InternalMed_Harrison

InternalMed_Harrison. Although 85% of the ~600 g of body phosphorus is present in bone mineral, phosphorus is also a major intracellular constituent both as the free anion(s) and as a component of numerous organophosphate compounds, including structural proteins, enzymes, transcription factors, carbohydrate and lipid intermediates, high-energy stores (adenosine triphosphate [ATP], creatine phosphate), and nucleic acids. Unlike calcium, phosphorus exists intracellularly at concentrations close to those present in ECF (e.g., 1–2 mmol/L). In cells and in the ECF, phosphorus exists in several forms, predominantly as H2PO4− or NaHPO4−, with perhaps 10% as HPO42−. This mixture of anions will be referred to here as “phosphate.” In serum, about 12% of phosphorus is bound to proteins. Concentrations of phosphates in blood and ECF generally are expressed in terms of elemental phosphorus, with the normal range in adults being 0.75–1.45 mmol/L (2.5–4.5 mg/dL). Because the volume of the intracellular fluid compartment


InternalMed_Harrison

InternalMed_Harrison. and ECF generally are expressed in terms of elemental phosphorus, with the normal range in adults being 0.75–1.45 mmol/L (2.5–4.5 mg/dL). Because the volume of the intracellular fluid compartment is twice that of the ECF, measurements of ECF phosphate may not accurately reflect phosphate availability within cells that follows even modest shifts of phosphate from one compartment to the other.


InternalMed_Harrison

InternalMed_Harrison. Phosphate is widely available in foods and is absorbed efficiently (65%) by the small intestine even in the absence of vitamin D. However, phosphate absorptive efficiency may be enhanced (to 85–90%) via active transport mechanisms that are stimulated by 1,25(OH)2D. These mechanisms involve activation of Na+/PO42− co-transporters that move phosphate into intestinal cells against an unfavorable electrochemical gradient. Daily net intestinal phosphate absorption varies widely with the composition of the diet but is generally in the range of 500–1000 mg/d. Phosphate absorption can be inhibited by large doses of calcium salts or by sevelamer hydrochloride (Renagel), strategies commonly used to control levels of serum phosphate in renal failure. Aluminum hydroxide antacids also reduce phosphate absorption but are used less commonly because of the potential for aluminum toxicity. Low serum phosphate stimulates renal proximal tubular synthesis of 1,25(OH)2D, perhaps by suppressing blood


InternalMed_Harrison

InternalMed_Harrison. absorption but are used less commonly because of the potential for aluminum toxicity. Low serum phosphate stimulates renal proximal tubular synthesis of 1,25(OH)2D, perhaps by suppressing blood levels of FGF23 (see below).


InternalMed_Harrison

InternalMed_Harrison. Serum phosphate levels vary by as much as 50% on a normal day. This reflects the effect of food intake but also an underlying circadian rhythm that produces a nadir between 7:00 and 10:00 a.m. Carbohydrate administration, especially as IV dextrose solutions in fasting subjects, can decrease serum phosphate by >0.7 mmol/L (2 mg/ dL) due to rapid uptake into and utilization by cells. A similar response is observed in the treatment of diabetic ketoacidosis and during metabolic or respiratory alkalosis. Because of this wide variation in serum phosphate, it is best to perform measurements in the basal, fasting state.


InternalMed_Harrison

InternalMed_Harrison. Control of serum phosphate is determined mainly by the rate of renal tubular reabsorption of the filtered load, which is ~4–6 g/d. Because intestinal phosphate absorption is highly efficient, urinary excretion is not constant but varies directly with dietary intake. The fractional excretion of phosphate (ratio of phosphate to creatinine clearance) is generally in the range of 10–15%. The proximal tubule is the principal site at which renal phosphate reabsorption is regulated. This is accomplished by changes in the levels of apical expression and activity of specific Na+/PO42− co-transporters (NaPi-2a and NaPi-2c) in the proximal tubule. Levels of these transporters at the apical surface of these cells are reduced rapidly by PTH, a major hormonal regulator of renal phosphate excretion. FGF23 can impair phosphate reabsorption dramatically by a similar mechanism. Activating FGF23 mutations cause the rare disorder autosomal dominant hypophosphatemic rickets. In contrast to PTH, FGF23 also


InternalMed_Harrison

InternalMed_Harrison. can impair phosphate reabsorption dramatically by a similar mechanism. Activating FGF23 mutations cause the rare disorder autosomal dominant hypophosphatemic rickets. In contrast to PTH, FGF23 also leads to reduced synthesis of 1,25(OH)2D, which may worsen the resulting hypophosphatemia by lowering intestinal phosphate absorption. Renal reabsorption of phosphate is responsive to changes in dietary intake such that experimental dietary phosphate restriction leads to a dramatic lowering of urinary phosphate within hours, preceding any decline in serum phosphate (e.g., filtered load). This physiologic renal adaptation to changes in dietary phosphate availability occurs independently of PTH and may be mediated in part by changes in levels of serum FGF23. Findings in FGF23-knockout mice suggest that FGF23 normally acts to lower blood phosphate and 1,25(OH)2D levels. In turn, elevation of blood phosphate increases blood levels of FGF23.


