Forms of Ca2+ in Blood
The total Ca2+ concentration in blood is normally 10 mg/dL (Fig. 9-33). Of the total Ca2+, 40% is bound to plasma proteins, mainly albumin. The remaining 60%, which is not protein-bound, is ultrafilterable. The ultrafilterable component includes a small portion that is complexed to anions (e.g., phosphate, sulfate, citrate) and free, ionized Ca2+. Free, ionized Ca2+ amounts to 50% of the total (i.e., 5 mg/dL), and it is the only form of Ca2+that is biologically active.
Figure 9–33 Forms of Ca2+ in blood. Percentages give percent of total Ca2+ concentration in each form. Only free, ionized Ca2+ is physiologically active.
Hypocalcemia is a decrease in the plasma Ca2+ concentration. The symptoms of hypocalcemia are hyperreflexia, spontaneous twitching, muscle cramps, and tingling and numbness. Specific indicators of hypocalcemia include the Chvostek sign, or twitching of the facial muscles elicited by tapping on the facial nerve, and the Trousseau sign, which is carpopedal spasm upon inflation of a blood pressure cuff. It may be surprising to learn that hypocalcemia causes twitching and cramping of skeletal muscle (as Ca2+ is required for cross-bridge cycling in muscle contraction). However, the Ca2+ that initiates the cross-bridge cycle in skeletal muscle contraction is intracellular Ca2+. This discussion of the effects of hypocalcemia refers to low extracellular Ca2+. Decreased extracellular Ca2+ causes increased excitability of excitable cells including sensory and motor nerves and muscle. Decreased extracellular Ca2+lowers (makes more negative) the threshold potential; by lowering threshold potential, less inward current is required to depolarize to threshold and to fire action potentials. Thus, hypocalcemia produces tingling and numbness (effects on sensory nerves) and spontaneous muscle twitches (effects on motoneurons and the muscle itself).
Hypercalcemia is an increase in the plasma Ca2+ concentration. Manifestations of hypercalcemia include constipation, polyuria, polydipsia, and neurologic signs of hyporeflexia, lethargy, coma, and death.
Changes in plasma protein concentration, changes in complexing anion concentration, and acid-base disturbances may alter the forms of Ca2+ in plasma. Such changes will be physiologically significant, however, only if they alter the ionized Ca2+ concentration because that is the form with biologic activity.
Changes in plasma protein concentration alter the total Ca2+ concentration in the same direction as the protein concentration; thus, increases in protein concentration are associated with increases in total Ca2+ concentration, and decreases in protein concentration are associated with decreases in total Ca2+ concentration. Because changes in plasma protein concentration usually are chronic and develop slowly over time, they do not cause a parallel change in ionized Ca2+ concentration. Regulatory mechanisms such as those involving parathyroid hormone (see later) sense any transient change in ionized Ca2+concentration and have time to make the appropriate correction.
Changes in anion concentration alter the ionized Ca2+ concentration by changing the fraction of Ca2+ complexed with anions. For example, if the plasma phosphate concentration increases, the fraction of Ca2+ that is complexed increases, thereby decreasing the ionized Ca2+ concentration. If the plasma phosphate concentration decreases, the complexed Ca2+ decreases and the ionized Ca2+ increases.
Acid-base abnormalities alter the ionized Ca2+ concentration by changing the fraction of Ca2+ bound to plasma albumin, as illustrated in Figure 9-34. Albumin has negatively charged sites, which can bind either H+ ions or Ca2+ions. In acidemia, there is an excess of H+ in blood; thus, more H+ binds to albumin, leaving fewer sites for Ca2+ to bind. In acidemia, the free ionized Ca2+ concentration increases because less Ca2+ is bound to albumin. In alkalemia, there is a deficit of H+ in blood, and less H+ will be bound to albumin, leaving more sites for Ca2+ to bind. Thus, in alkalemia (e.g., acute respiratory alkalosis) the free, ionized Ca2+ concentration decreases, often accompanied by symptoms of hypocalcemia.
Figure 9–34 Effects of acid-base disturbances on plasma protein-binding of Ca2+ and the ionized Ca2+ concentration in blood.
Overall Calcium Homeostasis
Ca2+ homeostasis involves the coordinated interaction of three organ systems (bone, kidney, and intestine) and three hormones (parathyroid hormone, calcitonin, and vitamin D). The relationship between the organ systems and the hormones in maintaining Ca2+ balance is depicted in Figure 9-35.
