Dolores M. Shoback, MD, & Deborah E. Sellmeyer, MD
This chapter presents a general overview of the key hormones involved in the regulation of calcium, phosphate, and bone mineral metabolism. These include parathyroid hormone, vitamin D—principally the 1,25-(OH)2 vitamin D metabolite (1,25-dihydroxycholecalciferol)—calcitonin, and fibroblast growth factor (FGF)-23. The cycle of bone remodeling is described as a basis for understanding normal maintenance of skeletal integrity in adults and of mineral homeostasis. The symptoms and signs caused by excess or deficiency of the calciotropic hormones are presented along with the natural histories of primary hyperparathyroidism, familial (benign) hypocalciuric hypercalcemia, hypercalcemia of malignancy, different forms of hypoparathyroidism, and medullary carcinoma of the thyroid. Two of the most commonly encountered causes of low bone mass—osteoporosis and osteomalacia—are reviewed, along with discussions regarding their pathogenesis.
NORMAL REGULATION OF CALCIUM & PHOSPHORUS METABOLISM
PARATHYROID GLANDS
Anatomy
Normal parathyroid glands each weigh 30–40 mg and are gray-tan to yellow-gray. Each individual typically has four glands, so that the average total parathyroid tissue mass in the adult is 120–160 mg.
The superior pair of parathyroid glands arise from the fourth branchial pouches in the embryo. These glands are located near the point of intersection of the middle thyroid artery and the recurrent laryngeal nerve. The superior parathyroid glands may be attached to the thyroid capsule posteriorly or, rarely, embedded in the thyroid gland itself. Alternative locations include the tracheoesophageal groove and the retroesophageal space. The blood supply to the superior parathyroid glands is from the inferior thyroid artery or, less commonly, the superior thyroid artery.
The inferior parathyroid glands develop from the third branchial pouch, as does the thymus gland. These glands typically lie at or near the lower pole of the thyroid gland lateral to the trachea. The inferior glands receive their blood supply from the inferior thyroid arteries. The location of the inferior parathyroid glands is variable. When there are ectopic glands, they are typically found in association with thymic remnants. A common site for ectopic glands is the anterior mediastinum. Less common ectopic locations are the carotid sheath, pericardium, and pharyngeal submucosa. About 10% of people have additional (supernumerary) parathyroid glands. This becomes a critically important issue when such ectopic glands develop hyperparathyroidism.
Histology
The parathyroid gland is composed of three different cell types: chief cells, clear cells, and oxyphil cells. Chief cells are small in diameter (4–8 μm) with central nuclei and are thought to be responsible for the synthesis and secretion of parathyroid hormone (PTH). In their active state, they have a prominent endoplasmic reticulum and dense Golgi regions where PTH is synthesized and packaged for secretion. Clear cells are probably chief cells with an increased glycogen content. Oxyphil cells appear in the parathyroid glands after puberty. They are larger than chief cells (6–10 μm), and their number increases with age. It is not clear whether these cells secrete PTH and whether they are derived from chief cells.
The normal adult parathyroid gland contains fat. The relative contribution of fat to the glandular mass increases with age and may reach 60–70% of gland volume in the elderly. If hyperplasia or adenomatous changes occur, the glandular fat content decreases dramatically.
Physiology
Approximately 99% of total body calcium is found in the skeleton and teeth; the remainder is in the extracellular fluids. Calcium in these fluids exists in three forms: ionized, protein bound, and complexed. About 47% of total blood calcium is protein bound, predominantly to albumin but also to globulins. A similar fraction is ionized. The remainder is complexed to organic ions such as citrate, phosphate, and bicarbonate. Serum ionized calcium controls vital cellular functions such as hormone secretion and action, muscle contraction, neuromuscular transmission, and blood clotting. The binding of calcium to albumin is pH dependent, increasing with alkalosis and decreasing with acidosis. Thus, if the ionized calcium is low, acidosis tends to protect against symptomatic hypocalcemia. Conversely, alkalosis predisposes to symptomatic hypocalcemia.
Circulating levels of PTH can change within seconds after an alteration in serum calcium. PTH secretory rates are related to the serum ionized calcium concentration by an inverse sigmoidal relationship (Figure 17-1). Low ionized calcium concentrations maximally stimulate secretion, whereas increases in calcium suppress the production and release of PTH. PTH secretion is exquisitely sensitive to very small changes in the calcium concentration, which have substantial effects on the rate of hormone synthesis and release.
FIGURE 17-1 Inverse sigmoidal relationship between parathyroid hormone (PTH) release and the extracellular calcium concentration in human studies (upper panel) and in vitro in human parathyroid cells (bottom panel). Studies shown in the upper panel were performed by infusing calcium and the calcium chelator EDTA into normal subjects. Serum intact PTH was measured by a two-site immunoradiometric assay. In the lower panel, PTH was measured in the medium surrounding parathyroid cells in vitro by an assay for intact PTH. The midpoint between the maximal and minimal secretory rates is defined as the set point for secretion. (Redrawn, with permission, from Brown E. Extracellular Ca2+ sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular [first] messengers. Physiol Rev. 1991;71:371.)
The extracellular calcium-sensing receptor (CaSR) is expressed by parathyroid and many other types of cells. Its job is to detect changes in the extracellular calcium concentration. This receptor is activated by increases in the calcium concentration and couples to intracellular pathways, which inhibits hormone secretion (Figure 17-2) and parathyroid cell proliferation. CaSRs are also expressed in the kidney, thyroid C cells, brain, and many other tissues. Hypocalcemia is also sensed by the CaSR, and PTH secretion is stimulated. Chronic hypocalcemia stimulates proliferation of parathyroid cells, which eventually results in glandular hyperplasia. Thus, the CaSR controls secretion and proliferation in appropriate directions to respond to physiologic needs.
FIGURE 17-2 Sequence of events by which the calcium ion concentration is sensed by the parathyroid calcium-sensing receptor (CaSR). Activation of this receptor is eventually linked through intracellular signal transduction pathways to the inhibition of PTH secretion and parathyroid cell proliferation. (Redrawn with modification from Taylor R. A new receptor for calcium ions. J NIH Res. 1994;6:25.)
PTH is produced in the parathyroid glands as a 115-amino-acid precursor molecule (preproPTH) that is successively cleaved within the cell to form the mature 84-amino-acid peptide PTH(1–84) (Figure 17-3). This form of the hormone is packaged into secretory granules and released into the circulation. PTH(1–84) is the biologically active form of PTH at target cells and has a very short half-life in vivo of approximately 10 minutes. PTH(1–84) is metabolized in the liver and other tissues to midregion and carboxyl terminal forms that are probably biologically inactive. These circulating fragments accumulate to very high levels in patients with renal failure, because the kidney is an important site for clearance of PTH from the body. Intact PTH assays in routine use measure PTH(1–84) using immunoradiometric or immunochemiluminometric methods that employ two antibodies: one directed against an amino terminal epitope, which is labeled, and the other directed against a carboxyl terminal epitope of PTH(1–84), which is immobilized (Figure 17-4). It is now clear that these “intact” PTH assays also detect amino-terminally truncated fragments of hormone such as PTH(7–84) that accumulate particularly in the serum of uremic patients. It is estimated that 30–50% of circulating “intact PTH” in uremic sera may represent these amino terminal fragments. This led to the development of “whole PTH” assays that only detect PTH(1–84). The amino terminal antibody in these assays specifically recognizes the first six amino acids of PTH(1–84). Such assays, however, have not replaced the original intact assays for routine clinical use.
FIGURE 17-3 Biosynthetic events in the production of parathyroid hormone (PTH) within the parathyroid cell. PreproPTH gene is transcribed to its mRNA, which is translated on the ribosomes to preproPTH (amino acids −29 to +84). The presequence is removed within the endoplasmic reticulum, yielding proPTH (−6 to +84). An additional six-amino-acid fragment is removed in the Golgi. Mature PTH(1−84) released from the Golgi is packaged in secretory granules and released into the circulation in the presence of hypocalcemia. The calcium-sensing receptor (CaSR) or CaR is proposed to sense changes in extracellular calcium that affect both the release of PTH and the transcription of the preproPTH gene. High extracellular calcium concentrations also promote the intracellular degradation of PTH. (Redrawn, with permission, from Habener JF et al. Biosynthesis of parathyroid hormone. Recent Prog Horm Res. 1977;33:249.)
FIGURE 17-4 Schematic representation of the principle of the two-site assay for parathyroid hormone (PTH), in this case full-length, biointact PTH(1–84). The label may be a luminescent probe or 125I in the immunochemiluminometric or immunoradiometric assay, respectively. Two different region-specific antibodies are used (Ab1 and Ab2). The epitope for Ab1 is at the extreme N-terminus ensuring that only the hormone species containing both N- and C-terminal/midregion immunodeterminants are counted in the assay.
Mechanism of Parathyroid Hormone Action
There are two types of PTH receptors. The type 1 receptor recognizes PTH and parathyroid hormone–related peptide (PTHrP) and is also called the PTH-1 receptor. The type 2 receptor is specific for PTH. PTH and PTHrP (described later) bind to the type 1 receptor through residues in their amino terminal domains. PTH activates adenylyl cyclase and produces the second-messenger cAMP (Figure 17-5). The type 1 receptor also couples to the stimulation of phospholipase C activity, leading to the generation of inositol trisphosphate and diacylglycerol (Figure 17-5). Activation of this signal transduction pathway induces intracellular calcium mobilization and protein kinase C activation in PTH- and PTHrP-responsive cells. The type 2 PTH receptor is expressed in nonclassic PTH target tissues (ie, brain, pancreas, testis, and placenta). This receptor is not thought to be involved in mineral balance, and its natural ligand may be a hypothalamic peptide called tubuloinfundibular peptide.
FIGURE 17-5 Signal transduction pathways activated by parathyroid hormone (PTH) binding to the PTH-1 receptor (PTH-R) in a target cell. PTH interacts with its receptor. This enhances guanosine triphosphate binding to the stimulatory G protein of adenylyl cyclase Gs, which activates the enzyme. Cyclic adenosine monophosphate (cAMP) is formed. PTH also increases G protein-dependent activation of phospholipase C (PLC), which catalyzes the breakdown of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). This produces the second messengers, inositol trisphosphate (1,4,5-InsP3) and diacylglycerol. 1,4,5-InsP3 mobilizes intracellular calcium, and diacylglycerol activates protein kinase C.
Effects of Parathyroid Hormone
The serum ionized calcium and phosphate concentrations reflect the net transfer of these ions from bone, GI tract, and glomerular filtrate. PTH and 1,25-(OH)2D play key roles in the regulation of calcium and phosphate balance (Figure 17-6). When the serum calcium concentration falls, PTH is rapidly released and acts quickly to promote calcium reabsorption in the distal tubule and the medullary thick ascending limb of Henle loop. PTH also stimulates the release of calcium from bone. These actions serve to restore serum calcium levels to normal.
FIGURE 17-6 Main actions of parathyroid hormone (PTH) and 1,25-(OH)2D in the maintenance of calcium and phosphate homeostasis. (Redrawn, with permission, from Chandrasoma P et al, eds. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.)
The renal action of PTH is rapid, occurring within minutes after an increase in the hormone. The overall effect of PTH on the kidney, however, depends on several factors. When hypocalcemia is present and PTH is elevated, urinary calcium excretion is low. This reflects the full expression of the primary renal effect of PTH to enhance renal calcium reabsorption. When PTH levels are high in primary hyperparathyroidism, hypercalcemia results from increased mobilization of calcium from bone and enhanced intestinal calcium absorption. These events increase the delivery of calcium to the glomerular filtrate. Because more calcium is filtered, more is excreted in the urine, despite the high PTH levels. If the filtered load of calcium is normal or low in a patient with primary hyperparathyroidism—because of a low dietary calcium intake or demineralized bone—urinary calcium excretion may be normal or even low. Thus, there may be considerable variability in calcium excretion among patients with hyperparathyroidism.
If kidney function is normal, chronic elevation in serum PTH increases renal 1,25-(OH)2D production. This steroid hormone stimulates both calcium and phosphate absorption across the small intestine (Figure 17-6). The effect requires at least 24 h to develop fully and begin to restore normal calcium levels. Achievement of eucalcemia then leads to a downward readjustment in the PTH secretory rate. Any increase in 1,25-(OH)2D serves to inhibit further PTH synthesis by binding to vitamin D receptors in the parathyroid.
