3164 PART 12 Endocrinology and Metabolism

calcinosis is caused by a rare group of genetic disorders in which

FGF23 is processed in a way that leads to low levels of active FGF23

in the bloodstream. This may result from mutations in the FGF23

sequence or via inactivating mutations in the GALNT3 gene, which

encodes a galactosaminyl transferase that normally adds sugar residues to FGF23 that slow its proteolysis. A similar syndrome results

from FGF23 resistance due to inactivating mutations of the FGF23 coreceptor Klotho. These abnormalities cause elevated serum 1,25(OH)2

D,

parathyroid suppression, increased intestinal calcium absorption, and

focal hyperostosis with large, lobulated periarticular heterotopic ossifications (especially at shoulders or hips) and are accompanied by hyperphosphatemia. In some forms of tumoral calcinosis, serum phosphorus

levels are normal.

When large amounts of phosphate are delivered rapidly into the

ECF, hyperphosphatemia can occur despite normal renal function.

Examples include overzealous IV phosphate therapy, oral or rectal

administration of large amounts of phosphate-containing laxatives or

enemas (especially in children), extensive soft tissue injury or necrosis

(crush injuries, rhabdomyolysis, hyperthermia, fulminant hepatitis,

cytotoxic chemotherapy), extensive hemolytic anemia, and transcellular phosphate shifts induced by severe metabolic or respiratory

acidosis.

Clinical Findings The clinical consequences of acute, severe

hyperphosphatemia are due mainly to the formation of widespread

calcium phosphate precipitates and resulting hypocalcemia. Thus,

tetany, seizures, accelerated nephrocalcinosis (with renal failure, hyperkalemia, hyperuricemia, and metabolic acidosis), and pulmonary or

cardiac calcifications (including development of acute heart block)

may occur. The severity of these complications relates to the elevation

of serum phosphate levels, which can reach concentrations as high as

7 mmol/L (20 mg/dL) in instances of massive soft tissue injury or

tumor lysis syndrome.

TREATMENT

Hyperphosphatemia

Therapeutic options for management of severe hyperphosphatemia

are limited. Volume expansion may enhance renal phosphate clearance. Aluminum hydroxide antacids or sevelamer may be helpful

in chelating and limiting absorption of offending phosphate salts

present in the intestine. Hemodialysis is the most effective therapeutic strategy and should be considered early in the course of

severe hyperphosphatemia, especially in the setting of renal failure

and symptomatic hypocalcemia.

MAGNESIUM METABOLISM

Magnesium is the major intracellular divalent cation. Normal concentrations of extracellular magnesium and calcium are crucial for normal neuromuscular activity. Intracellular magnesium forms a key complex with

ATP and is an important cofactor for a wide range of enzymes, transporters, and nucleic acids required for normal cellular function, replication,

and energy metabolism. The concentration of magnesium in serum

is closely regulated within the range of 0.7–1 mmol/L (1.5–2 meq/L;

1.7–2.4 mg/dL), of which 30% is protein-bound and another 15% is

loosely complexed to phosphate and other anions. One-half of the 25

g (1000 mmol) of total body magnesium is located in bone, only onehalf of which is insoluble in the mineral phase. Almost all extraskeletal

magnesium is present within cells, where the total concentration is 5

mM, 95% of which is bound to proteins and other macromolecules.

Because only 1% of body magnesium resides in the ECF, measurements

of serum magnesium levels may not accurately reflect the level of total

body magnesium stores.

Dietary magnesium content normally ranges from 6 to 15 mmol/d

(140–360 mg/d), of which 30–40% is absorbed, mainly in the jejunum

and ileum. Intestinal magnesium absorptive efficiency is stimulated

by 1,25(OH)2

D and can reach 70% during magnesium deprivation.

Urinary magnesium excretion normally matches net intestinal absorption and is ~4 mmol/d (100 mg/d). Regulation of serum magnesium

concentrations is achieved mainly by control of renal magnesium

reabsorption. Only 20% of filtered magnesium is reabsorbed in the

proximal tubule, whereas 60% is reclaimed in the cTAL and another

5–10% in the DCT. Magnesium reabsorption in the cTAL occurs via a

paracellular route that requires both a lumen-positive potential, created

by NaCl reabsorption, and tight-junction proteins encoded by members of the Claudin gene family. Magnesium reabsorption in the cTAL

is increased by PTH but inhibited by hypercalcemia or hypermagnesemia, both of which activate the CaSR in this nephron segment.