Figure 9–35 Ca2+ homeostasis in an adult eating 1000 mg/day of elemental Ca2+. Hormonal effects on Ca2+ absorption from the gastrointestinal tract, bone remodeling, and Ca2+ reabsorption in the kidney are shown. PTH, Parathyroid hormone.
To illustrate, the “person” shown in Figure 9-35 is said to be in Ca2+ balance. In this person, net excretion of Ca2+ by the kidney is equal to net absorption of Ca2+ from the gastrointestinal tract.
If the person ingests 1000 mg of elemental Ca2+ daily, approximately 350 mg is absorbed from the gastrointestinal tract, a process that is stimulated by the active form of vitamin D, 1,25-dihydroxycholecalciferol. However, about 150 mg/day is secreted into the gastrointestinal tract in salivary, pancreatic, and intestinal fluids. Thus, net absorption of Ca2+ is 200 mg/day (350 mg-150 mg), and the remaining 800 mg/day (of the 1000 mg ingested) is excreted in feces. The absorbed Ca2+ enters the Ca2+ pool in ECF.
The person depicted in Figure 9-35 is presumed to have no net gain or loss of Ca2+ from bone. Nevertheless, there is continuous bone remodeling, in which new bone is formed (deposited) and old bone is resorbed. Bone resorption is stimulated by parathyroid hormone and 1,25-dihydroxycholecalciferol and is inhibited by calcitonin.
Ultimately, to maintain Ca2+ balance, the kidneys must excrete the same amount of Ca2+ that is absorbed from the gastrointestinal tract, or, in this case, 200 mg/day. The renal mechanisms (which are discussed in Chapter 6) include filtration of Ca2+, followed by extensive reabsorption.
The role of parathyroid hormone (PTH) is to regulate the concentration of Ca2+ in ECF (i.e., plasma or serum). When the plasma Ca2+ concentration decreases, PTH is secreted by the parathyroid glands. In turn, PTH has physiologic actions on bone, kidney, and intestine that are coordinated to increase the plasma Ca2+ concentration back to normal.
Structure of Parathyroid Hormone
There are four parathyroid glands in humans, located in the neck under the thyroid gland. The chief cells of the parathyroid glands synthesize and secrete PTH, a single-chain polypeptide with 84 amino acids. The molecule’s biologic activity resides entirely in the N-terminal 34 amino acids. PTH is synthesized on the ribosomes as preproPTH, which has 115 amino acids. A 25-amino acid signal peptide sequence is cleaved while synthesis of the molecule is being completed on the ribosomes. The 90-amino acid proPTH then is transported to the Golgi apparatus, where 6 more amino acids are cleaved, yielding the final 84-amino acid form of the hormone. PTH is packaged in secretory granules for subsequent release.
Regulation of Parathyroid Hormone Secretion
PTH secretion is regulated by the plasma Ca2+ concentration. As shown in Figure 9-36, when the total Ca2+ concentration is in the normal range (i.e., 10 mg/dL) or higher, PTH is secreted at a low (basal) level. However, when the plasma Ca2+ concentration decreases to less than 10 mg/dL, PTH secretion is stimulated, reaching maximal rates when the Ca2+ concentration is 7.5 mg/dL. The relationship betweentotal Ca2+ concentration and PTH secretion is shown in Figure 9-36, although it is actually the ionized Ca2+ concentration that regulates secretion by the parathyroid glands. The response of the parathyroid glands to a decrease in ionized Ca2+ concentration is remarkably prompt, occurring within seconds. Furthermore, the faster the ionized Ca2+ falls, the greater the PTH secretory response.
Figure 9–36 Relationship between plasma Ca2+ concentration and parathyroid hormone (PTH) secretion.
It may seem paradoxical that the chief cells would secrete PTH in response to a decrease in Ca2+ concentration because many endocrine glands secrete their hormones in response to an increase in intracellular Ca2+ concentration. Actually, this is no paradox because what is sensed by the chief cells is a decrease in extracellular Ca2+ concentration, not a decrease in intracellular Ca2+. The mechanism of PTH secretion is explained as follows: The parathyroid cell membrane contains Ca2+ sensing receptors that are linked, via a G protein (Gq), to phospholipase C. When the extracellular Ca2+ concentration is increased, Ca2+binds to the receptor and activates phospholipase C. Activation of phospholipase C leads to increased levels of IP3/Ca2+, which inhibits PTH secretion. When extracellular Ca2+ is decreased, there is decreased Ca2+ binding to the receptor, which stimulates PTH secretion.