The major effect of PTH on phosphate handling is to promote its excretion by inhibition of sodium-dependent phosphate transport in the proximal tubule. Serum phosphate levels are thought to affect PTH secretion rates directly, with hyperphosphatemia serving as a stimulus to PTH secretion by an uncertain mechanism. Hypophosphatemia enhances the conversion of 25-(OH)D to 1,25-(OH)2D in the kidney, which through its intestinal and renal effects promotes phosphate retention. Hyperphosphatemia also inhibits 1,25-(OH)2D production (see below) and lowers serum calcium by complexing with it in the circulation.
PTH also increases urinary excretion of bicarbonate through its action on the proximal tubule. This can produce proximal renal tubular acidosis. These physiologic responses to PTH are the basis for the hypophosphatemia and hyperchloremic acidosis commonly observed in patients with hyperparathyroidism. Dehydration is also common in moderate to severe hypercalcemia of any origin. This is due to the effect of hypercalcemia on vasopressin action in the medullary thick ascending limb of the kidney. High calcium levels, presumably by interacting with renal CaSRs, blunt the ability of endogenous vasopressin to stimulate water reabsorption. Thus, hypercalcemia induces vasopressin-resistant nephrogenic diabetes insipidus.
In conjunction with 1,25-(OH)2D, PTH increases bone resorption to restore normocalcemia (see below). PTH enhances osteoclastic activity through the stimulation of RANK-L (receptor activator of nuclear factor kappa B ligand), which is expressed by cells of the osteoblastic lineage (including stromal cells and osteoblasts). RANK-L interacts with its receptor RANK on cells of the osteoclast lineage to stimulate their differentiation and function, which is bone resorption (Figure 17-7). Once resorption ceases, bone formation ensues, because the processes of resorption and formation are coupled. In primary and secondary hyperparathyroidism, when PTH production rates are excessive, net bone loss may occur over time, perhaps because even though the processes of formation and resorption are coupled, they may not occur with 100% efficiency.
FIGURE 17-7 Cell-cell interactions and molecules essential for the differentiation and activation of osteoclasts. A cell surface molecule known as RANK-L on osteoblastic bone marrow stromal cells can interact with osteoclastic precursor cells in the bone marrow (derived from cells of the monocytic lineage) through their cell surface molecules designated RANK. This interaction, in the presence of sufficient macrophage colony-stimulating factor (mCSF), promotes the differentiation and fusion of these cells eventually to form mature osteoclasts and enables otherwise quiescent osteoclasts to resorb bone. These pathways are interfered with by the elaboration of a secreted decoy receptor molecule for RANK-L known as OPG, which blocks activation and differentiation of osteoclasts. (Oc, osteoclast.) (Redrawn, with permission, from Goltzman D. Osteolysis and cancer. J Clin Invest. 2001;107:1219.)
PARATHYROID HORMONE–RELATED PEPTIDE
PTHrP is a 141-amino-acid peptide that is homologous with PTH at its amino terminal region (Figure 17-8) and is recognized by the type 1 PTH receptor. Consequently, PTHrP has effects on bone and kidney similar to those of PTH; it increases bone resorption, increases phosphate excretion, and decreases renal calcium excretion. PTHrP is secreted by tumor cells and was originally identified as the cause of hypercalcemia of malignancy, a syndrome that can mimic primary hyperparathyroidism (see later).
FIGURE 17-8 The amino acid sequence of the 34 amino acid residue at the N terminal parathyroid hormone (PTH)–related peptide. Amino acids that are identical to those in PTH are shown with dark yellow borders. (Redrawn, with permission, from Felig P et al, eds. Endocrinology and Metabolism, 3rd ed. McGraw-Hill, 1995.)
Unlike PTH, which is exclusively produced by parathyroid cells, PTHrP is produced in many tissues. It functions mainly as a tissue growth and differentiation factor at the local level and a regulator of smooth muscle tone. In the normal development of cartilage and bone, PTHrP stimulates the proliferation of chondrocytes and inhibits the mineralization of cartilage. Embryos without PTHrP are nonviable, with multiple abnormalities of bone and cartilage. PTHrP also appears to regulate the normal development of skin, hair follicles, teeth, and the breast. PTHrP plays an important role in determining the calcium content of the milk from lactating animals.
Despite PTHrP binding to the same PTH-1 receptor (see above) to achieve most of its physiologic effects, new studies indicate that the consequences of PTH and PTHrP interacting with the receptor are surprisingly different. Each peptide has different effects on the conformational state and the extent of activation of the receptor. PTHrP can also be transcribed from a promoter that bypasses the signal peptide. This allows PTHrP (and not PTH) to enter the nucleus and mediate additional biological effects there. Thus, there are several ways by which cells can differentially react to these similar peptides.
CHECKPOINT
1. Describe the cell types in the parathyroid gland.
2. How do serum albumin concentration and blood pH influence the distribution of calcium into ionized and protein-bound fractions?
3. What advances have occurred in two-site immunoassays for PTH that affect uremic patients?
4. What are the actions of PTH and 1,25-(OH)2D on bone, kidney, and the GI tract?
5. What is PTHrP? How is its action similar to and different from that of PTH?
BONE
Bone has two compartments. On the outside is cortical or compact bone, which makes up 80% of the skeletal mass and plays a significant role in giving bone its strength. The other compartment is trabecular or cancellous bone, which makes up 20% of skeletal mass. Trabecular bone consists of interconnected plates, the trabeculae, which are covered by bone cells and are sites of active remodeling. The spaces in this irregular honeycomb are filled with bone marrow: either red marrow, in which hematopoiesis is active, or white marrow, which is mainly fat. Because of its high surface-to-volume ratio and abundant cellular activity, trabecular bone is remodeled more rapidly than cortical bone. Because of the low ratio of surface to volume, cortical bone is remodeled slowly.
To understand the remodeling process, it is important to know something about bone cells.
Osteocytes, the most abundant cells in bone, are derived from the osteoblast lineage and reside deep in the matrix. Osteocytes function as mechanoreceptors, detecting strain on the bone and signaling changes in bone remodeling. Osteoclasts, multinucleated giant cells specialized for resorption of bone, are terminally differentiated cells that arise continuously from hematopoietic precursors in the macrophage/monocyte lineage. The formation of osteoclasts requires the hematopoietic growth factor macrophage colony-stimulating factor (m-CSF) and a signal from marrow stromal cells. The critical signal, RANK-L, either resides on the surface of bone marrow stromal cells and osteoblastic cells or is secreted in the extracellular environment. This molecule, which is required for osteoclast differentiation and activation, binds to its receptor RANK on osteoclast precursors and signals to the cell interior. A variety of cells, including those from the marrow, produce a soluble, secreted decoy receptor, osteoprotegerin (OPG), that binds RANK-L, thereby preventing its interaction with RANK and halting osteoclast differentiation and activation (Figure 17-7). As osteoclasts mature, they acquire the capacity to produce osteoclast-specific enzymes and fuse to produce the mature multinucleated cell. The maturation process is accelerated by bone-resorbing hormones such as PTH and 1,25-(OH)2D, presumably through their effects on the RANK-L/OPG system.
To resorb bone, the motile osteoclast alights on a bone surface and seals off an area by forming an adhesive ring in which cellular integrins bind tightly to bone matrix proteins (Figure 17-9). Having isolated an area of bone surface, the osteoclast develops above the surface an elaborately invaginated plasma membrane structure called the ruffled border. The ruffled border is a distinctive organelle, but it acts essentially as a huge lysosome, which dissolves bone mineral by secreting acid onto the isolated bone surface, and simultaneously breaks down the bone matrix by secretion of collagenase and proteases. One important protease is cathepsin K, an enzyme being studied as a potential target for the pharmacologic treatment of bone loss. The resulting collagen peptides have pyridinoline cross-links that can be assayed in urine as a measure of bone resorption rates. Bone resorption can be controlled in two ways: by regulating the formation of osteoclasts and by regulating the activity of mature osteoclasts. The osteoblast, or bone-forming cell, arises from a mesenchymal precursor induced to differentiate in the bone marrow stroma. When actively forming bone, the osteoblast is a tall, plump cell with an abundant Golgi apparatus. On active bone-forming surfaces, osteoblasts are found side by side, laying down bone matrix by secreting proteins and proteoglycans. The most important protein of bone matrix is type I collagen, which makes up 90% of bone matrix and is deposited in regular layers that serve as the main scaffold for deposition of minerals.
FIGURE 17-9 Schematic view of an active osteoclast. Calcitonin receptors, the ruffled border, and enzymes and channels involved in secretion of acid onto the bone surface are shown. Integrins (alpha V, beta 3) are transmembrane-spanning receptors on osteoclasts, which bind to determinants (RGD) in bone matrix proteins such as fibronectins. The integrins are responsible for the tight attachment of osteoclasts to the bone surface. Cathepsin K and other lysosomal enzymes are secreted into the resorption pit to dissolve the matrix. (Redrawn, with permission, from Felig P et al, eds. Endocrinology and Metabolism, 3rd ed. McGraw-Hill, 1995.)
After laying down bone matrix, osteoblasts mineralize it by depositing hydroxyapatite crystals in an orderly array on the collagen layers to produce lamellar bone. The process of mineralization is poorly understood but requires an adequate supply of extracellular calcium and phosphate as well as the enzyme alkaline phosphatase, which is secreted in large amounts by active osteoblasts.
Bone remodeling occurs in an orderly cycle in which old bone is resorbed and new bone is deposited. Cortical bone is remodeled from within by cutting cones (Figure 17-10), groups of osteoclasts that cut tunnels through the compact bone. They are followed by trailing osteoblasts, lining the tunnels and laying down a cylinder of new bone on their walls, so that the tunnels are progressively narrowed until all that remains are the tiny haversian canals, by which the cells that are left behind as resident osteocytes are fed.
FIGURE 17-10 A cutting cone remodeling cortical bone. (Redrawn, with permission, from Felig P et al, eds. Endocrinology and Metabolism, 3rd ed. McGraw-Hill, 1995.)
In trabecular bone, the remodeling process occurs on the surface (Figure 17-11). Osteoclasts first excavate a pit, and the pit is then filled in with new bone by osteoblasts. In a normal adult, this cycle takes approximately 200 days. At each remodeling site, bone resorption and new bone formation are ordinarily tightly coupled, so that in a state of zero net bone balance, the amount of new bone formed is precisely equivalent to the amount of old bone resorbed. This degree of balance is brief, however. From approximately 20 to 30 years of age, bone mass is consolidated after gains in growth and mineral deposition that were achieved during adolescence. After age 30 or 35 years, adult females begin to lose bone slowly.
FIGURE 17-11 Sequential steps in remodeling of trabecular bone. (Redrawn, with permission, from Felig P et al, eds. Endocrinology and Metabolism, 3rd ed. McGraw-Hill, 1995.)
How osteoclasts and osteoblasts communicate to achieve the coupling that ensures perfect (or near-perfect) bone balance is not fully known. It appears that the important signals are local, not systemic. Although they have not been identified with certainty, one candidate is RANK-L (described above). RANK-L on the cell surface or as a soluble molecule binds to osteoclast precursors and supports their development and differentiation. RANK-L also binds to RANK on mature osteoclasts, and this may mediate the coupling of bone formation and bone resorption. The process of bone remodeling does not absolutely require systemic hormones except to ensure an adequate supply of calcium and phosphate. However, systemic hormones use the bone as a source of minerals for regulation of extracellular calcium homeostasis. Osteoblasts have receptors for PTH and 1,25-(OH)2D, but osteoclasts do not. Isolated osteoclasts do not respond to PTH or vitamin D, except in the presence of osteoblasts. This coupling mechanism makes certain that when bone resorption is activated by PTH (eg, to provide calcium to correct hypocalcemia) bone formation will also increase, tending to replenish lost bone.
CHECKPOINT
6. Describe the two compartments of bone.
7. How is bone resorption by osteoclasts controlled?
8. What is the role of osteoblasts in bone formation? How are the actions of osteoblasts and osteoclasts coupled?
VITAMIN D
Vitamin D is actually a prohormone produced in the dermis in response to ultraviolet B (UVB) exposure and metabolized to its active forms in the liver first, then in the kidney. The amount of sunlight exposure necessary to produce sufficient vitamin D is difficult to estimate because of individual differences in skin pigmentation, latitude, and time of day. Dietary sources are relatively modest in vitamin D content. For example, fish ingest ultraviolet-irradiated sterols (in phytoplankton and zooplankton) that are converted to vitamin D and stored in their livers.