■ HYPOMAGNESEMIA

Causes Hypomagnesemia usually signifies substantial depletion

of body magnesium stores (0.5–1 mmol/kg). Hypomagnesemia can

result from intestinal malabsorption; protracted vomiting, diarrhea, or

intestinal drainage; defective renal tubular magnesium reabsorption;

or rapid shifts of magnesium from the ECF into cells, bone, or third

spaces (Table 409-4). Dietary magnesium deficiency is unlikely except

possibly in the setting of alcoholism. A rare genetic disorder that causes

selective intestinal magnesium malabsorption has been described

(primary infantile hypomagnesemia). Another rare inherited disorder

(hypomagnesemia with secondary hypocalcemia) is caused by mutations in the gene encoding TRPM6, a protein that, along with TRPM7,

forms a channel important for both intestinal and distal-tubular

renal transcellular magnesium transport. Malabsorptive states, often

compounded by vitamin D deficiency, can critically limit magnesium

absorption and produce hypomagnesemia despite the compensatory

effects of secondary hyperparathyroidism and of hypocalcemia and

hypomagnesemia to enhance cTAL magnesium reabsorption. Diarrhea or surgical drainage fluid may contain ≥5 mmol/L of magnesium.

Proton pump inhibitors (omeprazole and others) may produce hypomagnesemia by an unknown mechanism that does not involve renal

wasting of magnesium.

Several genetic magnesium-wasting syndromes have been described,

including inactivating mutations of genes encoding the DCT NaCl

co-transporter (Gitelman’s syndrome), proteins required for cTAL

Na-K-2Cl transport (Bartter’s syndrome), claudin 16 or claudin 19

(autosomal recessive renal hypomagnesemia with hypercalciuria),

a DCT Na+,K+-ATPase γ-subunit (autosomal dominant renal hypomagnesemia with hypocalciuria), DCT K+ channels (Kv1.1, Kir4.1),

and a mitochondrial gene encoding a tRNA. Activating mutations

of the CaSR can cause hypomagnesemia as well as hypocalcemia.

ECF expansion, hypercalcemia, and severe phosphate depletion may

impair magnesium reabsorption, as can various forms of renal injury,

including those caused by drugs such as cisplatin, cyclosporine, aminoglycosides, and pentamidine as well as the epidermal growth factor

(EGF) receptor inhibitory antibody cetuximab (EGF action is required

for normal DCT apical expression of TRPM6) (Table 409-4). A rising

blood concentration of ethanol directly impairs tubular magnesium

reabsorption, and persistent glycosuria with osmotic diuresis leads to

magnesium wasting and probably contributes to the high frequency of

hypomagnesemia in poorly controlled diabetic patients. Magnesium

depletion is aggravated by metabolic acidosis, which causes intracellular losses as well.

Hypomagnesemia due to rapid shifts of magnesium from ECF into

the intracellular compartment can occur during recovery from diabetic

ketoacidosis, starvation, or respiratory acidosis. Less acute shifts may

be seen during rapid bone formation after parathyroidectomy, with

treatment of vitamin D deficiency, or with osteoblastic metastases.

Large amounts of magnesium may be lost with acute pancreatitis,

extensive burns, or protracted and severe sweating and during pregnancy and lactation.

Clinical and Laboratory Findings Hypomagnesemia may cause

generalized alterations in neuromuscular function, including tetany,

tremor, seizures, muscle weakness, ataxia, nystagmus, vertigo, apathy, depression, irritability, delirium, and psychosis. Patients are

usually asymptomatic when serum magnesium concentrations are

>0.5 mmol/L (1 meq/L; 1.2 mg/dL), although the severity of symptoms may not correlate well with serum magnesium levels. Cardiac

3165Bone and Mineral Metabolism in Health and Disease CHAPTER 409

arrhythmias may occur, including sinus tachycardia, other supraventricular tachycardias, and ventricular arrhythmias. Electrocardiographic abnormalities may include prolonged PR or QT intervals,

T-wave flattening or inversion, and ST straightening. Sensitivity to

digitalis toxicity may be enhanced.

Other electrolyte abnormalities often seen with hypomagnesemia,

including hypocalcemia (with hypocalciuria) and hypokalemia, may

not be easily corrected unless magnesium is administered as well.

The hypocalcemia may be a result of concurrent vitamin D deficiency, although hypomagnesemia can cause impaired synthesis of

1,25(OH)2

D, cellular resistance to PTH, and, at very low serum

magnesium (<0.4 mmol/L [<0.8 meq/L; <1 mg/dL]), a defect in PTH

secretion; these abnormalities are reversible with therapy.