InternalMed_Harrison

InternalMed_Harrison. Renal phosphate reabsorption is impaired by hypocalcemia, hypomagnesemia, and severe hypophosphatemia. Phosphate clearance is enhanced by ECF volume expansion and impaired by dehydration. Phosphate retention is an important pathophysiologic feature of renal insufficiency (Chap. 335). HYPOPHOSPHATEMIA Causes Hypophosphatemia can occur by one or more of three primary mechanisms: (1) inadequate intestinal phosphate absorption, (2) excessive renal phosphate excretion, and (3) rapid redistribution of phosphate from the ECF into bone or soft tissue (Table 423-1). Because phosphate is so abundant in foods, inadequate intestinal absorption is almost never observed now that aluminum hydroxide antacids, which bind phosphate in the gut, are no longer widely used. Fasting or starvation, however, may result in depletion of body phosphate and predispose to subsequent hypophosphatemia during refeeding, especially if this is accomplished with IV glucose alone.


InternalMed_Harrison

InternalMed_Harrison. Chronic hypophosphatemia usually signifies a persistent renal tubular phosphate-wasting disorder. Excessive activation of PTH/ PTHrP receptors in the proximal tubule as a result of primary or secondary hyperparathyroidism or because of the PTHrP-mediated hypercalcemia syndrome in malignancy (Chap. 424) is among the more common causes of renal hypophosphatemia, especially because of the high prevalence of vitamin D deficiency in older Americans. Familial hypocalciuric hypercalcemia and Jansen’s chondrodystrophy are rare examples of genetic disorders in this category (Chap. 424).


InternalMed_Harrison

InternalMed_Harrison. Several genetic and acquired diseases cause PTH/PTHrPindependent tubular phosphate wasting with associated rickets and osteomalacia. All these diseases manifest severe hypophosphatemia; renal phosphate wasting, sometimes accompanied by aminoaciduria; inappropriately low blood levels of 1,25(OH)2D; low-normal serum levels of calcium; and evidence of impaired cartilage or bone mineralization. Analysis of these diseases led to the discovery of the hormone FGF23, which is an important physiologic regulator of phosphate metabolism. FGF23 decreases phosphate reabsorption in the proximal tubule and also suppresses the 1α-hydroxylase responsible for synthesis of 1,25(OH)2D. FGF23 is synthesized by cells of the osteoblast lineage, primarily osteocytes. High-phosphate diets increase FGF23 levels, and low-phosphate diets decrease them. Autosomal dominant hypophosphatemic rickets (ADHR) was the first disease linked to abnormalities in FGF23. ADHR results from activating mutations in the gene that


InternalMed_Harrison

InternalMed_Harrison. low-phosphate diets decrease them. Autosomal dominant hypophosphatemic rickets (ADHR) was the first disease linked to abnormalities in FGF23. ADHR results from activating mutations in the gene that encodes FGF23. These mutations alter a cleavage site that ordinarily allows for inactivation of intact FGF23. Several other genetic disorders exhibit elevated FGF23 and hypophosphatemia. The most common of these is X-linked hypophosphatemic rickets (XLH), which results from inactivating mutations in an endopeptidase termed PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) that is expressed most abundantly on the surface of osteocytes and mature osteoblasts. Patients with XLH usually have high FGF23 levels, and ablation of the FGF23 gene reverses the hypophosphatemia found in the mouse version of XLH. How inactivation


InternalMed_Harrison

InternalMed_Harrison. CAuSES of HyPoPHoSPHATEmiA I. Reduced renal tubular phosphate reabsorption A. PTH/PTHrP-dependent 1. 2. a. b. c. d. Autosomal recessive renal hypercalciuria with hypomagnesemia 3. PTHrP-dependent hypercalcemia of malignancy 4. B. PTH/PTHrP-independent 1. Excess FGF23 or other “phosphatonins” a. b. c. Autosomal dominant hypophosphatemic rickets (ADHR) (DMP1, ENPP1 deficiency) d. e. f. 2. Intrinsic renal disease a. b. c. Wilson’s disease d. NaPi-2a or NaPi-2c mutations 3. Other systemic disorders a. b. c. d. e. f. g. h. 4. Drugs or toxins a. b. Acetazolamide, other diuretics c. d. Heavy metals (lead, cadmium, saccharated ferric oxide) e. Toluene, N-methyl formamide f. Cisplatin, ifosfamide, foscarnet, rapamycin II. A. B. III. Shifts of extracellular phosphate into cells A. B. C. Catecholamines (epinephrine, dopamine, albuterol) D. E. Gram-negative sepsis, toxic shock syndrome F. G. 1. 2.