Physiology
7-Dehydrocholesterol, stored in the epidermis, is converted to vitamin D3 (cholecalciferol) by ultraviolet light (wavelengths 280–310 nm) (Figure 17-12). This step involves breakage of the B ring of the cholesterol structure to produce a secosteroid; hormones with an intact cholesterol nucleus (eg, estrogen) are called steroids. A similar process occurs in plants with one small structural difference, resulting in vitamin D2 rather than vitamin D3. Vitamin D2is activated similarly to D3 in humans but does appear to have a decreased binding affinity for vitamin D–binding protein, resulting in enhanced clearance. This is particularly evident when large intermittent doses (ie, once weekly) rather than single daily doses are used medically in the treatment of vitamin D deficiency.
FIGURE 17-12 The formation and activation of vitamin D. (Redrawn, with permission, from Felig P et al, eds. Endocrinology and Metabolism, 3rd ed. McGraw-Hill, 1995.)
Although cutaneous synthesis of vitamin D can be sufficient to prevent rickets (the overt skeletal manifestation of vitamin D deficiency), it is not clear that sunlight exposure can be obtained in sufficient quantities to optimize vitamin D stores without untoward skin consequences. Further, at most latitudes in the United States, there is insufficient UVB radiation in the sunlight during the winter months to induce cutaneous production of vitamin D. In 2011, the Institute of Medicine revised the recommended intakes of vitamin D, recommending consumption of 400 IU/d up to 1 year of age, 600 IU/d for individuals 1–70 years of age, and 800 IU/d for individuals older than 70 years. In the United States, milk is supplemented with 400 IU of vitamin D per quart. Dietary supplements of vitamin D consist of vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol).
While there is minimal regulation of vitamin D production in the skin, enhanced sun exposure does not result in vitamin D toxicity, as there is photo-conversion of vitamin D to inactive metabolites when skin levels of vitamin D rise. Vitamin D formed in the skin is a lipophilic substance that is transported to the liver bound to albumin and a specific vitamin D–binding protein (DBP). Ingested vitamin D is transported to the liver via chylomicrons. In the liver, vitamin D is hydroxylated to produce 25-hydroxyvitamin D (25-[OH]D) (Figure 17-12). This process is not closely regulated. 25-(OH)D is transported by DBP in the serum to target tissues and is stored in the liver and adipose tissues. The clinical test for vitamin D deficiency is measurement of the serum level of 25-(OH)D.
The final metabolic processing step in the synthesis of the circulating active hormone, 1,25-(OH)2D, takes place principally in the kidney, although many tissues can locally activate vitamin D for paracrine and autocrine functions. The conversion of 25-(OH)D to 1,25-(OH)2D by the 25-(OH)D 1-hydroxylase in the renal cortex is tightly regulated. The synthesis of 1,25-(OH)2D is increased by PTH, thus linking the formation of 1,25-(OH)2D closely to PTH in the integrated control of calcium homeostasis. The production of 1,25-(OH)2D is also stimulated by hypophosphatemia and hypocalcemia. On the other hand, hypercalcemia, hyperphosphatemia, fibroblast growth factor (FGF)-23, and decreased PTH will reduce 1,25-(OH)2D production. As an additional control, 1,25-(OH)2D induces the enzyme 24-hydroxylase, which catabolizes 25-(OH)D and 1,25-(OH)2D, thus reducing their levels. The coordinated control by PTH, blood mineral levels, and the vitamin D supply is very efficient. Serum levels of 1,25-(OH)2D vary only slightly over an enormous range of vitamin D production rates but respond precisely to changes in the serum levels of calcium and phosphate within the normal range.
Vitamin D Action
The vitamin D receptor is a member of the steroid receptor superfamily of nuclear DNA-binding receptors. Upon ligand binding, the receptor attaches to enhancer sites in target genes and directly regulates their transcription. Thus, many of the effects of vitamin D involve new RNA and protein synthesis. Although many vitamin D metabolites are recognized by the receptor, 1,25-(OH)2D has an affinity approximately 1000-fold greater than that of 25-(OH)D. 25-(OH)D is present in the circulation at nanogram quantities, whereas 1,25-(OH)2D circulates in picogram quantities; thus, other vitamin D metabolites besides 1,25-(OH)2D may interact with the vitamin D receptor to produce clinical effects.
The primary target organs for 1,25-(OH)2D are intestine and bone. The most essential action of 1,25-(OH)2D is to stimulate the active intestinal transport of calcium in the duodenum. Calcium also can be absorbed passively through a paracellular route throughout the small intestine. However, particularly at low calcium intakes, the majority of gastrointestinal calcium absorption is mediated by the active vitamin D–mediated process. 1,25-(OH)2D also induces the active transport of phosphate, but passive absorption dominates this process, and the net effect of 1,25-(OH)2D is small.
In bone, 1,25-(OH)2D regulates a number of osteoblastic functions. Vitamin D deficiency leads to rickets, a defect in mineralization. However, the defect in mineralization results mainly from decreased delivery of calcium and phosphate to sites of mineralization. 1,25-(OH)2D also stimulates osteoclasts to resorb bone, releasing calcium to maintain the extracellular calcium concentration. This likely results from activation of the RANK-L/RANK signaling pathway by 1,25-(OH)2D.
To demonstrate the interplay among calcium, phosphorus, PTH, and vitamin D, consider a person who switches from a high normal to a low intake of calcium and phosphate: from 1200 to 300 mg/day of calcium (the equivalent of leaving three glasses of milk out of the diet). The net absorption of calcium falls sharply, causing a transient decrease in the serum calcium level. This activates a homeostatic response led by an increase in PTH. The increased PTH level stimulates the release of calcium from bone and the retention of calcium by the kidney. In addition, the increase in PTH, the fall in calcium, and the concomitant fall in the serum phosphate level (because of both decreased intake and PTH-induced phosphaturia) activate renal 1,25-(OH)2D synthesis. 1,25-(OH)2D increases the fraction of calcium that is absorbed from the intestine, further increases calcium release from bone, and restores the serum calcium to normal. 1,25-(OH)2D also promotes the intestinal absorption of phosphorus, although phosphorus absorption is much less regulated than calcium absorption. While these mechanisms can compensate for a low dietary calcium intake and maintain normal serum calcium and phosphorus levels, this is at the expense of mobilizing stored calcium from bone and maintaining an elevated PTH level. Over the long term, these compensatory mechanisms will result in depletion of skeletal calcium, increased bone resorption, and compromised skeletal integrity.
FIBROBLAST GROWTH FACTOR-23 (FGF-23)
FGF-23 Biochemistry
FGF-23 is a member of the large family of FGFs, local factors that are important in the control of cell proliferation and differentiation. FGF-23, in contrast to other FGF family members, plays a central role in the regulation of systemic phosphate homeostasis, vitamin D metabolism, and bone mineralization. Studies of kindreds with rare genetic disorders as well as transgenic and knockout mouse models that target essential molecules in FGF-23 signaling cascades have demonstrated the importance of FGF-23 in phosphate metabolism and skeletal mineralization.
Physiology of FGF-23
FGF-23 is produced by many tissues in the body, but its primary source appears to be bone cells, particularly osteocytes. A critical regulator of FGF-23 production is the serum phosphate level (Figure 17-13). Under normal physiologic conditions, when phosphate levels rise (eg, high-phosphate diet, renal failure), FGF-23 levels increase. When serum phosphate levels fall (eg, phosphate depletion, low-phosphate diet), serum FGF-23 levels decrease. In states of phosphate excess, FGF-23 reduces the expression of the sodium phosphate co-transporters (NaPi 2a and 2c) in the kidney and intestine. This leads to the rapid excretion of phosphate by the kidney and reduced intestinal phosphate absorption, which in turn restore the serum phosphate level to normal. To further control the amount of phosphate being delivered to the circulation, FGF-23 also inhibits the renal production of 1,25-(OH)2D (see Figure 17-13), further decreasing intestinal phosphorus absorption. These direct actions of FGF-23 are mediated by FGF receptors and their co-receptor transmembrane protein klotho.
FIGURE 17-13 Phosphate homeostasis is maintained by the coordinated actions of FGF-23 and 1,25(OH)2D. Low serum phosphate (PO43−) levels suppress FGF-23 production, which increases 1,25(OH)2D production and the expression of renal and intestinal phosphate transporters (NaPi 2a, 2c). As a result, intestinal and renal phosphate reabsorption rise to restore serum phosphate back to normal. When serum phosphate levels increase, FGF-23 levels rise, thereby suppressing these same biochemical pathways, and restoring serum phosphate balance.
Role of FGF-23 in Disease
Several rare disorders have served to define the actions of FGF-23 in phosphate and vitamin D metabolism in humans. Disorders of FGF-23 excess include X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and tumor-induced osteomalacia (Table 17-12 and see the section on osteomalacia, below). Hypophosphatemia and osteomalacia resulting from phosphate wasting with a low or inappropriately normal serum 1,25-(OH)2D level are the hallmarks of these disorders. In contrast, loss of function of FGF-23, due to rare genetic disorders, is associated with syndromes of ectopic calcification, abnormal mineralization, and hyperphosphatemia. The role of FGF-23 in the hyperphosphatemia and osteodystrophy of chronic kidney disease is being actively investigated.
CHECKPOINT
9. How is vitamin D produced from 7-dehydrocholesterol?
10. Where is vitamin D stored?
11. Where does the final step in the activation of vitamin D take place, and how is it regulated?
12. What are the actions of vitamin D?
PARAFOLLICULAR CELLS (C CELLS)
Anatomy & Histology
C cells of the thyroid gland secrete the peptide hormone calcitonin. They constitute 0.1% or less of thyroid cell mass and are distributed in the central parts of the lateral lobes of the thyroid, especially between the upper and middle thirds of the lobes. C cells are neuroendocrine cells derived from the ultimobranchial body, a structure that fuses with the thyroid.
C cells are small spindle-shaped or polygonal cells distributed throughout the thyroid. They contain abundant granules, mitochondria, and Golgi. They may be present as single cells or arranged in nests, cords, and sheets within the thyroid parenchyma. They are often found within thyroid follicles, are larger than follicular cells, and stain positively for calcitonin.
Physiology
Calcitonin is a 32-amino-acid peptide hormone with a seven-member amino terminal disulfide ring and carboxyl terminal prolineamide (Figure 17-14). Differential processing of the calcitonin gene can lead to the production of either calcitonin in C cells or calcitonin gene-related peptide in neurons. Although both calcitonin and calcitonin gene-related peptide have demonstrated clinical effects in pharmacologic doses, the function of the peptides at normal physiologic levels is unknown. C-cell tumors may release both peptides.
FIGURE 17-14 Amino acid sequence of human calcitonin, demonstrating its biochemical features, including an amino terminal disulfide bridge and carboxyl terminal prolineamide.
Hypercalcemia stimulates the release of calcitonin through the activation of CaSRs in C cells. Substantial changes in serum calcium are normally required to modulate the release of calcitonin. It is not known whether small physiologic changes in serum calcium, which rapidly modulate PTH secretion, elicit significant changes in calcitonin levels. The GI hormones cholecystokinin and gastrin are also secretagogues for calcitonin.
Calcitonin secretion in vivo is assessed by measuring serum levels with a two-site radioimmunoassay.
Actions of Calcitonin
Calcitonin interacts with receptors in kidney and bone. This interaction stimulates adenylyl cyclase activity and the generation of cAMP (as shown in Figure 17-5 for PTH). In the kidney, receptors for calcitonin are localized in the cortical ascending limb of Henle loop, whereas in bone calcitonin receptors are found on osteoclasts.
The main function of calcitonin is to lower serum calcium, and this hormone is rapidly released in response to hypercalcemia. Calcitonin inhibits osteoclastic bone resorption and rapidly blocks the release of calcium and phosphate from bone. The latter effect is apparent within minutes after the administration of calcitonin. These effects ultimately lead to a fall in serum calcium and phosphate.
Calcitonin acts directly on osteoclasts and blocks the resorption of bone induced by hormones like PTH and vitamin D. The potency of calcitonin depends on the underlying rate of bone resorption. Calcitonin also has a modest effect on the kidney to produce mild phosphaturia. With continued administration of calcitonin, “escape” from its effects on serum calcium occurs.
The overall importance of calcitonin in the maintenance of calcium homeostasis is unclear. Serum calcium concentrations are normal in patients after thyroidectomy, which removes all functioning C cells. Similarly, calcitonin typically rises to very high levels in patients with medullary carcinoma of the thyroid with no apparent effect on serum calcium levels.