In addition to these acute (rapid) changes in PTH secretion, chronic (long-term) changes in plasma Ca2+ concentration alter transcription of the gene for preproPTH, synthesis and storage of PTH, and growth of the parathyroid glands. Thus, chronic hypocalcemia (decreased plasma Ca2+ concentration) causes secondary hyperparathyroidism, which is characterized by increased synthesis and storage of PTH and hyperplasia of the parathyroid glands. On the other hand, chronic hypercalcemia (increased plasma Ca2+ concentration) causes decreased synthesis and storage of PTH, increased breakdown of stored PTH, and release of inactive PTH fragments into the circulation.
Magnesium (Mg2+) has parallel, although less important, effects on PTH secretion. Thus, like hypocalcemia, hypomagnesemia stimulates PTH secretion and hypermagnesemia inhibits PTH secretion. An exception is the case of severe hypomagnesemia associated with chronic Mg2+ depletion (e.g., alcoholism); severe hypomagnesemia inhibits PTH synthesis, storage, and secretion by the parathyroid glands.
Actions of Parathyroid Hormone
PTH has actions on bone, kidney, and intestine, all of which are coordinated to produce an increase in plasma Ca2+ concentration. The actions on bone and kidney are direct and are mediated by cAMP; the action on intestine is indirect, via activation of vitamin D.
The mechanism of action of PTH on bone and kidney is initiated when PTH binds to its receptor on the cell membrane of the target tissue. The receptor for PTH is coupled, via a Gs protein, to adenylyl cyclase, as illustrated for one of its actions, inhibition of renal phosphate reabsorption, in Figure 9-37. The circled numbers in the figure correlate with the steps described as follows: The action of PTH on the renal proximal tubule begins at the basolateral membrane, where the hormone binds to its receptor. The receptor is coupled, via a Gs protein, to adenylyl cyclase (Step 1). When activated, adenylyl cyclase catalyzes the conversion of ATP to cAMP (Step 2), which activates a series of protein kinases (Step 3). Activated protein kinases phosphorylate intracellular proteins (Step 4), leading to the final physiologic action at the luminal membrane, inhibition of Na+-phosphate cotransport (Step 5). Inhibition of Na+-phosphate cotransport results in decreased phosphate reabsorption and phosphaturia (increased phosphate excretion).
Figure 9–37 Mechanism of action of PTH on the renal proximal tubule. See the text for an explanation of the circled numbers. AC, Adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; Gs, stimulatory G protein; PTH, parathyroid hormone; R, receptor for PTH.
The actions of PTH on bone, kidney, and intestine are summarized in Figure 9-38 and are described as follows:
Figure 9–38 Regulation of PTH secretion and PTH actions on bone, kidney, and intestine. cAMP, Cyclic adenosine monophosphate; PTH, parathyroid hormone.
Bone. PTH has several actions on bone, some direct and some indirect. In bone, PTH receptors are located on osteoblasts but not on osteoclasts. Initially and transiently, PTH causes an increase in bone formation by a direct action on osteoblasts. (This brief action is the basis for the usefulness of intermittent synthetic PTH administration in the treatment of osteoporosis.) In a second, long-lasting action on osteoclasts, PTH causes an increase in bone resorption. This second action on osteoclasts is indirect and mediated by cytokines released from osteoblasts; these cytokines then increase the number and activity of the bone-resorbing osteoclasts. Thus, the bone-forming cells, osteoblasts, are required for the bone-resorbing action of PTH on osteoclasts. When PTH levels are chronically elevated, as in hyperparathyroidism, the rate of bone resorption is persistently elevated, which increases the serum Ca2+ concentration.
The overall effect of PTH on bone is to promote bone resorption, delivering both Ca2+ and phosphate to ECF. Hydroxyproline that is released from bone matrix is excreted in urine.
Alone, the effects of PTH on bone cannot account for its overall action to increase the plasma-ionized Ca2+ concentration. The phosphate released from bone will complex with Ca2+ in ECF and limit the rise in ionized Ca2+concentration. Thus, an additional mechanism must coordinate with the PTH effect on bone to cause the plasma ionized Ca2+ concentration to increase. (That additional mechanism is the phosphaturic action of PTH.)