InternalMed_Harrison

InternalMed_Harrison. II. A. B. III. Shifts of extracellular phosphate into cells A. B. C. Catecholamines (epinephrine, dopamine, albuterol) D. E. Gram-negative sepsis, toxic shock syndrome F. G. 1. 2. Intensive erythropoietin, other growth factor therapy IV. A. B. Treatment of vitamin D deficiency, Paget’s disease C. Osteoblastic metastases Abbreviations: PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide.


InternalMed_Harrison

InternalMed_Harrison. Osteoblastic metastases Abbreviations: PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide. of PHEX leads to increased levels of FGF23 has not been determined. 2459 Two rare autosomal recessive hypophosphatemic syndromes associated with elevated FGF23 are due to inactivating mutations of dentin matrix protein-1 (DMP1) and ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1), both of which normally are highly expressed in bone and regulate FGF23 production. An unusual hypophosphatemic disorder, tumor-induced osteomalacia (TIO), is an acquired disorder in which tumors, usually of mesenchymal origin and generally histologically benign, secrete FGF23 and/or other molecules that induce renal phosphate wasting. The hypophosphatemic syndrome resolves completely within hours to days after successful resection of the responsible tumor. Such tumors typically express large amounts of FGF23 mRNA, and patients with TIO usually exhibit elevations of FGF23 in their blood.


InternalMed_Harrison

InternalMed_Harrison. Dent’s disease is an X-linked recessive disorder caused by inactivating mutations in CLCN5, a chloride transporter expressed in endosomes of the proximal tubule; features include hypercalciuria, hypophosphatemia, and recurrent kidney stones. Renal phosphate wasting is common among poorly controlled diabetic patients and alcoholics, who therefore are at risk for iatrogenic hypophosphatemia when treated with insulin or IV glucose, respectively. Diuretics and certain other drugs and toxins can cause defective renal tubular phosphate reabsorption (Table 423-1).


InternalMed_Harrison

InternalMed_Harrison. In hospitalized patients, hypophosphatemia is often attributable to massive redistribution of phosphate from the ECF into cells. Insulin therapy for diabetic ketoacidosis is a paradigm for this phenomenon, in which the severity of the hypophosphatemia is related to the extent of antecedent depletion of phosphate and other electrolytes (Chap. 417). The hypophosphatemia is usually greatest at a point many hours after initiation of insulin therapy and is difficult to predict from baseline measurements of serum phosphate at the time of presentation, when prerenal azotemia can obscure significant phosphate depletion. Other factors that may contribute to such acute redistributive hypophosphatemia include antecedent starvation or malnutrition, administration of IV glucose without other nutrients, elevated blood catecholamines (endogenous or exogenous), respiratory alkalosis, and recovery from metabolic acidosis.


InternalMed_Harrison

InternalMed_Harrison. Hypophosphatemia also can occur transiently (over weeks to months) during the phase of accelerated net bone formation that follows parathyroidectomy for severe primary hyperparathyroidism or during treatment of vitamin D deficiency or lytic Paget’s disease. This is usually most prominent in patients who preoperatively have evidence of high bone turnover (e.g., high serum levels of alkaline phosphatase). Osteoblastic metastases can also lead to this syndrome.


InternalMed_Harrison

InternalMed_Harrison. Clinical and Laboratory Findings The clinical manifestations of severe hypophosphatemia reflect a generalized defect in cellular energy metabolism because of ATP depletion, a shift from oxidative phosphorylation toward glycolysis, and associated tissue or organ dysfunction. Acute, severe hypophosphatemia occurs mainly or exclusively in hospitalized patients with underlying serious medical or surgical illness and preexisting phosphate depletion due to excessive urinary losses, severe malabsorption, or malnutrition. Chronic hypophosphatemia tends to be less severe, with a clinical presentation dominated by musculoskeletal complaints such as bone pain, osteomalacia, pseudo-fractures, and proximal muscle weakness or, in children, rickets and short stature.