CHECKPOINT
13. What are the actions of calcitonin?
14. What is the effect of thyroidectomy on serum calcium?
PATHOPHYSIOLOGY OF SELECTED DISORDERS OF CALCIUM METABOLISM
PRIMARY & SECONDARY HYPERPARATHYROIDISM
Etiology
Primary hyperparathyroidism is due to excessive production and release of PTH by the parathyroid glands. The prevalence of hyperparathyroidism is approximately 1:1000 in the United States, and the incidence of the disease increases with age. The patient group most frequently affected is postmenopausal women.
Primary hyperparathyroidism may be caused by any of the following: adenoma, hyperplasia, or carcinoma (Table 17-1). Chief cell adenomas are the most common cause, accounting for almost 85% of all cases. The vast majority of parathyroid adenomas occur sporadically and are solitary.
TABLE 17-1 Causes of primary hyperparathyroidism.
Parathyroid hyperplasia refers to an enlargement or abnormality of all four glands. In atypical forms of hyperplasia, only one gland may be enlarged, but the other three glands typically show at least slight microscopic abnormalities such as increased cellularity and reduced fat content. The distinction between hyperplasia and multiple adenomas is challenging and usually requires the examination of all four glands. Key characteristics for judging whether a gland is normal or not are its size, weight, and histologic features.
Parathyroid hyperplasia may be part of the autosomal dominant multiple endocrine neoplasia (MEN) syndromes (Table 17-2). In patients with MEN-1, caused by mutations in the MEN1 gene, which encodes the protein menin, there is high penetrance of hyperparathyroidism, affecting as many as 95% of patients. When their glands are examined microscopically, there are usually abnormalities in all four glands. Recurrent hyperparathyroidism, even after initially successful surgery, is common in these patients. Hyperparathyroidism also occurs in MEN-2A, although at a much lower frequency (about 20%). Familial hyperparathyroidism, without other features of MEN syndromes, characteristically involves all four glands, but there is often asynchrony in the presentation of the hyperparathyroidism. Kindreds with isolated hyperparathyroidism and mutations in menin are considered to be allelic variants of MEN-1. The hyperparathyroidism-jaw tumor syndrome and familial isolated hyperparathyroidism are causes of autosomal dominant hyperparathyroidism. The former often includes ossifying fibromas of the jaw and renal tumors and is caused by inactivating germline mutations in the HRPT2 gene that encodes the protein parafibromin.
TABLE 17-2 Clinical features of multiple endocrine neoplasia syndromes.
Parathyroid carcinoma is a rare malignancy, but the diagnosis should be considered in a patient with severe hypercalcemia and a palpable cervical mass. At surgery, cancers are firmer than adenomas and more likely to be attached to adjacent structures. It is sometimes difficult to distinguish parathyroid carcinomas from adenomas on histopathologic grounds. Vascular or capsular invasion by tumor cells is a good indicator of malignancy, but these features are not always present. In many cases, local recurrences or distant metastases to liver, lung, or bone are the clinical findings that support this diagnosis. Approximately 20% of patients with the hyperparathyroidism-jaw tumor syndrome and germline mutations in the HRPT2 gene (described above) develop parathyroid cancer. Furthermore, mutations in HRPT2 have also been found in familial isolated hyperparathyroidism and in sporadic parathyroid cancers. The normal cellular function of parafibromin is unknown.
Secondary hyperparathyroidism implies diffuse glandular hyperplasia resulting from a defect outside the parathyroids. Secondary hyperparathyroidism in patients with normal kidney function may be observed in patients with severe calcium and vitamin D deficiency states (see below). In patients with chronic kidney disease, there are many causative factors that contribute to the often dramatic enlargement of the parathyroid glands. These include decreased 1,25-(OH)2D production, reduced intestinal calcium absorption, skeletal resistance to PTH, and renal phosphate retention.
Pathogenesis
PTH secretion in primary hyperparathyroidism is excessive given the level of the serum calcium. At the cellular level, there is both increased cell mass and a secretory defect. The latter is characterized by reduced sensitivity of PTH secretion to suppression by the elevated serum calcium concentration. This qualitative regulatory defect is more common than truly autonomous secretion. Thus, parathyroid glands from patients with primary hyperparathyroidism are typically enlarged and, in vitro, demonstrate a “shift to the right” in their calcium setpoint for secretion (Figure 17-15). How these two defects interact in the pathogenesis of the disease remains to be fully elucidated.
FIGURE 17-15 PTH secretion in vitro from human parathyroid cells from patients with parathyroid adenomas and hyperplasia. The set-point for secretion is the calcium concentration at which PTH release is suppressed by 50%. This is shifted to the right in the majority of parathyroid adenomas compared to normal tissues, in which the set-point is approximately 1.0 mmol/L ionized calcium. (Redrawn, with permission, from Brown EM et al. Dispersed cells prepared from human parathyroid glands: distinct calcium sensitivity of adenomas vs primary hyperplasia. J Clin Endocrinol Metab. 1978;46:267.)
The genetic defects responsible for primary hyperparathyroidism have received considerable attention. Genes that regulate the cell cycle are thought to be important in the pathogenesis of a significant subset of parathyroid tumors. The PRAD1 gene (parathyroid rearrangement adenoma), whose product is a D1 cyclin, has been implicated in parathyroid tumor development and also in the pathogenesis of several malignant tumors (B-cell lymphomas, breast and lung cancers, and squamous cell cancers of the head and neck). Cyclins are cell cycle regulatory proteins. The PRAD1 gene is located on the long arm of chromosome 11, as is the gene encoding for PTH. Analysis of parathyroid tumor DNA suggests that a chromosome inversion event occurred, which led to juxtaposition of the 5-regulatory domain of the PTHgene upstream to the PRAD1 gene (Figure 17-16). Because regulatory sequences in the PTH gene are responsible for its cell-specific transcription, this inversion was initially postulated to lead to a parathyroid cell-specific overproduction of the PRAD1 gene product. Excessive cyclin would enhance the proliferative potential of the cells bearing this inversion and, given sufficient time, could induce PTH excess. A transgenic mouse model in which cyclin D1 is overexpressed in parathyroid tissue under the control of the PTH gene promoter provides proof for this pathogenetic mechanism of primary hyperparathyroidism.
FIGURE 17-16 Proposed genetic rearrangement of chromosome 11 in a subset of sporadic parathyroid adenomas. An inversion of DNA sequence near the centromere of chromosome 11 places the 5′-regulatory region of the PTHgene (also on chromosome 11) adjacent to the PRAD1 gene, whose product is involved in cell cycle control. This places the PRAD1 gene under the control of PTH regulatory sequences, which would be predicted to be highly active in parathyroid cells. (Redrawn, with permission, from Arnold A. Molecular genetics of parathyroid gland neoplasia. J Clin Endocrinol Metab. 1993;77:1109.)
The gene responsible for MEN-1, which produces the protein product menin, was identified in 1997. It is thought to function as a tumor suppressor gene. In keeping with the “two-hit” hypothesis of oncogenesis, patients with MEN-1 inherit an abnormal or inactivated MEN1 allele from one parent. This germline defect is present in all cells. During postnatal life, the other MEN1 allele in a parathyroid cell, for example, undergoes spontaneous mutation or deletion. If this second mutation confers a growth advantage on the descendant cells, there is clonal outgrowth of cells bearing the second mutation, and eventually a tumor results. In approximately 25% of nonfamilial benign parathyroid adenomas, there is allelic loss of DNA from chromosome 11, where the MEN1 gene is located.
Menin localizes to the nucleus, where it binds to the transcription factor JunD in vitro and suppresses transcription. The role of menin in normal physiology and the mechanisms by which it promotes tumor formation in the pituitary, pancreas, and parathyroid glands are unknown. Mice with targeted deletion of both genes encoding the murine menin homologues (or Men1) die in utero. Mice that are heterozygous for Men1 deletion survive but develop tumors in their pancreatic islets, adrenal cortices, and parathyroid, thyroid, and pituitary glands as they age, serving as a model for the MEN-1 syndrome.
Genetic testing is available to detect mutations in the MEN1 gene so that appropriate case management and genetic counseling can be done.
Hyperparathyroidism in MEN-2A is caused by mutations in the RET protein. RET clearly plays an important role in the pathogenesis of the other endocrine tumors in these syndromes as well as in familial medullary carcinoma of the thyroid (see below). How RET mutations alter parathyroid cell growth or PTH secretion has not been elucidated.
Clinical Manifestations
Hyperparathyroidism may present in a variety of ways. Patients with this disease may be asymptomatic, and their diagnosis is made by screening laboratory tests. Other patients may have skeletal complications or nephrolithiasis. Because calcium affects the functioning of nearly every organ system, the symptoms and signs of hypercalcemia are protean (Table 17-3). Depending on the nature of the complaints, the patient with primary hyperparathyroidism may be suspected of having a psychiatric disorder, a malignancy, or, less commonly, a granulomatous disease such as tuberculosis or sarcoidosis.
TABLE 17-3 Symptoms and signs of primary hyperparathyroidism.
Primary hyperparathyroidism is a chronic disorder in which longstanding PTH excess and hypercalcemia may produce increasing symptomatology, especially symptoms from renal stones or low bone mass. Recurrent stones containing calcium phosphate or calcium oxalate occur in 10–15% of patients with primary hyperparathyroidism. Nephrolithiasis may be complicated by urinary outflow tract obstruction, infection, and progressive renal insufficiency. Patients with significant PTH excess may experience increased bone turnover and progressive loss of bone mass, especially in postmenopausal women. This is reflected in subperiosteal resorption, osteoporosis (particularly of cortical bone), and even pathologic fractures.
A sizable proportion of patients with primary hyperparathyroidism, however, are asymptomatic. These patients may experience no clinical deterioration if their hyperparathyroidism is monitored rather than treated surgically. Because it is difficult to identify these patients with certainty when the diagnosis of hyperparathyroidism is made, regular follow-up is mandatory. Recent studies indicate that bone mass may deteriorate significantly, especially at cortical sites (ie, hip, forearm) after conservative follow-up beyond 8–10 years. These observations have reopened the issue about the advisability of long-term medical observation in this condition. By comparison, patients with mild disease who undergo definitive parathyroid surgery will experience improvements in bone mass over time. These data raise the question as to how a presumed innocuous mild primary hyperparathyroidism may be deleterious to the skeleton.
Radiologic features of primary hyperparathyroidism are caused by the chronic effects of excess PTH on bone. These include subperiosteal resorption (evident most strikingly in the clavicles and distal phalanges), generalized low bone mass, and the classic but now rare brown tumors. Uncommonly, osteosclerosis may result from excessive PTH action on bone. Abdominal films or computed tomography may show nephrocalcinosis or nephrolithiasis.
The complete differential diagnosis of hypercalcemia should be considered in all patients with this abnormality (Table 17-4). Primary hyperparathyroidism accounts for most cases of hypercalcemia in the outpatient setting (>90%). The diagnosis of primary hyperparathyroidism is confirmed by at least two simultaneous measurements of calcium and intact PTH. An elevated or inappropriately normal PTH in the setting of hypercalcemia is the key feature in making the diagnosis of primary hyperparathyroidism—the most common cause of PTH-dependent hypercalcemia (Table 17-5).
TABLE 17-4 Differential diagnosis of hypercalcemia.
TABLE 17-5 Laboratory findings in hypercalcemia from various causes.
Patients with secondary hyperparathyroidism may have normal or subnormal calcium levels (see below). If renal function is normal, serum phosphate is also often reduced, due to the phosphaturic effects of the high PTH levels. Although serum PTH is elevated, the demineralized state of the bone and the chronic vitamin D deficiency combine to produce a low filtered load of calcium. Hence, urinary calcium excretion is often quite low. The 25-(OH)D level is also low or undetectable in vitamin D deficiency resulting from a variety of causes.
FAMILIAL (BENIGN) HYPOCALCIURIC HYPERCALCEMIA
Etiology
In patients with asymptomatic hypercalcemia, the diagnosis of familial (benign) hypocalciuric hypercalcemia should be considered. Individuals with this condition typically have an elevated serum calcium and magnesium, normal or mildly elevated PTH levels, and hypocalciuria (Table 17-5). This disorder is inherited in an autosomal dominant manner and is typically due to point mutations in one allele of the CaSR gene. In families with this form of benign hypercalcemia, there are rare occurrences of neonatal severe primary hyperparathyroidism. Infants with this form of hyperparathyroidism, usually the result of consanguinity, generally have inherited two copies of mutant CaSR genes.
Pathogenesis
The CaSR, a member of the G protein-coupled receptor superfamily, is highly expressed in the parathyroid gland and kidney. In the parathyroid, the molecule functions to detect changes in ambient serum calcium concentration and then adjust the rate of PTH secretion. In the kidney, the CaSR sets the level of urinary calcium excretion, based on its perception of the serum calcium concentration.
In familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, the ability to detect serum calcium is faulty in both the kidney and parathyroid. Familial hypocalciuric hypercalcemia is due to a partial reduction—and neonatal hyperparathyroidism to a marked reduction—in the ability to sense extracellular calcium. Parathyroid chief cells missense the serum calcium as “low,” and PTH secretion occurs when it should be suppressed (Figure 17-2). This produces inappropriately normal or slightly high PTH levels. In the kidney, serum calcium concentrations are also detected (inappropriately) as low, and calcium is retained. This produces the hypocalciuria typical of this condition. Depending on the mutant gene dosage, the clinical symptoms tend to be mild in familial hypocalciuric hypercalcemia and profound and life-threatening in neonatal severe hyperparathyroidism.
Clinical Manifestations
Patients with familial hypocalciuric hypercalcemia typically have lifelong asymptomatic elevations in serum calcium. However, they are not thought to suffer the consequences of end-organ dysfunction characteristic of long-standing hyperparathyroidism and hypercalcemia. These individuals are generally spared the nephrolithiasis, low bone mass, and renal dysfunction that can occur in patients with primary hyperparathyroidism. Individuals with familial hypocalciuric hypercalcemia do not benefit from parathyroidectomy. Their hypercalcemia does not remit with surgery unless a total parathyroidectomy is performed. Surgery is not recommended because the condition is benign.
In contrast, infants with neonatal severe hyperparathyroidism have marked hypercalcemia, dramatic elevations in serum PTH, bone demineralization at birth, hypotonia, and failure to thrive. These infants usually require total parathyroidectomy in the newborn period for survival.
In the asymptomatic hypercalcemic patient, a careful family history should be obtained in an effort to document hypercalcemia or the occurrence of failed parathyroidectomies in other family members. Simultaneous serum and urinary calcium and creatinine levels should be measured to rule out familial hypocalciuric hypercalcemia. In this condition, urinary calcium levels are typically low and almost always less than 100 mg/24 h (Table 17-5). The calcium-creatinine clearance ratio derived from 24-hour urine collections is often below 0.01 but can be as high as 0.02. The ratio is calculated as urine calcium (mg/dL) × serum creatinine (mg/dL)/serum calcium (mg/dL) × urine creatinine (mg/dL). Genetic testing for CaSR gene mutations is commercially available in several reference laboratories and is the best approach to achieving a definitive diagnosis.
CHECKPOINT
15. What is the most common cause of primary hyperparathyroidism?
16. What is the occurrence of hyperparathyroidism in the multiple endocrine neoplasia syndromes?
17. In what conditions does secondary hyperparathyroidism occur? By what symptoms and signs is it distinguished from primary hyperparathyroidism?
18. What are the common symptoms and signs of primary hyperparathyroidism? How can primary hyperparathyroidism be distinguished from familial hypocalciuric hypercalcemia? What is the mechanism for this difference?
HYPERCALCEMIA OF MALIGNANCY
Etiology
Hypercalcemia occurs in approximately 10% of all malignancies. It is commonly seen in solid tumors, particularly squamous cell carcinomas (eg, lung, esophagus), renal carcinoma, and breast carcinoma. Hypercalcemia occurs in more than one third of patients with multiple myeloma but is unusual in lymphomas and leukemias.
Pathogenesis
Solid tumors usually produce hypercalcemia by secreting PTHrP, whose properties have been described previously. This is humoral hypercalcemia, which mimics primary hyperparathyroidism and results from a diffuse increase in bone resorption induced by high circulating levels of PTHrP. The syndrome is exacerbated by the ability of PTHrP to reduce renal excretion of calcium and the ability of hypercalcemia (acting via renal CaSRs) to blunt renal concentrating ability, which results in progressive dehydration.
Multiple myeloma produces hypercalcemia by a different mechanism; myeloma cells induce local bone resorption or osteolysis in the bone marrow, probably by releasing cytokines with bone-resorbing activity, such as interleukin-1 and tumor necrosis factor. Rarely, lymphomas produce hypercalcemia by secreting 1,25-(OH)2D.
Finally, even though many hypercalcemic patients have bone metastases, these may not contribute directly to the pathogenesis of hypercalcemia.
Clinical Manifestations
Unlike patients with primary hyperparathyroidism, who often are minimally symptomatic, patients with hypercalcemia of malignancy are typically very ill. Hypercalcemia typically occurs in advanced malignancy—the average survival of hypercalcemic patients is usually several weeks to months—and the tumor is almost invariably obvious on examination of the patient. In addition, hypercalcemia is often severe and symptomatic, with nausea, vomiting, dehydration, confusion, or coma. Biochemically, malignancy-associated hypercalcemia is characterized by a decreased serum phosphate and a suppressed level of intact PTH (Table 17-5). With most solid tumors, the serum level of PTHrP is increased. These findings, together with the differences in clinical presentation, usually make the differentiation of this syndrome from primary hyperparathyroidism relatively easy.
CHECKPOINT
19. What tumors commonly result in hypercalcemia?
20. What are the mechanisms by which a tumor may cause hypercalcemia?
21. What are the clinical symptoms and signs of hypercalcemia of malignancy?
HYPOPARATHYROIDISM & PSEUDOHYPOPARATHYROIDISM
Etiology
The total serum calcium includes the ionized, protein bound, and complexed forms of calcium. It should be recognized, however, that symptoms of hypocalcemia occur only if the ionized fraction of calcium is reduced. Furthermore, only patients with low ionized calcium levels should be evaluated for the possibility of a hypocalcemic disorder.
A common cause of low serum total calcium is hypoalbuminemia. A low serum albumin lowers only the protein-bound, and not the ionized, calcium. Thus, such patients need not be evaluated for mineral disorders. To determine whether a hypoalbuminemic patient has a low ionized calcium, this parameter can be measured directly. If this laboratory test is not readily available, a reasonable alternative is to correct the serum total calcium for the low serum albumin. This is done by adjusting the serum total calcium upward by 0.8 mg/dL for each 1 g/dL reduction in serum albumin. This simple correction usually brings the adjusted serum total calcium into the normal range.
The differential diagnosis of a low ionized calcium is lengthy (Table 17-6). Hypocalcemia can result from reduced PTH secretion caused by hypoparathyroidism or hypomagnesemia. It can also be due to decreased end-organ responsiveness to PTH despite adequate or even excessive levels of the hormone; this is termed pseudohypoparathyroidism.
TABLE 17-6 Differential diagnosis of hypocalcemia.
All forms of hypoparathyroidism are uncommon (Table 17-7). Most cases are the result of inadvertent trauma to, removal of, or devascularization of the parathyroid glands during thyroid or parathyroid surgery. The incidence of postoperative hypoparathyroidism (range: 0.2–30%) depends on the extent of the antecedent surgery and the surgeon’s skill in identifying normal parathyroid tissue and preserving its blood supply. Postoperative hypocalcemia may be transient or permanent. Some patients may also be left with diminished parathyroid reserve.
TABLE 17-7 Causes of hypoparathyroidism.
A variety of causes other than postsurgical complications may produce an absolute or relative state of PTH deficiency (Table 17-7). These include autoimmune destruction, magnesium depletion, autosomal dominant or recessive or X-linked hypoparathyroidism, hypoparathyroidism resulting from activating mutations of the CaSR or stimulating antibodies directed against the CaSR (see below), and hypoparathyroidism resulting from iron overload or Wilson disease. Abnormal development of the glands resulting in varying degrees of severity of hypoparathyroidism is seen in the DiGeorge syndrome. This syndrome can present in infancy, childhood, or even adulthood and may be accompanied by defective cell-mediated immunity and other congenital anomalies (Table 17-7). Mutations in the gene for transcription factor GCMB (glial cell missing-B), which is essential in the development of the parathyroid glands, are linked to familial isolated hypoparathyroidism. Mutations in the transcription factor GATA3 cause abnormal otic vesicle, renal, and parathyroid gland development resulting in deafness, renal anomalies, and hypoparathyroidism.
There are two syndromes of autoimmune polyendocrine failure syndrome termed APS. Patients with APS-1 commonly have mucocutaneous candidiasis, Addison disease (adrenal insufficiency), and hypoparathyroidism and less commonly ovarian failure and thyroid dysfunction. Various components of APS-1 present by the teens or early 20s (Figure 17-17).
FIGURE 17-17 Cumulative incidence of three common manifestations of autoimmune polyglandular failure type 1 (APS-1) compared with age at onset in a cohort of 68 patients. The figures in parentheses reflect incidences at age 20. (Data plotted from Ahonen P et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED] in a series of 68 patients. N Engl J Med. 1990;322:1829.)
Autoantibodies to adrenal and parathyroid tissue are seen in most of these patients. Eventually, other endocrine glands may become involved (eg, gonads, thyroid, and pancreas). APS-1 is an autosomal recessive disorder due to mutations in the autoimmune regulator (AIRE) gene. AIRE is expressed normally in a subpopulation of epithelial cells in the thymus that are thought to be involved in negative selection of autoreactive T cells during clonal selection. These T-cell clones are involved in self-recognition, and the failure to delete these T-cell clones is thought to underlie the autoimmune destruction of the endocrine cells affected in APS-1.
APS-2 or Schmidt syndrome is characterized by hypothyroidism and adrenal insufficiency and does not involve the parathyroid glands (see Chapter 21).
Pathogenesis
The pathogenesis of hypoparathyroidism is straightforward. The mineral disturbance occurs because the amount of PTH released is inadequate to maintain normal serum calcium concentrations, mainly due to the loss of the renal calcium-conserving effects of PTH and the inability to generate 1,25-(OH)2D. Hypocalcemia results, and hyperphosphatemia is also observed because the proximal tubular effect of PTH to promote phosphate excretion is lost. Because PTH is required to stimulate the renal production of 1,25-(OH)2D, levels of 1,25-(OH)2D are low in patients with hypoparathyroidism. Hyperphosphatemia further suppresses 1,25-(OH)2D synthesis. Low 1,25-(OH)2D levels lead to reduced intestinal calcium absorption. In the absence of adequate 1,25-(OH)2D and PTH, the mobilization of calcium from bone is abnormal. Because PTH is deficient, urinary calcium excretion is often high, despite the hypocalcemia.
Magnesium depletion is a common cause of hypocalcemia. The pathogenesis of hypocalcemia in this clinical setting relates to a functional and reversible state of hypoparathyroidism. There is also decreased renal and skeletal responsiveness to PTH. Magnesium depletion may occur from a variety of causes, including chronic alcoholism, diarrhea, and drugs such as loop diuretics, aminoglycoside antibiotics, amphotericin B, and cisplatin (Table 17-6). Magnesium is required to maintain normal PTH secretory responses. Once body magnesium stores are replete, PTH levels rise appropriately in response to the hypocalcemia, and the mineral imbalance is corrected.
In pseudohypoparathyroidism, PTH levels are usually elevated, but the ability of target tissues (particularly kidney) to respond to the hormone is subnormal. In pseudohypoparathyroidism type 1, the ability of PTH to generate an increase in the second-messenger cAMP is reduced. In patients with type 1a, this is due to a deficiency in the cellular content of the α subunit of the stimulatory G protein (Gs-α), which couples the PTH receptor to the adenylyl cyclase enzyme. In patients with type 1b, Gs-α protein levels are normal, and in some cases there is altered regulation of the Gs-α gene transcription due to abnormal DNA methylation. In patients with pseudohypoparathyroidism type 2, urinary cAMP is normal but the phosphaturic response to infused PTH is reduced. The pathogenesis of this more rare form of PTH resistance remains obscure.
Patients with activating mutations of the CaSR typically present with autosomal dominant hypocalcemia and hypercalciuria. Both defects are due to overly sensitive CaSRs, which turn off PTH secretion and renal calcium reabsorption at subnormal serum calcium levels. These individuals rarely experience symptoms of their often mild hypocalcemia, but if given vitamin D, they are prone to develop marked hypercalciuria, nephrocalcinosis, and even renal failure.
Clinical Manifestations
The symptoms and signs of hypocalcemia are similar, regardless of the underlying cause (Table 17-8). Patients may be asymptomatic or may have latent or overt tetany. Tetany is defined as spontaneous tonic muscular contractions. Painful carpal spasms and laryngeal stridor are striking manifestations of tetany. Latent tetany may be demonstrated by testing for Chvostek and Trousseau signs. Chvostek sign is elicited by tapping on the facial nerve anterior to the ear. Twitching of the ipsilateral facial muscles indicates a positive test. A positive Trousseau sign is demonstrated by inflating the sphygmomanometer with the cuff around the arm above the systolic blood pressure for 3 min. In hypocalcemic individuals, this causes painful carpal muscle contractions and spasms (Figure 17-18). If hypocalcemia is severe and unrecognized, airway compromise, altered mental status, generalized seizures, and even death may occur.