TREATMENT

Hypomagnesemia

Mild, asymptomatic hypomagnesemia may be treated with oral

magnesium salts (MgCl2

, MgO, Mg[OH]2

) in divided doses totaling 20–30 mmol/d (40–60 meq/d). Diarrhea may occur with larger

doses. More severe hypomagnesemia should be treated parenterally, preferably with IV MgCl2

, which can be administered safely

as a continuous infusion of 50 mmol/d (100 meq Mg2+/d) if renal

function is normal. If GFR is reduced, the infusion rate should be

lowered by 50–75%. Use of IM MgSO4

 is discouraged; the injections

are painful and provide relatively little magnesium (2 mL of 50%

MgSO4

 supplies only 4 mmol). MgSO4

 may be given IV instead

of MgCl2

, although the sulfate anions may bind calcium in serum

and urine and aggravate hypocalcemia. Serum magnesium should

be monitored at intervals of 12–24 h during therapy, which may

continue for several days because of impaired renal conservation

of magnesium (only 50–70% of the daily IV magnesium dose is

retained) and delayed repletion of intracellular deficits, which may

be as high as 1–1.5 mmol/kg (2–3 meq/kg).

It is important to consider the need for calcium, potassium,

and phosphate supplementation in patients with hypomagnesemia.

Vitamin D deficiency frequently coexists and should be treated with

oral or parenteral vitamin D or 25(OH)D (but not with 1,25(OH)2

D,

which may impair tubular magnesium reabsorption, possibly via

PTH suppression). In severely hypomagnesemic patients with concomitant hypocalcemia and hypophosphatemia, administration of

IV magnesium alone may worsen hypophosphatemia, provoking

neuromuscular symptoms or rhabdomyolysis, due to rapid stimulation of previously suppressed PTH secretion. This is avoided by

administering both calcium and magnesium.

■ HYPERMAGNESEMIA

Causes Hypermagnesemia is rarely seen in the absence of renal

insufficiency as normal kidneys can excrete large amounts (250 mmol/d)

of magnesium. Mild hypermagnesemia due to excessive reabsorption

in the cTAL occurs with CaSR mutations in familial hypocalciuric

hypercalcemia and has been described in some patients with adrenal insufficiency, hypothyroidism, or hypothermia. Massive exogenous magnesium exposures, usually via the gastrointestinal tract,

can overwhelm renal excretory capacity and cause life-threatening

hypermagnesemia (Table 409-5). A notable example of this is prolonged retention of even normal amounts of magnesium-containing

cathartics in patients with intestinal ileus, obstruction, or perforation.

Extensive soft tissue injury or necrosis also can deliver large amounts of

magnesium into the ECF in patients who have suffered trauma, shock,

TABLE 409-4 Causes of Hypomagnesemia

I. Impaired intestinal absorption

A. Hypomagnesemia with secondary hypocalcemia (TRPM6 mutations)

B. Malabsorption syndromes

C. Vitamin D deficiency

D. Proton pump inhibitors

II. Increased intestinal losses

A. Protracted vomiting/diarrhea

B. Intestinal drainage, fistulas

III. Impaired renal tubular reabsorption

A. Genetic magnesium-wasting syndromes

1. Gitelman’s syndrome

2. Bartter’s syndrome

3. Claudin 16 or 19 mutations

4. Potassium channel mutations (Kv1.1, Kir4.1)

5. Na+

,K+

-ATPase γ-subunit mutations (FXYD2)

B. Acquired renal disease

1. Tubulointerstitial disease

2. Postobstruction, ATN (diuretic phase)

3. Renal transplantation

C. Drugs and toxins

1. Ethanol

2. Diuretics (loop, thiazide, osmotic)

3. Cisplatin

4. Pentamidine, foscarnet

5. Cyclosporine

6. Aminoglycosides, amphotericin B

7. Cetuximab

D. Other

1. Extracellular fluid volume expansion

2. Hyperaldosteronism

3. SIADH

4. Diabetes mellitus

5. Hypercalcemia

6. Phosphate depletion

7. Metabolic acidosis

8. Hyperthyroidism

IV. Rapid shifts from extracellular fluid

A. Intracellular redistribution

1. Recovery from diabetic ketoacidosis

2. Refeeding syndrome

3. Correction of respiratory acidosis

4. Catecholamines

B. Accelerated bone formation

1. Post-parathyroidectomy

2. Treatment of vitamin D deficiency

3. Osteoblastic metastases

C. Other

1. Pancreatitis, burns, excessive sweating

2. Pregnancy (third trimester) and lactation

Abbreviations: ATN, acute tubular necrosis; SIADH, syndrome of inappropriate

antidiuretic hormone.

