphorus after dietary ingestion such that sustained hyperphosphatemia is clinically not seen without kidney disease. Although the effects are more minor, renal phosphorus excretion is also increased by volume expansion, metabolic acidosis, glucocorticoids and calcitonin, and decreased by growth hormone and thyroid hormone31
The normal homoestasis for magnesium is less studied but there has been recent increased interest. Magnesium is critical for normal ATP (adenosine triphosphate) function and glucose metabolism and therefore has widespread cellular effects. Magnesium is also important in cellular cytoskeleton contraction and at the myoneural junction, and therefore can alter skeletal and cardiac muscle function. Magnesium is the second must abundant intracellular cation, with 67% of total body stores found in bone, 31% intracellular, and only 2% in the extracellular (measurable space). Normal serum levels are 1.5 to 2.5 meq/L, and approximately 30% is bound to albumin. Similar to the other divalent mineral ions, less than 1% of the total body magnesium is in the extracellular space (and therefore measurable) and thus levels do not accurately reflect total body stores22
. Unfortunately, there is no ‘ionized’ magnesium test clinically available to diagnose deficiency. Magnesium is absorbed via intestinal epithelial channels in the intestine in a non-vitamin D dependent process. At the kidney, magnesium is reabsorbed along with calcium in a paracellular manner in the thick ascending limb, and via specific magnesium transport channels in the distal tubule. Although there is biologic plausibility of a magnesium sensing hormone, at this time there is no evidence for one. Thus, the major regulator of magnesium is the serum concentration itself43