Kidney. PTH has two actions on the kidney. (1) PTH inhibits phosphate reabsorption by inhibiting Na+-phosphate cotransport in the proximal convoluted tubule. As a result of this action, PTH causesphosphaturia, an increased excretion of phosphate in urine. The cAMP generated in cells of the proximal tubule is excreted in urine and is called nephrogenous or urinary cAMP. The phosphaturic action of PTH is critical because the phosphate that was resorbed from bone is excreted in the urine; this phosphate would have otherwise complexed Ca2+ in ECF. Excreting phosphate in urine “allows” the plasma ionized Ca2+ concentration to increase! (2) PTH stimulates Ca2+ reabsorption. This second renal action of PTH is on the distal convoluted tubule and complements the increase in plasma Ca2+ concentration that resulted from the combination of bone resorption and phosphaturia.
Small intestine. PTH does not have direct actions on the small intestine, although indirectly it stimulates intestinal Ca2+ absorption via activation of vitamin D. PTH stimulates renal 1α-hydroxylase, the enzyme that converts 25-hydroxycholecalciferol to the active form, 1,25-dihydroxycholecalciferol. In turn, 1,25-dihydroxycholecalciferol stimulates intestinal Ca2+ absorption.
Pathophysiology of Parathyroid Hormone
The pathophysiology of the PTH system can involve an excess of PTH, a deficiency of PTH, or target tissue resistance to PTH. Disorders associated with PTH are summarized in Table 9-17.
Table 9–17 Pathophysiology of Parathyroid Hormone
*Primary events or disturbances.
Primary hyperparathyroidism. Primary hyperparathyroidism is most commonly caused by parathyroid adenomas (tumors), which secrete excessive amounts of PTH (Box 9-3). The consequences of primary hyperparathyroidism are predictable from the known physiologic actions of PTH on bone, kidney, and intestine: increased circulating levels of PTH, hypercalcemia, and hypophosphatemia.Hypercalcemia results from increased bone resorption, increased renal Ca2+ reabsorption, and increased intestinal Ca2+ absorption. Hypophosphatemia results from decreased renal phosphate reabsorption and phosphaturia.
BOX 9–3 Clinical Physiology: Primary Hyperparathyroidism
DESCRIPTION OF CASE. A 52-year-old woman reports that she suffers from symptoms of generalized weakness, easy fatigability, loss of appetite, and occasional vomiting. Also, she reports that her urine output is higher than normal and that she is unusually thirsty. Laboratory tests show hypercalcemia (increased serum [Ca2+]), hypophosphatemia (decreased serum phosphate concentration), and phosphaturia (increased urinary phosphate excretion). Suspecting that the woman may have a disorder of the parathyroid glands, her physician orders a PTH level, which is found to be significantly elevated.
The woman undergoes surgery, and a single parathyroid adenoma is located and removed. The woman’s blood and urine values return to normal. She regains her strength and reports feeling well.
EXPLANATION OF CASE. The woman has primary hyperparathyroidism caused by a single parathyroid adenoma, a benign lesion. The tumor secretes large amounts of PTH chemically identical to the hormone secreted by the normal parathyroid glands. This excess PTH acts directly on bone and kidney and indirectly on the intestine to cause hypercalcemia and hypophosphatemia. Her hypercalcemia results from the effects of PTH to increase bone resorption, renal Ca2+ reabsorption, and intestinal Ca2+ absorption via activation of vitamin D to 1,25-dihydroxycholecalciferol. Her hypophosphatemia is caused by the effect of PTH to decrease renal phosphate reabsorption and produce phosphaturia.
Most of the woman’s symptoms including hyporeflexia, weakness, loss of appetite, and vomiting are caused by hypercalcemia. Her polyuria and polydipsia result from deposition of Ca2+ in the inner medulla of the kidney, where ADH acts on the collecting ducts. High Ca2+ in the inner medulla inhibits the action of ADH on the collecting ducts, causing a form of nephrogenic diabetes insipidus.
TREATMENT. Surgery was curative for this patient.