TABLE 409-5 Causes of Hypermagnesemia

I. Excessive magnesium intake

A. Cathartics, urologic irritants

B. Parenteral magnesium administration

II. Rapid mobilization from soft tissues

A. Trauma, shock, sepsis

B. Cardiac arrest

C. Burns

III. Impaired magnesium excretion

A. Renal failure

B. Familial hypocalciuric hypercalcemia

IV. Other

A. Adrenal insufficiency

B. Hypothyroidism

C. Hypothermia

3166 PART 12 Endocrinology and Metabolism

sepsis, cardiac arrest, or severe burns. Further, infusion of magnesium

in pregnant women with eclampsia can lead to hypocalcemia.

Clinical and Laboratory Findings The most prominent clinical

manifestations of hypermagnesemia are vasodilation and neuromuscular blockade, which may appear at serum magnesium concentrations

>2 mmol/L (>4 meq/L; >4.8 mg/dL). Hypotension that is refractory

to vasopressors or volume expansion may be an early sign. Nausea,

lethargy, and weakness may progress to respiratory failure, paralysis,

and coma, with hypoactive tendon reflexes, at serum magnesium levels

>4 mmol/L. Other findings may include gastrointestinal hypomotility

or ileus; facial flushing; pupillary dilation; paradoxical bradycardia;

prolongation of PR, QRS, and QT intervals; heart block; and, at serum

magnesium levels approaching 10 mmol/L, asystole.

Hypermagnesemia, acting via the CaSR, causes hypocalcemia and

hypercalciuria due to both parathyroid suppression and impaired cTAL

calcium reabsorption.

TREATMENT

Hypermagnesemia

Successful treatment of hypermagnesemia generally involves identifying and interrupting the source(s) of magnesium and employing

measures to increase magnesium clearance from the ECF. Use of

magnesium-free cathartics or enemas may be helpful in clearing

ingested magnesium from the gastrointestinal tract. Vigorous IV

hydration should be attempted, if appropriate. Hemodialysis is

effective and may be required in patients with significant renal

insufficiency. Calcium, administered IV in doses of 100–200 mg

over 1–2 h, has been reported to provide temporary improvement

in signs and symptoms of hypermagnesemia.

VITAMIN D

■ SYNTHESIS AND METABOLISM

1,25-Dihydroxyvitamin D [1,25(OH)2

D] is the major steroid hormone

involved in regulation of mineral ion homeostasis. Vitamin D and

its metabolites are hormones and hormone precursors rather than

vitamins, since in the proper biologic setting, they can be synthesized

endogenously (Fig. 409-4). In response to ultraviolet radiation of the

skin, a photochemical cleavage results in the formation of vitamin D

from 7-dehydrocholesterol. Cutaneous production of vitamin D is

decreased by melanin and high solar protection factor sunblocks,

which effectively impair skin penetration by ultraviolet light. The

increased use of sunblocks in North America and Western Europe and

a reduction in the magnitude of solar exposure of the general population over the past several decades has led to an increased reliance on

dietary sources of vitamin D. In the United States and Canada, these

sources largely consist of fortified cereals and dairy products, in addition to fish oils and egg yolks. Vitamin D from plant sources is in the

form of vitamin D2

, whereas that from animal sources is vitamin D3

.

These two forms have equivalent biologic activity and are activated

equally well by the vitamin D hydroxylases in humans. Vitamin D

enters the circulation, whether absorbed from the intestine or synthesized cutaneously, bound to vitamin D–binding protein, an α-globulin

synthesized in the liver. Vitamin D is subsequently 25-hydroxylated

in the liver by a cytochrome P450 oxidase in the mitochondria and

microsomes. The activity of this hydroxylase is not tightly regulated,

and the resultant metabolite, 25-hydroxyvitamin D [25(OH)D], is the

major circulating and storage form of vitamin D. Approximately 88% of

25(OH)D circulates bound to the vitamin D–binding protein, 0.03% is

free, and the rest circulates bound to albumin. The half-life of 25(OH)

D is ~2–3 weeks, with that of 25(OH)D2

 being shorter than that of

25(OH)D3

 due to a lower affinity of vitamin D–binding protein for the

former. The half-life of 25(OH)D is also greatly shortened when vitamin D–binding protein levels are reduced, as can occur with increased

urinary losses in the nephrotic syndrome.