InternalMed_Harrison

InternalMed_Harrison. Neuromuscular manifestations of severe hypophosphatemia are variable but may include muscle weakness, lethargy, confusion, disorientation, hallucinations, dysarthria, dysphagia, oculomotor palsies, anisocoria, nystagmus, ataxia, cerebellar tremor, ballismus, hyporeflexia, impaired sphincter control, distal sensory deficits, paresthesia, hyperesthesia, generalized or Guillain-Barré–like ascending paralysis, seizures, coma, and even death. Serious sequelae such as paralysis, confusion, and seizures are likely only at phosphate concentrations <0.25 mmol/L (<0.8 mg/dL). Rhabdomyolysis may develop during rapidly progressive hypophosphatemia. The diagnosis of hypophosphatemiainduced rhabdomyolysis may be overlooked, as up to 30% of patients with acute hypophosphatemia (<0.7 mM) have creatine phosphokinase 2460 elevations that peak 1–2 days after the nadir in serum phosphate, when the release of phosphate from injured myocytes may have led to a near normalization of circulating levels of


InternalMed_Harrison

InternalMed_Harrison. phosphokinase 2460 elevations that peak 1–2 days after the nadir in serum phosphate, when the release of phosphate from injured myocytes may have led to a near normalization of circulating levels of phosphate. Respiratory failure and cardiac dysfunction, which are reversible with phosphate treatment, may occur at serum phosphate levels of 0.5–0.8 mmol/L (1.5–2.5 mg/dL). Renal tubular defects, including tubular acidosis, glycosuria, and impaired reabsorption of sodium and calcium, may occur. Hematologic abnormalities correlate with reductions in intracellular ATP and 2,3-diphosphoglycerate and may include erythrocyte microspherocytosis and hemolysis; impaired oxyhemoglobin dissociation; defective leukocyte chemotaxis, phagocytosis, and bacterial killing; and platelet dysfunction with spontaneous gastrointestinal hemorrhage.


InternalMed_Harrison

InternalMed_Harrison. Severe hypophosphatemia (<0.75 mmol/L [<2 mg/dL]), particularly in the setting of underlying phosphate depletion, constitutes a dangerous electrolyte abnormality that should be corrected promptly. Unfortunately, the cumulative deficit in body phosphate cannot be predicted easily from knowledge of the circulating level of phosphate, and therapy must be approached empirically. The threshold for IV phosphate therapy and the dose administered should reflect consideration of renal function, the likely severity and duration of the underlying phosphate depletion, and the presence and severity of symptoms consistent with those of hypophosphatemia. In adults, phosphate may be safely administered IV as neutral mixtures of sodium or potassium phosphate salts at initial doses of 0.2–0.8 mmol/kg of elemental phosphorus over 6 h (e.g., 10–50 mmol over 6 h), with doses >20 mmol/6 h reserved for those who have serum levels <0.5 mmol/L (1.5 mg/dL) and normal renal function. A suggested approach is


InternalMed_Harrison

InternalMed_Harrison. elemental phosphorus over 6 h (e.g., 10–50 mmol over 6 h), with doses >20 mmol/6 h reserved for those who have serum levels <0.5 mmol/L (1.5 mg/dL) and normal renal function. A suggested approach is presented in Table 423-2. Serum levels of phosphate and calcium must be monitored closely (every 6–12 h) throughout treatment. It is necessary to avoid a serum calcium-phosphorus product >50 to reduce the risk of heterotopic calcification. Hypocalcemia, if present, should be corrected before administering IV phosphate. Less severe hypophosphatemia, in the range of 0.5–0.8 mmol/L (1.5–2.5 mg/dL), usually can be treated with oral phosphate in divided doses of 750–2000 mg/d as elemental phosphorus; higher doses can cause bloating and diarrhea.


InternalMed_Harrison

InternalMed_Harrison. Management of chronic hypophosphatemia requires knowledge of the cause(s) of the disorder. Hypophosphatemia related to the secondary hyperparathyroidism of vitamin D deficiency usually responds to treatment with vitamin D and calcium alone. XLH, ADHR, TIO, and related renal tubular disorders usually are managed with divided oral doses of phosphate, often with calcium and 1,25(OH)2D supplements to bypass the block in renal 1,25(OH)2D synthesis and prevent secondary hyperparathyroidism caused by suppression of ECF calcium levels. Thiazide diuretics may be used to prevent nephrocalcinosis in patients who are managed this way. Complete normalization of hypophosphatemia is generally not possible in these conditions. Optimal therapy for TIO is extirpation of the responsible tumor, which may be localized by radiographic skeletal survey or bone scan (many are located in bone) or by radionuclide scanning using sestamibi or labeled octreotide. Successful treatment of TIO-induced


InternalMed_Harrison

InternalMed_Harrison. which may be localized by radiographic skeletal survey or bone scan (many are located in bone) or by radionuclide scanning using sestamibi or labeled octreotide. Successful treatment of TIO-induced hypophosphatemia with octreotide has been reported in a small number of patients.