Persons with primary hyperparathyroidism excrete excessive amounts of phosphate, cAMP, and Ca2+ in their urine. The increased urinary Ca2+ (hypercalciuria) can precipitate in the urine as Ca2+-phosphate or Ca2+-oxalate stones. The presence of hypercalciuria may seem surprising because the direct effect of PTH on the renal tubule is to increase Ca2+ reabsorption, thus decrease Ca2+ excretion. The presence of hypercalciuria is explained, however, because the high plasma Ca2+ concentration in primary hyperparathyroidism results in a high filtered load of Ca2+, which overwhelms the reabsorptive capacity of the nephron—the Ca2+ that is not reabsorbed is spilled into the urine. Persons with primary hyperparathyroidism are said to have “stones,” “bones,” and “groans”—stones from hypercalciuria, bones from increased bone resorption, and groans from constipation. Treatment of primary hyperparathyroidism usually is parathyroidectomy (surgical removal of the parathyroid glands).
Secondary hyperparathyroidism. The causes of secondary hyperparathyroidism are different from the causes of primary hyperparathyroidism. In primary hyperparathyroidism, the disorder is in the parathyroid gland, which is secreting excessive PTH. In secondary hyperparathyroidism, the parathyroid glands are normal but are stimulated to secrete excessive PTH secondary to hypocalcemia, which can be caused by vitamin D deficiency or chronic renal failure. In secondary hyperparathyroidism, circulating levels of PTH are elevated and blood levels of Ca2+ are low or normal but never high.
Hypoparathyroidism. Hypoparathyroidism is a relatively common, inadvertent consequence of thyroid surgery (for treatment of thyroid cancer or Graves disease) or parathyroid surgery (for treatment of hyperparathyroidism). Autoimmune and congenital hypoparathyroidism are less common. The characteristics of hypoparathyroidism are predictable: low circulating levels of PTH, hypocalcemia, and hyperphosphatemia. Hypocalcemia results from decreased bone resorption, decreased renal Ca2+ reabsorption, and decreased intestinal Ca2+ absorption. Hyperphosphatemia results from increased phosphate reabsorption. This disorder usually is treated with the combination of an oral Ca2+ supplement and the active form of vitamin D, 1,25-dihydroxycholecalciferol.
Pseudohypoparathyroidism. Patients with pseudohypoparathyroidism type Ia were described in the early 1940s by the endocrinologist Fuller Albright as follows: They had hypocalcemia, hyperphosphatemia, and a characteristic phenotype consisting of short stature, short neck, obesity, subcutaneous calcification, and shortened fourth metatarsals and metacarpals. Thereafter, this phenotype was called Albright hereditary osteodystrophy.
As in hypoparathyroidism, patients with pseudohypoparathyroidism have hypocalcemia and hyperphosphatemia. However, in pseudohypoparathyroidism, circulating levels of PTH are increased rather than decreased, and administration of exogenous PTH produces no phosphaturic response and no increase in urinary cAMP. It is now known that pseudohypoparathyroidism is an inherited autosomal dominant disorder in which the Gs protein for PTH in kidney and bone is defective. When PTH binds to its receptor in these tissues, it does not activate adenylyl cyclase or produce its usual physiologic actions. As a result, hypocalcemia and hyperphosphatemia develop.
Humoral hypercalcemia of malignancy. Some malignant tumors (e.g., lung, breast) secrete PTH-related peptide (PTH-rp), which is structurally homologous with the PTH secreted by the parathyroid glands. PTH-rp is not only structurally similar but has all the physiologic actions of PTH including increased bone resorption, inhibition of renal phosphate reabsorption, and increased renal Ca2+ reabsorption. Together, the effects of PTH-rp on bone and kidney cause hypercalcemia and hypophosphatemia, a blood profile similar to that seen in primary hyperparathyroidism. However, in humoral hypercalcemia of malignancy, circulating levels of PTH are low, not high (as would occur in primary hyperparathyroidism); PTH secretion by the parathyroid glands, which are normal, is suppressed by the hypercalcemia. Humoral hypercalcemia of malignancy is treated with furosemide, which inhibits renal Ca2+reabsorption and increases Ca2+ excretion, and inhibitors of bone resorption such as etidronate.