The second hydroxylation, required for the formation of the mature

hormone, occurs in the kidney (Fig. 409-5). The 25-hydroxyvitamin

D-1α-hydroxylase (encoded by the CYP27B1 gene) is a tightly regulated cytochrome P450–like mixed-function oxidase expressed in the

proximal convoluted tubule cells of the kidney. PTH and hypophosphatemia are the major inducers of this microsomal enzyme in the kidney, whereas calcium, FGF23, and the enzyme’s product, 1,25(OH)2

D,

repress it. The 25-hydroxyvitamin D-1α-hydroxylase is also present

in numerous other cell types, where it is not subject to hormonal

regulation. It is expressed in epidermal keratinocytes, but keratinocyte

production of 1,25(OH)2

D is not thought to contribute to circulating

levels of this hormone. In addition to being present in the trophoblastic

layer of the placenta, the 1α-hydroxylase is produced by macrophages

associated with granulomas and lymphomas. In these latter pathologic

states, the activity of the enzyme is induced by interferon γ and TNF-α

but is not regulated by calcium or 1,25(OH)2

D; therefore, hypercalcemia, associated with elevated levels of 1,25(OH)2

D, may be observed.

Treatment of sarcoidosis-associated hypercalcemia with glucocorticoids, ketoconazole, or chloroquine reduces 1,25(OH)2

D production

and effectively lowers serum calcium. In contrast, chloroquine has not

been shown to lower the elevated serum 1,25(OH)2

D levels in patients

with lymphoma.

The major pathway for inactivation of vitamin D metabolites is an

additional hydroxylation step by the vitamin D 24-hydroxylase, an

enzyme that is expressed in most tissues. 1,25(OH)2

D is the major

inducer of this enzyme; therefore, this hormone promotes its own

inactivation, thereby limiting its biologic effects. FGF23 also induces

this hydroxylase, thereby reducing circulating 1,25(OH)2

D levels

by increasing its inactivation, as well as by impairing its synthesis.

Skin

7-Dehydrocholesterol

25(OH)D

1,25(OH)2D

Gut

Vitamin D

Vitamin D

Liver

Kidney

FIGURE 409-4 Vitamin D synthesis and activation. Vitamin D is synthesized in the

skin in response to ultraviolet radiation and also is absorbed from the diet. It is

then transported to the liver, where it undergoes 25-hydroxylation. This metabolite

is the major circulating form of vitamin D. The final step in hormone activation,

1α-hydroxylation, occurs in the kidney.

3167Bone and Mineral Metabolism in Health and Disease CHAPTER 409

Mutations of the gene encoding this enzyme (CYP24A1) can lead to

infantile hypercalcemia, and in those less severely affected, long-standing hypercalciuria, nephrocalcinosis, and nephrolithiasis can occur.

Polar metabolites of 1,25(OH)2

D are secreted into the bile and

reabsorbed via the enterohepatic circulation. Impairment of this recirculation, which is seen with diseases of the terminal ileum, leads to

accelerated losses of vitamin D metabolites.

■ ACTIONS OF 1,25(OH)2

D

1,25(OH)2

D mediates its biologic effects by binding to a member of

the nuclear receptor superfamily, the vitamin D receptor (VDR). This

receptor belongs to the subfamily that includes the thyroid hormone

receptors, the retinoid receptors, and the peroxisome proliferator–

activated receptors; however, in contrast to the other members of this

subfamily, only one VDR isoform has been isolated. The VDR binds to

target DNA sequences as a heterodimer with the retinoid X receptor,

recruiting a series of coactivators that modify chromatin and approximate the VDR to the basal transcriptional apparatus, resulting in the

induction of target gene expression. The mechanism of transcriptional

repression by the VDR varies with different target genes but has been

shown to involve either interference with the action of activating

transcription factors or the recruitment of novel proteins to the VDR

complex, resulting in transcriptional repression.

The affinity of the VDR for 1,25(OH)2

D is approximately three

orders of magnitude higher than that for other vitamin D metabolites.

In normal physiologic circumstances, these other metabolites are not

thought to stimulate receptor-dependent actions. However, in states

of vitamin D toxicity, the markedly elevated levels of 25(OH)D may

lead to hypercalcemia by interacting directly with the VDR and by

displacing 1,25(OH)2

D from vitamin D–binding protein, resulting in

increased bioavailability of the active hormone.