InternalMed_Harrison

InternalMed_Harrison. HYPERPHOSPHATEMIA Causes When the filtered load of phosphate and glomerular filtration rate (GFR) are normal, control of serum phosphate levels is achieved by adjusting the rate at which phosphate is reabsorbed by the proximal tubular NaPi-2 co-transporters. The principal hormonal regulators of NaPi-2 activity are PTH and FGF23. Hyperphosphatemia, defined in adults as a fasting serum phosphate concentration >1.8 mmol/L (5.5 mg/dL), usually results from impaired glomerular filtration, hypoparathyroidism, excessive delivery of phosphate into the ECF (from bone, gut, or parenteral phosphate therapy), or a combination of these factors (Table 423-3). The upper limit of normal serum phosphate concentrations is higher in children and neonates (2.4 mmol/L [7 mg/ dL]). It is useful to distinguish hyperphosphatemia caused by impaired renal phosphate excretion from that which results from excessive delivery of phosphate into the ECF (Table 423-3).


InternalMed_Harrison

InternalMed_Harrison. In chronic renal insufficiency, reduced GFR leads to phosphate retention. Hyperphosphatemia in turn further impairs renal synthesis of 1,25(OH)2D, increases FGF23 levels, and stimulates PTH secretion and hypertrophy both directly and indirectly (by lowering blood ionized calcium levels). Thus, hyperphosphatemia is a major cause of the secondary hyperparathyroidism of renal failure and must be addressed early in the course of the disease (Chaps. 335 and 424).


InternalMed_Harrison

InternalMed_Harrison. Hypoparathyroidism leads to hyperphosphatemia via increased expression of NaPi-2 co-transporters in the proximal tubule. Hypoparathyroidism, or parathyroid suppression, has multiple potential causes, including autoimmune disease; developmental, surgical, or radiation-induced absence of functional parathyroid tissue; vitamin D intoxication or other causes of PTH-independent hypercalcemia; cellular PTH resistance (pseudohypoparathyroidism or hypomagnesemia); infiltrative disorders such as Wilson’s disease and hemochromatosis; and impaired PTH secretion caused by hypermagnesemia, severe hypomagnesemia, or activating mutations in the CaSR. Hypocalcemia may also contribute directly to impaired phosphate clearance, as calcium infusion can induce phosphaturia in hypoparathyroid subjects. Increased tubular phosphate reabsorption also occurs in acromegaly, during heparin administration, and in tumoral calcinosis. Tumoral calcinosis is caused by a rare group of genetic disorders in which FGF23


InternalMed_Harrison

InternalMed_Harrison. tubular phosphate reabsorption also occurs in acromegaly, during heparin administration, and in tumoral calcinosis. Tumoral calcinosis is caused by a rare group of genetic disorders in which FGF23 is processed in a way that leads to low levels of active FGF23 in the bloodstream. This may result from mutations in the FGF23 sequence or via inactivating mutations in the GALNT3 gene, which encodes a galactosaminyl transferase that normally adds sugar residues to FGF23 that slow its proteolysis. A similar syndrome results from FGF23 resistance due to inactivating mutations of the FGF23 co-receptor Klotho. These abnormalities cause elevated serum 1,25(OH)2D, parathyroid


InternalMed_Harrison

InternalMed_Harrison. Likely severity of underlying phosphate depletion Concurrent parenteral glucose administration Presence of neuromuscular, cardiopulmonary, or hematologic complications of hypophosphatemia Renal function (reduce dose by 50% if serum creatinine >220 μmol/L [>2.5 mg/dL]) Serum calcium level (correct hypocalcemia first; reduce dose by 50% in hypercalcemia) Guidelines Serum Phosphorus, mM (mg/dL) Rate of Infusion, mmol/h Duration, h Total Administered, mmol <0.8 (<2.5) 2 6 12 <0.5 (<1.5) 4 6 24 <0.3 (<1) 8 6 48 Note: Rates shown are calculated for a 70-kg person; levels of serum calcium and phosphorus must be measured every 6–12 h during therapy; infusions can be repeated to achieve stable serum phosphorus levels >0.8 mmol/L (>2.5 mg/dL); most formulations available in the United States provide 3 mmol/mL of sodium or potassium phosphate. CAuSES of HyPERPHoSPHATEmiA I. Impaired renal phosphate excretion A. Renal insufficiency B. Hypoparathyroidism 1. 2. 3. 4.