TABLE 17-8 Symptoms and signs of hypocalcemia.
FIGURE 17-18 Position of fingers in carpal spasm resulting from hypocalcemic tetany. (Redrawn, with permission, from Ganong WAF: Review of medical physiology, 16th ed. McGraw-Hill Companies, Inc, 1993.)
Chronic hypocalcemia can produce intracranial calcifications that have a predilection for the basal ganglia. These may be detectable by CT scanning, MRI, or skull radiographs. Chronic hypocalcemia may also enhance calcification of the lens and the formation of cataracts.
In addition to the symptoms and signs of hypocalcemia, patients with pseudohypoparathyroidism type 1a may have a constellation of features collectively known as Albright hereditary osteodystrophy. They include short stature, obesity, mental retardation, round facies, shortened fourth and fifth metacarpal and metatarsal bones, and subcutaneous ossifications. In considering the differential diagnosis of hypocalcemia, one must be guided by the clinical setting. A positive family history is very important in supporting a diagnosis of pseudohypoparathyroidism and other hereditary forms of hypoparathyroidism (Table 17-7). The patient with hypocalcemia, hyperphosphatemia, and a normal serum creatinine most likely has hypoparathyroidism. A history of neck surgery should be sought. There may be a long latent period before symptomatic hypocalcemia presents in postsurgical hypoparathyroidism. The physical examination can be helpful if it identifies signs of hypocalcemia, stigmata of Albright hereditary osteodystrophy, or other features of APS-1 (ie, vitiligo, mucocutaneous candidiasis, adrenal insufficiency). Patients with pseudohypoparathyroidism type 1a often have other endocrine abnormalities such as primary hypothyroidism or gonadal failure.
In the differential diagnosis of hypocalcemia, laboratory findings are extremely useful (Table 17-9). Serum phosphate is often (not invariably) elevated in hypoparathyroidism and pseudohypoparathyroidism. In magnesium depletion, serum phosphate is usually normal. In secondary hyperparathyroidism not due to renal failure, serum phosphate is typically low. Serum PTH levels are crucial in determining the cause of hypocalcemia. PTH is classically elevated in untreated pseudohypoparathyroidism but not in hypoparathyroidism or magnesium depletion. Intact PTH may be undetectable, low, or normal in patients with hypoparathyroidism depending on the parathyroid functional reserve. In patients with secondary hyperparathyroidism resulting from defects in the production or bioavailability of vitamin D, the clinical setting often suggests a problem with vitamin D (eg, regional enteritis, bowel resection, liver disease). The presence of a low 25-(OH)D level and an increased PTH confirms this diagnosis.
TABLE 17-9 Laboratory findings in hypocalcemia.
Measurement of serum magnesium is the first step in ruling out magnesium depletion as the cause of hypocalcemia and should be part of the initial evaluation. If urinary magnesium is inappropriately high relative to the serum magnesium, renal magnesium wasting is present. PTH levels in this setting are typically low or normal. Normal PTH levels, however, are inappropriate in the presence of hypocalcemia.
Patients with autoimmune hypoparathyroidism due to AIRE mutations can be suspected clinically by having at least two of the three features of the syndrome. Recent work indicates that autoantibodies to interferon-α or interferon-ω are present in more than 95% of patients with APS-1 and are an excellent screening test for the disorder.
The diagnosis of pseudohypoparathyroidism can be confirmed by infusing synthetic human PTH(1–34) and measuring urinary cAMP and phosphate responses. This maneuver is designed to prove that there is end-organ resistance to PTH and to determine whether the diagnosis is pseudohypoparathyroidism type 1 or type 2.
Hypoparathyroidism may vary in its severity and, therefore, in the need for therapy. In some patients with decreased parathyroid reserve, only situations of increased stress on the glands, such as pregnancy or lactation, induce hypocalcemia. In other patients, PTH deficiency is a chronic symptomatic disorder necessitating lifelong therapy with calcium supplements and vitamin D analogues. All patients so treated should have periodic monitoring of serum calcium, urinary calcium, and renal function. Patients with autoimmune hypoparathyroidism should also be examined regularly for the development of adrenal insufficiency as well as malabsorption, chronic hepatitis, keratitis, pernicious anemia, alopecia, vitiligo, and other nonendocrine complications of APS-1.
CHECKPOINT
22. What are the causes of hypoparathyroidism?
23. What is the mechanism of pseudohypoparathyroidism?
24. What are the symptoms and signs of hypocalcemia?
25. How can laboratory studies be used to distinguish various causes of hypocalcemia?
MEDULLARY CARCINOMA OF THE THYROID
Etiology
Medullary carcinoma of the thyroid gland, a C-cell neoplasm, accounts for only 5–10% of all thyroid malignancies. Approximately 80% are sporadic and 20% are familial, occurring in autosomal dominant MEN-2A and MEN-2B and in non-MEN syndromes. In sporadic cases, the tumor is usually unilateral. In hereditary forms, however, tumors are often bilateral and multifocal. Germline activating mutations in the RET proto-oncogene on chromosome 10 are known to play a causal role in three forms of medullary carcinoma. These include cases of familial isolated medullary thyroid cancer, MEN-2A, and MEN-2B. Over half of sporadically occurring medullary thyroid carcinoma have a somatic mutation identical to that causing the familial syndromes; however, because the mutation is present only in the tumor and not in the genomic DNA, these cases are not heritable.
Pathogenesis
The growth pattern of medullary carcinoma is slow but progressive, and local invasion of adjacent structures is common. The tumor spreads hematogenously, with metastases typically to lymph nodes, bone, and lung. The clinical progression of this cancer is variable. Although there may be early metastases to cervical and mediastinal lymph nodes in as many as 70% of patients, the tumor still usually behaves in an indolent fashion. In a minority of cases, a more aggressive pattern of tumor growth has been noted. Early detection in high-risk individuals, such as those with a family history of medullary carcinoma or MEN-2A or MEN-2B, is crucial to prevent advanced disease and distant metastases. Overall survival is estimated to be 80% at 5 years and 60% at 10 years. Some studies suggest individuals who are younger than 40 years at the time of diagnosis may have higher survival rates than older individuals. The RET proto-oncogene mutation on codon 918 seen in nearly 95% of MEN-2B cases portends a worse prognosis.
Patients with MEN-2 develop medullary carcinoma at frequencies approaching 100%. In MEN-2A and MEN-B, the thyroid lesions are malignant. C-cell hyperplasia typically precedes the development of cancer, allowing for premalignancy detection and consideration of prophylactic thyroidectomy. The pheochromocytomas associated with either MEN-2A or MEN-2B are infrequently malignant. Hyperparathyroidism in MEN-2A, which is uncommon, is usually due to diffuse hyperplasia rather than malignancy of the parathyroids. Chronic hypercalcitoninemia as a result of the tumor may contribute to the pathogenesis of parathyroid hyperplasia. Parathyroid hyperplasia is rarely seen in patients with either MEN-2B or sporadic medullary carcinoma.
Clinical Manifestations
Sporadic medullary carcinoma occurs with about equal frequency in males and females and is typically found in patients older than 50 years. In MEN-2A or MEN-2B, the tumor occurs at a much younger age, often in childhood. In fact, medullary carcinoma in a patient younger than 40 years should suggest familial medullary carcinoma or MEN-2A or MEN-2B. Medullary carcinoma may present as a single nodule or as multiple thyroid nodules. Patients with sporadic medullary carcinoma often have palpable cervical lymphadenopathy.
Because C cells are neuroendocrine cells, these tumors have the capacity to release calcitonin and other hormones such as prostaglandins, serotonin, adrenocorticotropin, somatostatin, and calcitonin gene-related peptide. Serotonin, calcitonin, or the prostaglandins have been implicated in the pathogenesis of the secretory diarrhea observed in approximately 25% of patients with medullary carcinoma. If diarrhea is present, this usually indicates a large tumor burden or metastatic disease. Patients may also have flushing, which has been ascribed to the production by the tumor of substance P or calcitonin gene-related peptide, both of which are vasodilators.
In a patient suspected of having medullary carcinoma, a radionuclide thyroid scan may demonstrate one or more cold nodules. These nodules are solid on ultrasonography. Fine-needle aspiration biopsy shows the characteristic C-cell lesion with positive immuno-staining for calcitonin. Fine needle aspiration may be nondiagnostic in more than half of individuals with medullary thyroid carcinoma. Staining for calcitonin may improve diagnostic sensitivity; however, the diagnosis of medullary thyroid carcinoma may not be evident until examination of frozen section specimen slides during surgery or, later, of final pathological slides from the resected thyroid. The tumor has the propensity to contain large calcifications, which can be seen on x-ray films of the neck. Bone metastases may be lytic or sclerotic in their appearance, and pulmonary metastases may be surrounded by fibrotic reactions.
The most important laboratory test in determining the presence and extent of medullary carcinoma is the calcitonin level. Circulating calcitonin levels are typically elevated in most patients, and serum levels correlate with tumor burden. In C-cell hyperplasia, basal calcitonin may or may not be elevated. However, these patients usually demonstrate abnormal provocative testing. Intravenous calcium gluconate (2 mg/kg of elemental calcium) is injected over 1 minute, followed by pentagastrin (0.5 μg/kg) over 5 seconds. Provocative testing is based on the ability of calcium and the synthetic gastrin analogue pentagastrin to hyperstimulate calcitonin release in patients with increased C-cell mass resulting from either hyperplasia or carcinoma. An increase in serum calcitonin, more than twice the normal response, is considered abnormal. It must be borne in mind that false-positive provocative testing for calcitonin can occur. Provocative testing to detect C-cell hyperplasia (and hence elevation in serum calcitonin) in relatives of patients with medullary thyroid carcinoma has largely been replaced by genetic testing for germline mutations known to cause MEN or familial medullary thyroid carcinoma syndromes.
Serial calcitonin levels are a useful parameter for monitoring therapeutic responses in patients with medullary carcinoma or for diagnosing a recurrence, along with clinical examination and imaging procedures. Calcitonin levels usually reflect the extent of disease. If the tumor becomes less differentiated, calcitonin levels may no longer reflect tumor burden. Another useful tumor marker for medullary carcinoma is carcinoembryonic antigen (CEA). This antigen is frequently elevated in patients with medullary carcinoma and is present at all stages of the disease. Rapid increases in CEA predict a worse clinical course.
Surgery is the mainstay of therapy for patients with medullary thyroid carcinoma. Total thyroidectomy is advocated because the tumors are often multicentric. Patients should be monitored indefinitely for recurrences because these tumors may be very indolent. Indefinite monitoring is also required because individuals with presumed familial medullary thyroid carcinoma have developed pheochromocytoma or hyperparathyroidism long after their medullary thyroid carcinoma diagnosis and thus are eventually found to have MEN-2A rather than familial medullary thyroid carcinoma. All patients with medullary carcinoma of the thyroid, whether familial or sporadic, should be tested for RET oncogene mutations. This testing is commercially available and has supplanted calcitonin provocative testing. More than 95% of patients with MEN-2 have been found to harbor RET mutations. Sporadic cases of medullary carcinoma of the thyroid should also be tested to detect the occurrence of a new mutation for which other family members can then be screened. Properly performed DNA testing is essentially unambiguous in predicting gene carrier status and can be used prospectively to recommend prophylactic thyroidectomy in young patients and children with MEN-2 before the development of C-cell hyperplasia or frank carcinoma.
Patients with either MEN-2A or MEN-2B, even in the absence of symptoms, should undergo screening tests for the possibility of pheochromocytoma, while only patients with MEN-2A need to be screened for hyperparathyroidism before thyroid surgery. These tests include the determination of serum calcium and PTH together with plasma fractionated metanephrines and additional biochemical testing or imaging as needed. Pheochromocytomas may be clinically silent at the time medullary carcinoma is diagnosed, and they should be removed before thyroidectomy to prevent potentially serious surgical complications from uncontrolled catecholamine secretion. If hyperparathyroidism is present, it should be treated surgically at the time of thyroidectomy to avoid a second neck operation (Chapter 12).
