Hypercalcemia
1. What is hypercalcemia? How does protein binding affect the calcium level?
Hypercalcemia is a corrected total serum calcium value above the upper limit of the normal range or an elevated ionized calcium value. Calcium is 50% free (ionized), 40% protein-bound, and 10% complexed to phosphate, citrate, bicarbonate, sulfate, and lactate. Only elevations in the free calcium are associated with symptoms and signs. Of the protein-bound calcium, about 80% is bound to albumin and 20% to globulins. A decrease or increase in serum albumin of 1 g/dL from 4 g/dL decreases or increases the serum calcium by 0.8 mg/dL. An increase or decrease in serum globulin by 1 g/dL increases or decreases serum calcium by 0.16 mg/dL. Such protein changes do not affect free calcium and do not cause calcium-related symptoms.
2. How common are hypercalcemia and its main associated conditions?
Hypercalcemia affects 0.5% to 1% of the general population. The incidence may increase to 3% among postmenopausal women. Primary hyperparathyroidism (PHPT) causes 70% of outpatient and 20% of inpatient cases of hypercalcemia. Cancer causes 50% of inpatient cases of hypercalcemia. Ten percent of patients with malignancy experience hypercalcemia. Hyperparathyroidism and cancer cause 90% of all hypercalcemia. About 10% of patients with hyperparathyroidism experience nephrolithiasis. Although calcium oxalate stones are usually the most common stone type, calcium phosphate stones are more common in hyperparathyroidism.
3. How would you classify mild, moderate, and severe hypercalcemia?
First, consider the patient’s general health, hypercalcemic symptoms, and the normal upper limit for calcium in your laboratory. For example, a patient with renal failure and a serum phosphorus value of 8.5 mg/dL may have metastatic calcification with a serum calcium level of 10.5 mg/dL. Then the serum calcium (Ca) is corrected for the albumin concentration, as follows:
With this in mind, a serum calcium value 1.5 to 3.5 mg/dL above the upper normal limit defines moderate hypercalcemia. Mild hypercalcemia occurs below this range and severe hypercalcemia above. Thus if the upper normal limit for calcium is 10.5 mg/dL, a serum calcium value of 12 to 14 mg/dL indicates moderate hypercalcemia. A serum calcium value less than 12 mg/dL indicates mild hypercalcemia and a level greater than 14 mg/dL severe hypercalcemia.
4. Discuss the signs and symptoms of hypercalcemia.
No symptoms are usually present with mild hypercalcemia (< 12 mg/dL). Moderate or severe hypercalcemia and rapidly developing mild hypercalcemia may cause symptoms and signs. Common symptoms and signs involve (1) the central nervous system (lethargy, stupor, coma, mental changes, psychosis), (2) the gastrointestinal tract (anorexia, nausea, constipation, acid peptic disease, pancreatitis), (3) the kidneys (polyuria, nephrolithiasis), (4) the musculoskeletal system (arthralgias, myalgias, weakness), and (5) the vascular system (hypertension). The classic electrocardiographic (ECG) change associated with hypercalcemia is a short QT interval. Occasionally, severe hypercalcemia also causes dysrhythmias, sinus arrest, disturbances in atrioventricular (AV) conduction, and ST segment elevation mimicking myocardial infarction.
5. What are the sources of serum calcium?
Bone calcium approximates 1 kg and 99% of body calcium. A normal serum calcium level is maintained by integrated regulation of calcium absorption, resorption, and reabsorption; these processes occur, respectively, in the gut, bone, and kidney. Of the 1000 mg/day of dietary calcium intake, the gut absorbs 300 mg/day, secretes 100 mg/day, and excretes 800 mg/day. Net absorption averages 200 mg/day. Calcium absorption is usually about 30% of dietary calcium; however, absorption may increase to more than 50% when people also take large doses of 1,25(OH)2D. The kidney reabsorbs 98% of filtered calcium and excretes 200 mg/day. Bone exchanges about 500 mg of calcium per day with serum (Fig. 13-1).
Figure 13-1. Normal calcium balance. ECF, extracellular fluid.
6. What are the major anatomic and physiologic determinants of vitamin D?
Diet, skin, liver, and kidney control the amount, synthesis, and secretion of vitamin D. Dietary sources of vitamin D include liver, fish oils, egg yolks, vitamin D–fortified foods, and vitamin D supplements. Skin exposure to ultraviolet sunlight activates 7-dehydrocholesterol to pre–vitamin D, which subsequently rearranges to form vitamin D. Hepatic 25-hydroxylase then converts vitamin D to 25-hydroxyvitamin D (25-OHD). 25-OHD circulates and interacts with two renal mitochondrial hydroxylases. High parathyroid hormone (PTH), low phosphate, and low calcium levels stimulate 1α-hydroxylase activity to increase conversion of 25-OHD to 1,25(OH)2D (calcitriol)—the most potent metabolite of vitamin D. Low PTH, high phosphate, and high calcium levels suppress 1α-hydroxylase activity and stimulate 24-hydroxylase activity. This process inhibits calcitriol production and, through 24-hydroxylase, converts 25-OHD to 24,25-dihydroxyvitamin D [24,25(OH)2D], which promotes antiresorptive effects on bone and positive calcium balance. This same sequence occurs less intensely with normal levels of PTH, PO4 (phosphate), and calcium. Calcitriol feeds back negatively on its own synthesis by suppressing 1α-hydroxylase activity, stimulating 24-hydroxylase activity, decreasing PTH, and increasing calcium and phosphate. Calcitriol is also degraded primarily through the enzyme 24-hydroxylase. The activity of 1α-hydroxylase is classically thought of as occurring only in the kidneys, but this enzyme is also present in bone, brain, pancreas, heart, intestines, lymph nodes, adrenal gland, prostate, and other tissues (Fig. 13-2). Fibroblast growth factor-23 (FGF-23) also has an important role in calcium and vitamin D metabolism.