Familial hypocalciuric hypercalcemia (FHH). This autosomal dominant disorder is characterized by decreased urinary Ca2+ excretion and increased serum Ca2+ concentration. It is caused by inactivating mutations of the Ca2+sensing receptors in the parathyroid glands (that regulate PTH secretion) and parallel Ca2+ receptors in the thick, ascending limb of the kidney (that mediate Ca2+ reabsorption). When the renal receptors are defective, a high serum Ca2+ concentration is incorrectly sensed as “normal” and Ca2+ reabsorption is increased (leading to decreased urinary Ca2+ [hypocalciuria] and increased serum Ca2+concentration). Because the Ca2+ receptors in the parathyroid glands are also defective, they incorrectly sense the increased serum Ca2+ as normal and PTH secretion is not inhibited as it would be in normal persons.
Calcitonin is a straight-chain peptide with 32 amino acids. It is synthesized and secreted by the parafollicular or C (“C” for calcitonin) cells of the thyroid gland. The calcitonin gene directs the synthesis of preprocalcitonin and a signal peptide is cleaved to yield procalcitonin; other peptide sequences are then removed, and the final hormone, calcitonin, is stored in secretory granules for subsequent release.
The major stimulus for calcitonin secretion is increased plasma Ca2+ concentration (contrast this with the stimulus for PTH secretion, decreased plasma Ca2+ concentration). The major action of calcitonin is to inhibit osteoclastic bone resorption, which decreases the plasma Ca2+ concentration.
In contrast to PTH, calcitonin does not participate in the minute-to-minute regulation of the plasma Ca2+ concentration in humans. In fact, a physiologic role for calcitonin in humans is uncertain because neither thyroidectomy (with decreased calcitonin levels) nor thyroid tumors (with increased calcitonin levels) cause a derangement of Ca2+ metabolism, as would be expected if calcitonin had important regulatory functions.
Vitamin D, in conjunction with PTH, is the second major regulatory hormone for Ca2+ and phosphate metabolism. The roles of PTH and vitamin D can be distinguished as follows: The role of PTH is to maintain the plasma Ca2+concentration, and its actions are coordinated to increase the ionized Ca2+ concentration toward normal. The role of vitamin D is to promote mineralization of new bone, and its actions are coordinated to increase both Ca2+ and phosphate concentrations in plasma so that these elements can be deposited in new bone mineral.
Synthesis of Vitamin D
Vitamin D (cholecalciferol) is provided in the diet and is produced in the skin from cholesterol. Vitamin D has formal “hormone” status because cholecalciferol itself is inactive and must be successively hydroxylated to an active metabolite. Hydroxylation of cholecalciferol is regulated by negative feedback mechanisms. The pathways for vitamin D metabolism are shown in Figure 9-39.
Figure 9–39 Steps involved in the synthesis of 1,25-dihydroxycholecalciferol. PTH, Parathyroid hormone; UV, ultraviolet.
There are two sources of cholecalciferol in the body: It is either ingested in the diet or synthesized in the skin from 7-dehydrocholesterol in the presence of ultraviolet light. As noted, cholecalciferol itself is physiologically inactive. It is hydroxylated in the liver to form 25-hydroxycholecalciferol, which also is inactive. This hydroxylation step occurs in the endoplasmic reticulum and requires NADPH, O2, and Mg2+, but not cytochrome P-450. 25-Hydroxycholecalciferol is bound to an α-globulin in plasma and is the principal circulating form of vitamin D.
In the kidney, 25-hydroxycholecalciferol undergoes one of two routes of hydroxylation: It can be hydroxylated at the C1 position to produce 1,25-dihydroxycholecalciferol, which is the physiologicallyactive form, or it can be hydroxylated at C24 to produce 24,25-dihydroxycholecalciferol, which is inactive. C1 hydroxylation is catalyzed by the enzyme 1α-hydroxylase, which is regulated by several factors including the plasma Ca2+ concentration and PTH. C1 hydroxylation occurs in the renal mitochondria and requires NADPH, O2, Mg2+, and cytochrome P-450.
Regulation of Vitamin D Synthesis
Whether the renal cells produce 1,25-dihydroxycholecalciferol (the active metabolite) or 24,25-dihydroxycholecalciferol (the inactive metabolite) depends on the “status” of Ca2+ in the body. When Ca2+ is sufficient, with an adequate dietary intake of Ca2+ and normal or increased plasma Ca2+ concentration, the inactive metabolite is preferentially synthesized because there is no need for more Ca2+. When Ca2+ is insufficient, with a low dietary intake of Ca2+ and decreased plasma Ca2+ concentration, the active metabolite is preferentially synthesized to ensure that additional Ca2+ will be absorbed from the gastrointestinal tract.