CHECKPOINT
26. How can you make the diagnosis of medullary carcinoma of the thyroid?
27. What is the treatment for medullary carcinoma?
28. Which patients are at high risk for medullary carcinoma?
OSTEOPOROSIS
Etiology
Osteoporosis is defined as low bone mass. The bone is normal in composition but reduced in amount. Bone mass accrues rapidly throughout childhood and very rapidly in adolescence; half of adult bone mineral density is achieved during the teenage years (Figure 17-19). Peak bone mass is reached late in the third decade of life. Bone mass then remains relatively stable through the adult years, followed by a rapid loss of bone in women at the time of menopause. In the later stages of life, both men and women continue to lose bone, although at a slower rate than that seen at the time of menopause.
FIGURE 17-19 Bone mass in women as a function of age, demonstrating the potential effect of suboptimal nutrition and physical activity during the critical time of bone accrual in childhood and adolescence. (Redrawn, with permission, from Heaney RP et al. Peak bone mass. Osteo Int. 2000;11:985.)
Achieving maximum peak bone mass depends on optimal nutrition, physical activity, general health, and hormonal exposure throughout childhood and adolescence. Inadequacies in nutrition, weight-bearing exercise, and gonadal steroid exposure all have a negative impact on acquisition of peak bone mass. After bone growth is completed, the bone mass is determined by the level of peak bone mass that was attained and the subsequent rate of loss. Genetics are very important in determining bone mass. It has long been recognized that blacks have greater peak bone mass than whites or Asians and are relatively protected from osteoporosis. It now appears that, within the Caucasian population, more than half the variance in bone mass is genetically determined. However, a number of hormonal and environmental factors can reduce the genetically determined peak bone mass or hasten the loss of bone mineral and thus represent important risk factors for osteoporosis (Figure 17-19, Table 17-10).
TABLE 17-10 Causes of osteoporosis.
The most important etiologic factor in osteoporosis is gonadal steroid deficiency. The estrogen deficiency that occurs after menopause accelerates loss of bone mass; postmenopausal women consistently have lower bone mass than men and a higher incidence of osteoporotic fractures. With respect to bone remodeling in men, testosterone serves some of the same functions as estrogen in women, but estradiol generated from the peripheral aromatization of testosterone is the critical gonadal steroid mediating the development and preservation of male bone mass. Hypogonadal men experience accelerated bone loss. Men on androgen deprivation therapy for prostate cancer are at increased risk for bone loss and fracture. Another important risk factor for bone loss is the use of corticosteroids or endogenous cortisol excess in Cushing syndrome. Glucocorticoid-induced osteoporosis is one of the most devastating complications of chronic therapy with these agents. Certain other medications, including excessive thyroid hormone, anticonvulsants, and chronic heparin therapy, immobilization, alcohol abuse, and smoking are also risk factors for osteoporosis. Diet is important as well. As discussed below, an adequate intake of calcium and vitamin D is necessary to build peak bone mass optimally and to minimize the rate of loss. Other dietary factors may also be important. Osteoporosis is most prevalent in Western societies, and it has been speculated that their increased dietary protein and sodium chloride intake, along with suboptimal potassium intake or related factors, may predispose to osteoporosis, perhaps via enhanced urinary calcium losses. Many additional disorders affecting the GI, hematologic, and connective tissue systems can contribute to the development of osteoporosis (Table 17-10).
Pathogenesis
Because bone remodeling involves the coupled resorption of bone by osteoclasts and the deposition of new bone by osteoblasts, bone loss could result from increased bone resorption, decreased bone formation, or a combination of both processes. Younger individuals with low bone mass typically have experienced low bone formation and insufficient bone accrual, while postmenopausal osteoporosis is the consequence of accelerated bone resorption. The urinary excretion of calcium and breakdown products of type 1 collagen (eg, N- and C-telopeptides) increases and osteoclast numbers and resorption surfaces are increased. The bone formation rate is also enhanced, with an increase in serum alkaline phosphatase and the serum level of the bone matrix protein osteocalcin, both reflecting increased osteoblastic activity. Bone formation, while increased, does not keep pace with bone resorption, and there is a net loss of bone mass at the time of menopause. This high-turnover state is the direct result of estrogen deficiency and can be reversed by estrogen replacement therapy.
The accelerated phase of estrogen-deficient bone loss begins immediately at the time of menopause (natural or surgical). It is most evident in trabecular bone, the compartment that is remodeled most rapidly. As much as 5–10% of spinal trabecular bone mineral is lost yearly in early postmenopausal women; osteoporotic fractures in such early post-menopausal women are often in the spine, a site of primarily trabecular bone. After 5–15 years, the rate of bone loss slows, so that after age 65, the annual rate of bone loss is similar in both sexes.
The cellular basis for the activation of bone resorption in the estrogen-deficient state is not fully understood but involves increased release of cytokines such as interleukin-6 from cells in the bone microenvironment in estrogen deficiency. These cytokines increase the expression of RANK-L and decrease the expression of OPG on stromal cells and osteoblasts. These critical changes together promote an imbalance in bone remodeling that favors increased osteoclastogenesis and bone resorption.
The pathogenesis of age-related bone loss is less certain. Bone mass is relatively stable in the fourth and fifth decades of life, accelerates for 5–10 years in women at the time of menopause, and then continues throughout life at a slower rate that is similar in men and women.
One important factor in the pathogenesis of age-related bone loss is a relative deficiency of calcium and 1,25-(OH)2D. The capacity of the intestine to absorb calcium diminishes with age. Because renal losses of calcium are obligatory, a decreased efficiency of calcium absorption means that dietary calcium intake must be increased to prevent negative calcium balance. It is estimated that about 1200 mg/d of elemental calcium is required to maintain calcium balance in people over age 65 (Table 17-11). American women in this age group typically ingest 500–600 mg of calcium daily; the calcium intakes in men are somewhat higher. In addition, older individuals may be deficient in vitamin D, further impairing their ability to absorb calcium. 25-(OH)D shows seasonal variability with lower levels and mild secondary hyperparathyroidism evident by the end of winter.
TABLE 17-11 Recommended calcium and vitamin D intakes.
The PTH level increases with age due to changes in multiple organ systems with aging. There is a decrease in the mass of functioning renal tissue with age that could lead to decreased renal synthesis of 1,25-(OH)2D, which would directly release PTH secretion from its normal inhibition by 1,25-(OH)2D. The reduced 1,25-(OH)2D level decreases calcium absorption, exacerbating an intrinsic inability of the aging intestine to absorb calcium normally. Secondary hyperparathyroidism results from the dual effects of 1,25-(OH)2D deficiency on the parathyroid gland and the intestine. In addition, the responsiveness of the parathyroid gland to inhibition by calcium is reduced with aging. The hyperparathyroidism of aging may thus result from the combined effects of age on the kidney, intestine, and parathyroid glands.
Provision of a dietary supplement with adequate vitamin D reduces the rate of age-related bone loss and protects against fracture. This suggests that reduced calcium absorption and secondary hyperparathyroidism play significant roles in the pathogenesis of osteoporosis in the elderly. However, calcium and vitamin D supplements alone do not completely ameliorate fracture risk.
In secondary osteoporosis associated with glucocorticoid administration or alcoholism, there is a marked reduction in bone formation rates and serum osteocalcin levels. It is likely that glucocorticoids produce a devastating osteoporotic syndrome because of the rapid loss of bone that results from frankly depressed bone formation in the face of normal or even increased bone resorption. Additionally, glucocorticoids decrease intestinal calcium and vitamin D absorption and increase urine calcium losses.
The form of secondary osteoporosis associated with immobilization is another example of a resorptive state with marked uncoupling of bone resorption and bone formation and is characterized by hypercalciuria and suppression of PTH. When individuals with a high preexisting state of bone remodeling (eg, adolescents and patients with hyperthyroidism or Paget disease) are immobilized, bone resorption may be accelerated enough to produce hypercalcemia.
Clinical Manifestations
Osteoporosis is asymptomatic until it produces fractures and deformity. Typical osteoporotic fractures occur in the spine, the hip, and the wrist (Colles fracture). In women, wrist fractures increase in incidence at menopause and then stay relatively stable at this increased rate with age. The incidence of hip and vertebral fractures increases rapidly with aging in both men and women (Figure 17-20). The vertebral bodies may be crushed, resulting in loss of height, or may be wedged anteriorly, resulting in height loss and kyphosis. The dorsal kyphosis of elderly women (“dowager’s hump”) results from anterior wedging of multiple thoracic vertebrae. Spinal fractures may be acute and painful or may occur gradually and be manifested only as kyphosis or loss of height.
FIGURE 17-20 Age-specific incidence rates of wrist, hip, and vertebral fractures in men and women derived from Rochester, Minnesota data. (Redrawn, with permission, from Cooper C et al. Epidemiology of osteoporosis. Trends Endo Metab. 1992;3:224.)
The complication of osteoporosis with the highest morbidity and mortality is hip fracture. Hip fractures typically occur in the elderly, with a sharply rising incidence in both sexes after age 80 years. This is due to a variety of factors, including the tendency for a slower rate of bone loss in the cortical bone that makes up the hip compared with the predominantly trabecular bone of the spine as well as diminished motor and visual function with aging that result in more frequent falls. The personal and social costs of hip fracture are enormous. One third of American women who survive past age 80 years will suffer a hip fracture. The 6-month mortality rate is approximately 20%, much of it resulting from the complications of immobilizing frail persons in a hospital bed. The complications include pulmonary embolus and pneumonia. About half of elderly people with a hip fracture will never walk freely again. The long-term costs of chronic care for these persons are a major social concern.
The diagnosis of osteoporosis is sometimes made radiologically, but in general x-ray films are a poor diagnostic tool. A chest x-ray film will miss 30–50% of cases of spinal osteoporosis and, if overpenetrated, may lead to the diagnosis of osteoporosis in someone with a normal bone mass. The best way to diagnose osteoporosis is by measuring bone mineral density by dual-energy x-ray absorptiometry (DXA). The technique is precise, rapid, and inexpensive. The relationship between bone mineral density and fracture risk is a continuous one (ie, the lower the bone mineral density, the higher the fracture risk). Osteoporosis has been defined by the World Health Organization (WHO) as a bone mineral density value 2.5 standard deviations or more below the young adult normal value (ie, a T score of −2.5 or less). This cutoff was selected based on the observation that 16% of postmenopausal Caucasian women at age 50 years will have femoral neck bone density values below −2.5, and this population has a 16% lifetime risk of hip fracture. However, it should be remembered that there is no threshold at this value and that bone mineral density measurements need to be interpreted in light of other risk factors for fracture such as age and propensity for falls. An absolute 10-year fracture risk calculation algorithm (termed FRAX) has recently been developed by the WHO. The algorithm incorporates femoral neck bone mineral density values and several clinical risk factors to determine an individual’s 10-year probability of a major osteoporotic or hip fracture. The URL www.shef.ac.uk/FRAX/provides access to the WHO absolute fracture risk calculator. This tool is useful for determining the need for treatment in addition to the bone density values themselves.
It is additionally important to realize that not all of the risk for fracture is captured by measurements of bone mineral density because the strength of bone is also a function of bone quality. Bone quality, determined by the microarchitecture of a bone, its mechanical strength, its material properties, and its ability to withstand stress, may be substantially different in two individuals with the same bone mineral density. Techniques to assess bone quality noninvasively are being actively investigated.
Elderly persons with osteoporosis are unlikely to sustain a hip fracture unless they fall. Risk factors for falling include muscle weakness, impaired vision, impaired balance, sedative use, and environmental factors. Therefore, strategies to prevent falls are an important part of the approach to the osteoporotic patient.
Individuals at risk for osteoporosis benefit from a total calcium intake of about 1200–1500 mg/d. This can be accomplished with dairy products or other calcium-rich foods, with calcium-fortified foods, or with a calcium supplement such as calcium carbonate or calcium citrate. Vitamin D should be provided in age-appropriate doses (600–800 IU/d). The serum level of 25-(OH)D that represents sufficiency remains controversial, with the Institute of Medicine recommending a level of 20 ng/mL, while many metabolic bone experts recommend a level of more than 32 ng/mL. The current recommended intakes for calcium and vitamin D are given in Table 17-11. Calcium supplementation in younger individuals may increase peak bone mass and decrease premenopausal bone loss, but its optimal role in this age group has not been determined. Estrogen replacement reduces bone loss, relieves hot flushes after menopause, and reduces fracture risk. It requires concomitant use of progestins in women who have not had a hysterectomy to prevent endometrial carcinoma and also increases the risk of breast cancer, stroke, myocardial infarction, and venous thromboembolism. The side-effect profile of estrogen has limited its use to short-term therapy at the time of menopause, typically in women suffering from hot flushes. Other antiresorptive agents available for treatment of osteoporosis include alendronate, risedronate, ibandronate, zoledronic acid, calcitonin, raloxifene, and denosumab. The first four agents are bisphosphonates that directly inhibit osteoclastic bone resorption. Given therapeutically, calcitonin decreases bone resorption and may protect against bone loss and vertebral fractures. Raloxifene, a selective estrogen response modulator, inhibits bone resorption as estrogen does. Raloxifene does not induce endometrial changes, and it has estrogen antagonist actions in breast cells that may appear to decrease the incidence of breast carcinoma in postmenopausal women. Denosumab is a monoclonal antibody to RANK ligand and inhibits osteoclast development and activation. The only agent currently available that can stimulate bone formation is parathyroid hormone (PTH1-34) (teriparatide). In contrast to the bone resorption that is caused by continuous elevations in PTH such as occur in hyperparathyroidism, a single daily injection of PTH stimulates bone formation and, to a lesser extent, bone resorption, resulting in net gains in bone density and decreased fracture risk.