InternalMed_Harrison

InternalMed_Harrison. CAuSES of HyPERPHoSPHATEmiA I. Impaired renal phosphate excretion A. Renal insufficiency B. Hypoparathyroidism 1. 2. 3. 4. Activating mutations of the calcium-sensing receptor C. Parathyroid suppression 1. Parathyroid-independent hypercalcemia a. b. Sarcoidosis, other granulomatous diseases c. Immobilization, osteolytic metastases d. 2. Severe hypermagnesemia or hypomagnesemia D. Pseudohypoparathyroidism E. Acromegaly F. Tumoral calcinosis G. Heparin therapy II. A. Rapid administration of exogenous phosphate (intravenous, oral, rectal) B. 1. 2. 3. 4. 5. 6. C. Transcellular phosphate shifts 1. 2. suppression, increased intestinal calcium absorption, and focal hyperostosis with large, lobulated periarticular heterotopic ossifications (especially at shoulders or hips) and are accompanied by hyperphosphatemia. In some forms of tumoral calcinosis, serum phosphorus levels are normal.


InternalMed_Harrison

InternalMed_Harrison. When large amounts of phosphate are delivered rapidly into the ECF, hyperphosphatemia can occur despite normal renal function. Examples include overzealous IV phosphate therapy, oral or rectal administration of large amounts of phosphate-containing laxatives or enemas (especially in children), extensive soft tissue injury or necrosis (crush injuries, rhabdomyolysis, hyperthermia, fulminant hepatitis, cytotoxic chemotherapy), extensive hemolytic anemia, and transcellular phosphate shifts induced by severe metabolic or respiratory acidosis.


InternalMed_Harrison

InternalMed_Harrison. Clinical Findings The clinical consequences of acute, severe hyperphosphatemia are due mainly to the formation of widespread calcium phosphate precipitates and resulting hypocalcemia. Thus, tetany, seizures, accelerated nephrocalcinosis (with renal failure, hyperkalemia, hyperuricemia, and metabolic acidosis), and pulmonary or cardiac calcifications (including development of acute heart block) may occur. The severity of these complications relates to the elevation of serum phosphate levels, which can reach concentrations as high as 7 mmol/L (20 mg/dL) in instances of massive soft tissue injury or tumor lysis syndrome.


InternalMed_Harrison

InternalMed_Harrison. Therapeutic options for management of severe hyperphosphatemia are limited. Volume expansion may enhance renal phosphate clearance. Aluminum hydroxide antacids or sevelamer may be helpful in chelating and limiting absorption of offending phosphate salts present in the intestine. Hemodialysis is the most effective thera-2461 peutic strategy and should be considered early in the course of severe hyperphosphatemia, especially in the setting of renal failure and symptomatic hypocalcemia.


InternalMed_Harrison

InternalMed_Harrison. Magnesium is the major intracellular divalent cation. Normal concentrations of extracellular magnesium and calcium are crucial for normal neuromuscular activity. Intracellular magnesium forms a key complex with ATP and is an important cofactor for a wide range of enzymes, transporters, and nucleic acids required for normal cellular function, replication, and energy metabolism. The concentration of magnesium in serum is closely regulated within the range of 0.7–1 mmol/L (1.5–2 meq/L; 1.7–2.4 mg/dL), of which 30% is protein-bound and another 15% is loosely complexed to phosphate and other anions. One-half of the 25 g (1000 mmol) of total body magnesium is located in bone, only one-half of which is insoluble in the mineral phase. Almost all extraskeletal magnesium is present within cells, where the total concentration is 5 mM, 95% of which is bound to proteins and other macromolecules. Because only 1% of body magnesium resides in the ECF, measurements of serum magnesium levels may not


InternalMed_Harrison

InternalMed_Harrison. where the total concentration is 5 mM, 95% of which is bound to proteins and other macromolecules. Because only 1% of body magnesium resides in the ECF, measurements of serum magnesium levels may not accurately reflect the level of total body magnesium stores.


InternalMed_Harrison

InternalMed_Harrison. Dietary magnesium content normally ranges from 6 to 15 mmol/d (140–360 mg/d), of which 30–40% is absorbed, mainly in the jejunum and ileum. Intestinal magnesium absorptive efficiency is stimulated by 1,25(OH)2D and can reach 70% during magnesium deprivation. Urinary magnesium excretion normally matches net intestinal absorption and is ~4 mmol/d (100 mg/d). Regulation of serum magnesium concentrations is achieved mainly by control of renal magnesium reabsorption. Only 20% of filtered magnesium is reabsorbed in the proximal tubule, whereas 60% is reclaimed in the cTAL and another 5–10% in the DCT. Magnesium reabsorption in the cTAL occurs via a paracellular route that requires both a lumen-positive potential, created by NaCl reabsorption, and tight-junction proteins encoded by members of the Claudin gene family. Magnesium reabsorption in the cTAL is increased by PTH but inhibited by hypercalcemia or hypermagnesemia, both of which activate the CaSR in this nephron segment.