The production of the active metabolite, 1,25-dihydroxycholecalciferol, is regulated by changing the activity of the 1α-hydroxylase enzyme (see Fig. 9-39). 1α-Hydroxylase activity is increased by each of the following three factors: decreased plasma Ca2+ concentration, increased circulating levels of PTH, and decreased plasma phosphate concentration.
Actions of Vitamin D
The overall role of vitamin D (1,25-dihydroxycholecalciferol) is to increase the plasma concentrations of both Ca2+ and phosphate and to increase the Ca2+ × phosphate product to promote mineralization of new bone. To increase plasma Ca2+ and phosphate concentrations, vitamin D has coordinated actions on intestine, kidney, and bone. Because 1,25-dihydroxycholecalciferol is a steroid hormone, its mechanism of action involves stimulation of gene transcription and synthesis of new proteins, which have the following physiologic actions:
Intestine. The major actions of 1,25-dihydroxycholecalciferol are on the intestine. There, 1,25-dihydroxycholecalciferol increases both Ca2+ and phosphate absorption, although far more is known about its effect on Ca2+absorption. In the intestine, 1,25-dihydroxycholecalciferol induces the synthesis of a vitamin D–dependent Ca2+-binding protein called calbindin D-28 K, a cytosolic protein that can bind four Ca2+ ions.
The mechanism of Ca2+ absorption in intestinal epithelial cells is illustrated in Figure 9-40. Ca2+ diffuses from the lumen into the cell, down its electrochemical gradient (Step 1). It is bound inside the cell to calbindin D-28K (Step 2) and subsequently is pumped across the basolateral membrane by a Ca2+ ATPase (Step 3). The exact role of calbindin D-28K in promoting absorption in intestinal epithelial cells is uncertain. It may act as a shuttle, moving Ca2+ across the cell from lumen to blood, or it may act as a Ca2+ buffer to keep intracellular free Ca2+low, thus maintaining the concentration gradient for Ca2+diffusion across the luminal membrane.
Figure 9–40 Role of calbindin D-28K in intestinal Ca2+ absorption. 1,25-Dihydroxycholecalciferol induces the synthesis of calbindin D-28K. See the text for an explanation of the circled numbers. ATP, Adenosine triphosphate.
Kidney. The actions of 1,25-dihydroxycholecalciferol on the kidney are parallel to its actions on the intestine—it stimulates both Ca2+ and phosphate reabsorption. In the kidney, the actions of 1,25-dihydroxycholecalciferol are clearly distinguishable from those of PTH. PTH stimulates Ca2+ reabsorption and inhibits phosphate reabsorption, and 1,25-dihydroxycholecalciferol stimulates the reabsorption of both ions.
Bone. In bone, 1,25-dihydroxycholecalciferol acts synergistically with PTH to stimulate osteoclast activity and bone resorption. This action may seem paradoxical because the overall action of 1,25-dihydroxycholecalciferol is to promote bone mineralization. However, mineralized “old” bone is resorbed to provide more Ca2+ and phosphate to ECF so that “new” bone can be mineralized (bone remodeling).
Pathophysiology of Vitamin D
In children, vitamin D deficiency causes rickets, a condition in which insufficient amounts of Ca2+ and phosphate are available to mineralize the growing bones. Rickets is characterized by growth failure and skeletal deformities. This condition is rare in areas of the world where vitamin D is supplemented and when there is adequate exposure to sunlight. In adults, vitamin D deficiency results in osteomalacia, in which new bone fails to mineralize, resulting in bending and softening of the weight-bearing bones.
Vitamin D resistance occurs when the kidney is unable to produce the active metabolite, 1,25-dihydroxycholecalciferol. This condition is called “resistant” because no matter how much vitamin D is supplemented in the diet, it will be inactive because the C1 hydroxylation step in the kidney is absent or is inhibited. Vitamin D resistance can be caused by the congenital absence of 1α-hydroxylase or, more commonly, by chronic renal failure. Chronic renal failure is associated with a constellation of bone abnormalities including osteomalacia, a consequence of the inability of the diseased renal tissue to produce 1,25-dihydroxycholecalciferol, the active form of vitamin D.