The VDR is expressed in a wide range of cells and tissues. The

molecular actions of 1,25(OH)2

D have been studied most extensively

in tissues involved in the regulation of mineral ion homeostasis. This

hormone is a major inducer of calbindin 9K, a calcium-binding protein

expressed in the intestine, which is thought to play an important role in

the active transport of calcium across the enterocyte. The two major calcium transporters expressed by intestinal epithelia, TRPV5 and TRPV6

(transient receptor potential vanilloid), are also vitamin D responsive.

By inducing the expression of these and other genes in the small intestine, 1,25(OH)2

D increases the efficiency of intestinal calcium absorption, and it also has been shown to have several important actions in

the skeleton. The VDR is expressed in osteoblasts and regulates the

expression of several genes in this cell. These genes include the bone

matrix proteins osteocalcin and osteopontin, which are upregulated

by 1,25(OH)2

D, in addition to type I collagen, which is transcriptionally repressed by 1,25(OH)2

D. Both 1,25(OH)2

D and PTH induce the

expression of RANK ligand, which promotes osteoclast differentiation

and increases osteoclast activity, by binding to RANK on osteoclast

progenitors and mature osteoclasts. This is the mechanism by which

1,25(OH)2

D induces bone resorption. 1,25(OH)2

D regulates phosphate

homeostasis, primarily by inducing the expression of FGF23 in osteocytes. However, the skeletal features associated with VDR-knockout

mice (rickets, osteomalacia) are largely corrected by increasing calcium

and phosphorus intake, underscoring the importance of vitamin D

action in the gut.

The VDR is expressed in the parathyroid gland, and 1,25(OH)2

D has

been shown to have antiproliferative effects on parathyroid cells and

to suppress the transcription of the parathyroid hormone gene. These

effects of 1,25(OH)2

D on the parathyroid gland are an important part

of the rationale for current therapies directed at preventing and treating

hyperparathyroidism associated with renal insufficiency.

The VDR is also expressed in tissues and organs that do not play a

role in mineral ion homeostasis. Notable in this respect is the observation that 1,25(OH)2

D has an antiproliferative effect on several cell

types, including keratinocytes, breast cancer cells, and prostate cancer

cells. The effects of 1,25(OH)2

D and the VDR on keratinocytes are

particularly intriguing, since the VDR is primarily a transcriptional

repressor in these cells. Alopecia is seen in humans and mice with

mutant VDRs but is not a feature of vitamin D deficiency; thus, the

effects of the VDR on the hair follicle are ligand-independent.

■ VITAMIN D DEFICIENCY

The mounting concern about the relationship between solar exposure

and the development of skin cancer has led to increased reliance on

dietary sources of vitamin D. Although the prevalence of vitamin D

deficiency varies, the third National Health and Nutrition Examination

Survey (NHANES III) revealed that vitamin D deficiency is prevalent

throughout the United States, with the prevalence being >29% in obese

children. The clinical syndrome of vitamin D deficiency can be a result

of deficient production of vitamin D in the skin, lack of dietary intake,

accelerated losses of vitamin D, impaired vitamin D activation, or resistance to the biologic effects of 1,25(OH)2

D (Table 409-6). The elderly

and nursing home residents are particularly at risk for vitamin D deficiency, since both the efficiency of vitamin D synthesis in the skin and

the absorption of vitamin D from the intestine decline with age. The

presence of terminal ileal disease also results in impaired enterohepatic

circulation of vitamin D metabolites. While intestinal malabsorption

of dietary fats and short bowel syndrome, including that associated

with intestinal bypass surgery, lead to vitamin D deficiency, the cause

1,25(OH)2D3

Ca2+ HPO4

2–

Calcification

Ca2+ HPO4

2–

Vitamin D3

Vitamin D25 hydroxylase

Liver

Kidney

Parathyroid

glands

Bone

25(OH)D-1αhydroxylase and

other factors

25(OH)D3

PTH

PTH

–

–

–

Blood

calcium

Intestine

Pi

– / +

1,25(OH)2D3

FIGURE 409-5 Schematic representation of the hormonal control loop for vitamin

D metabolism and function. A reduction in the serum calcium below ~2.2 mmol/L

(8.8 mg/dL) prompts a proportional increase in the secretion of parathyroid hormone

(PTH) and so mobilizes additional calcium from the bone. PTH promotes the

synthesis of 1,25(OH)2

D in the kidney, which in turn stimulates the mobilization of

calcium from bone and intestine and regulates the synthesis of PTH by negative

feedback.