InternalMed_Harrison

InternalMed_Harrison. HYPOMAGNESEMIA Causes Hypomagnesemia usually signifies substantial depletion of body magnesium stores (0.5–1 mmol/kg). Hypomagnesemia can result from intestinal malabsorption; protracted vomiting, diarrhea, or intestinal drainage; defective renal tubular magnesium reabsorption; or rapid shifts of magnesium from the ECF into cells, bone, or third spaces (Table 423-4). Dietary magnesium deficiency is unlikely except possibly in the setting of alcoholism. A rare genetic disorder that causes selective intestinal magnesium malabsorption has been described (primary infantile hypomagnesemia). Another rare inherited disorder (hypomagnesemia with secondary hypocalcemia) is caused by mutations in the gene encoding TRPM6, a protein that, along with TRPM7, forms a channel important for both intestinal and distal-tubular renal transcellular magnesium transport. Malabsorptive states, often compounded by vitamin D deficiency, can critically limit magnesium absorption and produce hypomagnesemia


InternalMed_Harrison

InternalMed_Harrison. and distal-tubular renal transcellular magnesium transport. Malabsorptive states, often compounded by vitamin D deficiency, can critically limit magnesium absorption and produce hypomagnesemia despite the compensatory effects of secondary hyperparathyroidism and of hypocalcemia and hypomagnesemia to enhance cTAL magnesium reabsorption. Diarrhea or surgical drainage fluid may contain ≥5 mmol/L of magnesium. Proton pump inhibitors (omeprazole and others) may produce hypomagnesemia by an unknown mechanism that does not involve renal wasting of magnesium.


InternalMed_Harrison

InternalMed_Harrison. Several genetic magnesium-wasting syndromes have been described, including inactivating mutations of genes encoding the DCT NaCl co-transporter (Gitelman’s syndrome), proteins required for cTAL Na-K-2Cl transport (Bartter’s syndrome), claudin 16 or claudin 19 (autosomal recessive renal hypomagnesemia with hypercalciuria), a DCT Na+,K+-ATPase γ-subunit (autosomal dominant renal hypomagnesemia with hypocalciuria), DCT K+ channels (Kv1.1, Kir4.1), and a mitochondrial gene encoding a tRNA. Activating mutations CAuSES of HyPomAgnESEmiA I. Impaired intestinal absorption A. Hypomagnesemia with secondary hypocalcemia (TRPM6 mutations) B. Malabsorption syndromes C. Vitamin D deficiency D. Proton pump inhibitors II. A. B. Intestinal drainage, fistulas III. A. 1. 2. 3. 4. Potassium channel mutations (Kv1.1, Kir4.1) 5. Na+,K+-ATPase γ-subunit mutations (FXYD2) B. Acquired renal disease 1. 2. Postobstruction, ATN (diuretic phase) 3. C. Drugs and toxins 1. 2.


InternalMed_Harrison

InternalMed_Harrison. 4. Potassium channel mutations (Kv1.1, Kir4.1) 5. Na+,K+-ATPase γ-subunit mutations (FXYD2) B. Acquired renal disease 1. 2. Postobstruction, ATN (diuretic phase) 3. C. Drugs and toxins 1. 2. Diuretics (loop, thiazide, osmotic) 3. 4. Pentamidine, foscarnet 5. 6. Aminoglycosides, amphotericin B 7. D. Other 1. 2. 3. 4. 5. 6. 7. 8. IV. A. 1. 2. 3. Correction of respiratory acidosis 4. B. Accelerated bone formation 1. 2. Treatment of vitamin D deficiency 3. C. Other 1. Pancreatitis, burns, excessive sweating 2. Abbreviations: ATN, acute tubular necrosis; SIADH, syndrome of inappropriate antidiuretic hormone.


InternalMed_Harrison

InternalMed_Harrison. C. Other 1. Pancreatitis, burns, excessive sweating 2. Abbreviations: ATN, acute tubular necrosis; SIADH, syndrome of inappropriate antidiuretic hormone. of the CaSR can cause hypomagnesemia as well as hypocalcemia. ECF expansion, hypercalcemia, and severe phosphate depletion may impair magnesium reabsorption, as can various forms of renal injury, including those caused by drugs such as cisplatin, cyclosporine, aminoglycosides, and pentamidine as well as the epidermal growth factor (EGF) receptor inhibitory antibody, cetuximab (EGF action is required for normal DCT apical expression of TRPM6) (Table 423-4). A rising blood concentration of ethanol directly impairs tubular magnesium reabsorption, and persistent glycosuria with osmotic diuresis leads to magnesium wasting and probably contributes to the high frequency of hypomagnesemia in poorly controlled diabetic patients. Magnesium depletion is aggravated by metabolic acidosis, which causes intracellular losses as well.