7. What is fibroblast growth factor-23 and what role does it play in calcium, phosphate, and vitamin D metabolism?
FGF-23 is a newly discovered phosphaturic hormone that is produced by osteocytes in response to increases in serum levels of phosphate, 1,25(OH)2D, and PTH. FGF-23 then decreases phosphate, 1,25(OH)2D, and PTH by reducing proximal renal tubular phosphate reabsorption, stimulating 24-hydroxylase, inhibiting 1α-hydroxylase, and variably inhibiting PTH synthesis and secretion by the parathyroid glands. FGF-23 accumulates to very high levels in chronic kidney disease (CKD) and is associated with increased mortality in CKD.
8. What are the classical and nonclassical effects of vitamin D and what is the role of the vitamin D receptor?
Calcitriol acts classically on intestine, bone, kidneys, and parathyroid glands to help regulate calcium and phosphate metabolism. When calcitriol activates the parathyroid vitamin D receptor (VDR), it decreases PTH messenger RNA (mRNA) synthesis by inhibiting the pre-pro-PTH gene at the vitamin D response element. This inhibition decreases PTH synthesis within the chief cell of the parathyroid gland and ultimately lowers PTH levels. Additionally, calcitriol increases intestinal calcium and phosphate absorption, increases bone calcium and phosphate resorption, enhances bone turnover, and enhances renal calcium and phosphate reabsorption. The VDR is a nuclear hormone receptor that is also regulated by calcium and PTH. Many proteins are downregulated and upregulated by the activated VDR. Downregulated proteins include PTH, 1α-hydroxylase, bone matrix protein, bone sialoprotein, type I collagen, interferons, interleukins, tumor necrosis factor (TNF), epidermal growth factor receptors, renin, and peroxisome proliferator-activated receptor (PPAR) gamma-2. Upregulated proteins include osteopontin, matrix Gla protein, type IV collagen, interleukins, VDR, calcium-sensing receptor (CaSR), and 24-hydroxylase. Through activation of the VDR, calcitriol has many (nonclassical) effects other than those related to calcium and phosphorus metabolism. VDR activation may ameliorate arterial calcification, retard neuronal degeneration, enhance host defenses against bacterial infection and tumor growth, enhance Sertoli cell function and spermatogenesis, enhance insulin synthesis and secretion from pancreatic beta cells, and assist with glycogen and transferrin synthesis in liver parenchymal cells. Additionally, calcitriol has antiproliferative and prodifferentiating effects on myeloid cell precursors, cardiac and smooth muscle cells, and a variety of skin cells, including keratinocytes, fibroblasts, hair follicles, and melanocytes.
9. What is the CaSR, and what role does it play in calcium metabolism?
The CaSR is a membrane-bound calcium sensor-receptor. The most important locations of the CaSRs are the parathyroid glands and the renal tubular cells but the receptors are located in many other tissues, including at low levels in pancreatic beta cells and thyroid C cells. The major function of the CaSR is to maintain extracellular calcium concentrations in the normal range and prevent hypercalcemia. In the parathyroid chief cells, the CaSR has a large extracellular domain of 700 amino acids (primary calcium binding site), a seven-segment transmembrane portion (primary calcimimetic binding site), and a cytoplasmic carboxyl-terminal component of about 200 amino acids (primary effector site for metabolic changes). The CaSR belongs to subfamily C of the G protein–coupled receptor family. The CaSR senses the minutest change in ionized calcium (0.1 mg/dL) and regulates PTH secretion in order to maintain steady-state calcium levels within a narrow optimal range. These changes center on a set point for calcium-regulated PTH release that is unique for each individual. Cinacalcet, a calcimimetic drug, binds to the transmembrane portion of the CaSR, making it markedly more responsive to any level of ambient calcium. After activation by calcium, the CaSR activates phospholipase C, inhibits adenylate cyclase, and opens nonselective cation channels. This effect increases cytoplasmic calcium by mobilizing calcium from thapsigargin-sensitive intracellular stores and enhancing calcium influx through voltage-insensitive cation channels. These CaSR-induced changes in intracellular calcium act on the calcium response element of the pre-pro-PTH gene to decrease chief cell PTH messenger RNA synthesis, reduce PTH secretion, and decrease parathyroid gland hyperplasia. The parathyroid glands secrete both intact PTH (iPTH) and carboxy-terminal PTH fragments (CPTH). Intact PTH acts directly on bone PTH receptors. CPTH remains in the circulation much longer and at higher concentrations than iPTH and, although it was previously thought to be inactive, data now suggest that CPTH fragments can exert direct effects on bone cells through a novel class of CPTH receptors. CPTH fragments accumulate in renal failure. PTH functions to keep calcium in the normal range and helps prevent hypocalcemia.
10. What is the function of the CaSR in the kidneys?
In the kidney, as in the parathyroid glands, the CaSR functions to prevent hypercalcemia. Activation of the CaSR located on the basolateral membrane in the thick ascending limb of Henle’s loop decreases tubular reabsorption of calcium and increases excretion. Activation of the renal CaSR generates an arachidonic acid metabolite that inhibits the luminal potassium channel and the sodium-potassium adenosine triphosphatase (ATPase) pump on the basolateral membrane. This diminishes the lumen-positive electrical gradient needed for passive calcium and magnesium reabsorption. Thus there is less reabsorption and more excretion of calcium. Because PTH is decreased by the CaSR activated in the parathyroid gland, there is less PTH-mediated distal tubular reabsorption of calcium, net calcium loss, and lower plasma calcium.
11. What are the overall effects of PTH, vitamin D, and FGF-23 on calcium metabolism?