CHECKPOINT
29. What is the relative importance of hereditary versus environmental or hormonal factors in contributing to osteoporosis?
30. What are the risk factors for osteoporosis?
31. What are the symptoms and signs of osteoporosis?
32. What are the risk factors for fracture in a patient with osteoporosis?
33. What treatments can prevent bone loss?
OSTEOMALACIA
Etiology
Osteomalacia is defined as a defect in the mineralization of bone. When it occurs in young individuals, it also affects the mineralization of cartilage in the growth plate, a disorder called rickets. Osteomalacia can result from a deficiency of vitamin D, a deficiency of phosphate, an inherited deficiency in alkaline phosphatase (hypophosphatasia), or agents that have adverse effects on bone (Table 17-12). Surprisingly, dietary calcium deficiency rarely produces osteomalacia, although a few cases have been reported.
TABLE 17-12 Causes of osteomalacia.
Vitamin D deficiency is becoming more common in the United States because of decreased sunlight exposure, increased use of sunscreens, and limited dietary sources of vitamin D. Individuals of dark-skinned ethnicities are particularly vulnerable because they have less cutaneous synthesis of vitamin D in response to sunlight. Fortified milk is the main food source of vitamin D, but at 100 IU/cup of milk, it can be difficult to achieve the daily recommended intake of 600–800 IU of vitamin D for adults. Some cereals and other foods have been also been fortified with vitamin D. In addition to insufficient intake, vitamin D deficiency can be the result of malabsorption of this fat-soluble vitamin. Severe rickets also occurs as part of three rare heritable disorders of vitamin D action: renal 1α-hydroxylase deficiency, in which vitamin D is not converted to 1,25-(OH)2D; mutant vitamin D receptors with reduced activity; and overproduction of a hormone response element binding protein that interferes with the activation (by the vitamin D receptor-retinoic acid receptor heterodimer) of vitamin D response elements on genes.
Phosphate deficiency with osteomalacia is usually caused by inherited or acquired renal phosphate wasting. Three hereditary forms of renal phosphate wasting include X-linked, autosomal dominant, or autosomal recessive hypophosphatemic rickets. Osteomalacia and hypophosphatemia can also result from tumors that are typically mesenchymal in origin and often located in the head and neck region. Many of these tumors overproduce FGF-23 (see above) and induce renal phosphate wasting and low 1,25-(OH)2D levels, eventually leading to osteomalacia. The FGF23 gene is mutated in kindreds with autosomal dominant hypophosphatemic rickets. Families with X-linked hypophosphatemic rickets have mutations in the PHEX gene, which encodes an endopeptidase, PHEX. This endopeptidase is involved in the production and degradation of FGF-23. In X-linked hypophosphatemic rickets, FGF-23 levels are elevated and appear to be responsible for the hypophosphatemic phenotype, although the exact role of PHEX in FGF-23 metabolism remains to be elucidated.
Pathogenesis
Vitamin D deficiency produces osteomalacia in stages. In the early stage, reduced calcium absorption produces secondary hyperparathyroidism, preventing hypocalcemia at the cost of increased renal phosphate excretion and hypophosphatemia. In later stages, hypocalcemia ensues, and hypophosphatemia progresses because of the combined effects of reduced absorption and the phosphaturic action of PTH. The poor delivery of minerals to bone (possibly coupled with the absence of direct effects of vitamin D on bone) impairs the mineralization of bone matrix. Since osteoblasts continue to synthesize bone matrix, unmineralized matrix or osteoid accumulates at bone-forming surfaces.
Clinical Manifestations
Patients with osteomalacia have bone pain, muscle weakness, and a waddling gait. Radiologically, they may have reduced bone mass, detectable by both x-ray and bone densitometry. The hallmark of the disorder, however, is the pseudofracture: local bone resorption that has the appearance of a nondisplaced fracture, classically in the pubic rami, clavicles, or scapulas. In children with rickets, the leg bones are bowed (osteomalacia means “softening of bones”), the costochondral junctions are enlarged (“rachitic rosary”), and the growth plates are widened and irregular, reflecting the increase in unmineralized cartilage that bends under the child’s weight, resulting in the bowing. Biochemically, the hallmarks of vitamin D–deficient osteomalacia are hypophosphatemia, hyperparathyroidism, variable hypocalcemia, and marked reductions in urinary calcium to less than 50 mg/d. The 25-(OH)D level is reduced, indicative of decreased body stores of vitamin D. In vitamin D deficiency and other forms of osteomalacia, the alkaline phosphatase level is increased.
Although the disorder can be suspected strongly on clinical grounds and the biochemical changes summarized previously are confirmatory, a firm diagnosis of osteomalacia requires either the radiologic appearance of rickets or pseudofractures or a characteristic bone biopsy. If bone is biopsied for quantitative histomorphometry, thickened osteoid seams and a reduction in the mineralization rate are found. Treatment with vitamin D or aggressive phosphate replacement in patients with renal phosphate wasting will reverse osteomalacia and heal rickets. In renal disease, and in the FGF-23–mediated disorders, calcitriol also must be provided to mineralize bone because in these disorders, endogenous synthesis is either absent (renal disease) or suppressed (FGF-23 disorders).
CHECKPOINT
34. What are the causes of osteomalacia?
35. What are the two stages in which vitamin D deficiency produces osteomalacia?
36. What are the symptoms and signs of osteomalacia?
CASE STUDIES
Yeong Kwok, MD
(See Chapter 25, p. 729 for Answers)
CASE 83
A 56-year-old woman presents to her primary care physician complaining of progressive fatigue, weakness, and diffuse bony pain. She says that her symptoms have been getting worse over the past 2 months. Her medical history is notable for well-controlled hypertension and recurrent renal stones. Physical examination is unremarkable. A serum calcium level is elevated.
Questions
A. What are some common causes of hypercalcemia? Which do you suspect in this patient, and why?
B. What is the pathogenesis of primary hyperparathyroidism? What genes have been implicated?
C. How would you make the diagnosis of primary hyperparathyroidism?
CASE 84
A 40-year-old woman comes to clinic to discuss some unexpected laboratory test abnormalities. She underwent these tests as part of a life insurance examination and was noted to have a mildly elevated serum calcium level. She has been healthy with no medical problems. She feels well and denies fatigue or pain. She does not take any medications or dietary supplements. There is no significant family history. Her physical examination is unremarkable. Repeated laboratory testing confirms a mildly elevated serum calcium level but also shows a normal serum phosphorus level, intact parathyroid hormone (PTH), and 1,25-OH2D levels. A 24-hour urinary calcium test returns low, at 60 mg/24 h.
Questions
A. What is the likely diagnosis in this patient?
B. What is the underlying pathophysiology of this disorder, and how does this lead to the elevated serum calcium?
CASE 85
A 69-year-old man presents to his primary care physician complaining of fatigue, nausea, weakness, and diffuse bony pain. He states his symptoms have been getting progressively worse over the past 2 months. In addition, he has noted a 15-pound weight loss over approximately the same time span. His wife, who has accompanied him, also noted that he seems increasingly confused. His medical history is notable for well-controlled hypertension and chronic obstructive pulmonary disease. He has a 100 pack–year smoking history. On physical examination he is chronically ill appearing and thin. Vital signs are notable for a blood pressure of 120/85 mm Hg, a heart rate of 98 bpm, and a respiratory rate of 16/min. Lungs have an increased expiratory phase, with mild expiratory wheeze. He has decreased breath sounds at the left base. The remainder of his examination is unremarkable. A serum calcium level is markedly elevated. Hypercalcemia of malignancy is suspected.
Questions
A. What tumors commonly cause hypercalcemia? Which is likely in this patient?
B. What would you expect his serum PTH level to be? What about his serum PTHrP? Why?
C. How does PTHrP secretion cause hypercalcemia?
CASE 86
A 32-year-old woman presents to the emergency department with complaints of involuntary hand spasms. She states that as she worked folding the laundry, she had a sudden severe spasm of her right hand such that her fingers flexed. The spasm was quite painful and lasted several minutes, resolving spontaneously. She is 6 months pregnant. Her medical history is otherwise notable for thyroid tumor status post-thyroidectomy 3 years ago. She is taking synthetic thyroid hormone and a prenatal multivitamin. Family history is unremarkable. On physical examination, she has positive Chvostek and Trousseau signs. Examination is otherwise unremarkable. Serum calcium level is low. Hypoparathyroidism as a complication of the thyroid surgery is suspected.
Questions
A. What is the mechanism by which thyroid surgery can result in hypocalcemia? Why may she only now be symptomatic?
B. What is the Chvostek sign? Trousseau sign? What does each represent?
C. What would you expect this patient’s serum phosphate level to be? Serum PTH? Why?
CASE 87
A 23-year-old woman presents to her primary care physician complaining of diarrhea. The diarrhea is described as profuse and watery and has been getting progressively worse over the last 2 months. She has had no bloody or black bowel movements. The condition is not made worse by food and is not associated with fever, chills, sweats, nausea, or vomiting. On review of systems, she does note a 5-pound weight loss in the last 3 months. She also notes occasional flushing. She denies any significant family history. On physical examination, she is a thin white woman in no acute distress. She is afebrile, with a blood pressure of 100/60 mm Hg, heart rate of 100 bpm, and respiratory rate of 14/min. Head examination is unremarkable. Neck examination reveals bilateral hard nodules of the thyroid, a 2-cm nodule on the right upper pole, and a 1.5-cm nodule on the left upper pole. She has a firm 1-cm lymph node in the right anterior cervical chain. Lungs are clear. Cardiac examination is mildly tachycardiac, with regular rhythm and no extra sounds. The abdomen has hyperactive bowel sounds and is soft, nontender, nondistended, and without masses. Skin examination discloses no rashes. Medullary carcinoma of the thyroid is suspected.
Questions
A. What is the cause of this patient’s diarrhea? Flushing?
B. How would you make a diagnosis of medullary carcinoma of the thyroid?
C. What other tests would you like to order? Why?
CASE 88
A 72-year-old woman presents to the emergency room after falling in her home. She slipped on spilled water in her kitchen. She was unable to get up after her fall and was found on the floor in her kitchen by her son, stopping by after work. She complains of severe right hip pain. On examination, she has bruising over her right hip. Range of motion in her right hip is markedly decreased, with pain on both internal and external rotation. X-ray film reveals a hip fracture and probable low bone mass. The history raises concern about osteoporosis.
Questions
A. What are some important causes of osteoporosis?
B. What are the likely causes of osteoporosis in this patient and the underlying pathogenesis of each?
C. What are the risk factors for fractures in patients with osteoporosis?
D. What are common complications of hip fractures?
E. What treatments are available to prevent bone loss?
CASE 89
A 93-year-old woman is brought to the emergency department by ambulance for “failure to thrive.” Today the women daughter was attempting to roll her to clean her, and the patient fell from the bed to the floor. They have been unable to pay for medications for several months. For many months, the patient has been eating only broth because of difficulty with chewing and swallowing. On examination, she is pale, with central obesity, wasting of her extremities, and flexion contractures of her right upper and lower extremities. On head-neck examination, she has temporal wasting, right facial droop, pale conjunctivas, and dry mucous membranes. Lungs are clear to auscultation. Cardiac examination is notable for an S4 gallop. She moans when her extremities are palpated. Laboratory reports show hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase. X-ray films of her pelvis reveal low bone mass and “pseudofracture” of the pubic rami. Osteomalacia is suspected.
Questions
A. What are the causes of osteomalacia? Which do you suspect in this patient? Why?
B. What is the pathogenesis of osteomalacia in this patient?
C. What would you expect to see on a bone biopsy for quantitative histomorphometry?
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