InternalMed_Harrison

InternalMed_Harrison. Hypomagnesemia due to rapid shifts of magnesium from ECF into the intracellular compartment can occur during recovery from diabetic ketoacidosis, starvation, or respiratory acidosis. Less acute shifts may be seen during rapid bone formation after parathyroidectomy, with treatment of vitamin D deficiency, or with osteoblastic metastases. Large amounts of magnesium may be lost with acute pancreatitis, extensive burns, or protracted and severe sweating and during pregnancy and lactation.


InternalMed_Harrison

InternalMed_Harrison. Clinical and Laboratory Findings Hypomagnesemia may cause generalized alterations in neuromuscular function, including tetany, tremor, seizures, muscle weakness, ataxia, nystagmus, vertigo, apathy, depression, irritability, delirium, and psychosis. Patients are usually asymptomatic when serum magnesium concentrations are >0.5 mmol/L (1 meq/L; 1.2 mg/dL), although the severity of symptoms may not correlate with serum magnesium levels. Cardiac arrhythmias may occur, including sinus tachycardia, other supraventricular tachycardias, and ventricular arrhythmias. Electrocardiographic abnormalities may include prolonged PR or QT intervals, T-wave flattening or inversion, and ST straightening. Sensitivity to digitalis toxicity may be enhanced.


InternalMed_Harrison

InternalMed_Harrison. Other electrolyte abnormalities often seen with hypomagnesemia, including hypocalcemia (with hypocalciuria) and hypokalemia, may not be easily corrected unless magnesium is administered as well. The hypocalcemia may be a result of concurrent vitamin D deficiency, although hypomagnesemia can cause impaired synthesis of 1,25(OH)2D, cellular resistance to PTH, and, at very low serum magnesium (<0.4 mmol/L [0.8 meq/L; <1 mg/dL]), a defect in PTH secretion; these abnormalities are reversible with therapy.


InternalMed_Harrison

InternalMed_Harrison. Mild, asymptomatic hypomagnesemia may be treated with oral magnesium salts (MgCl2, MgO, Mg[OH]2) in divided doses totaling 20–30 mmol/d (40–60 meq/d). Diarrhea may occur with larger doses. More severe hypomagnesemia should be treated parenterally, preferably with IV MgCl2, which can be administered safely as a continuous infusion of 50 mmol/d (100 meq Mg2+/d) if renal function is normal. If GFR is reduced, the infusion rate should be lowered by 50–75%. Use of IM MgSO4 is discouraged; the injections are painful and provide relatively little magnesium (2 mL of 50% MgSO4 supplies only 4 mmol). MgSO4 may be given IV instead of MgCl2, although the sulfate anions may bind calcium in serum and urine and aggravate hypocalcemia. Serum magnesium should be monitored at intervals of 12–24 h during therapy, which may continue for several days because of impaired renal conservation of magnesium (only 50–70% of the daily IV magnesium dose is retained) and delayed repletion of intracellular deficits,


InternalMed_Harrison

InternalMed_Harrison. which may continue for several days because of impaired renal conservation of magnesium (only 50–70% of the daily IV magnesium dose is retained) and delayed repletion of intracellular deficits, which may be as high as 1–1.5 mmol/kg (2–3 meq/kg).


InternalMed_Harrison

InternalMed_Harrison. It is important to consider the need for calcium, potassium, and phosphate supplementation in patients with hypomagnesemia. Vitamin D deficiency frequently coexists and should be treated with oral or parenteral vitamin D or 25(OH)D (but not with 1,25[OH]2D, which may impair tubular magnesium reabsorption, possibly via PTH suppression). In severely hypomagnesemic patients with concomitant hypocalcemia and hypophosphatemia, administration of IV magnesium alone may worsen hypophosphatemia, provoking neuromuscular symptoms or rhabdomyolysis, due to rapid stimulation of PTH secretion. This is avoided by administering both calcium and magnesium. HYPERMAGNESEMIA Causes Hypermagnesemia is rarely seen in the absence of renal insufficiency, as normal kidneys can excrete large amounts (250 mmol/d) of CAuSES of HyPERmAgnESEmiA I. Excessive magnesium intake A. Cathartics, urologic irrigants B. Parenteral magnesium administration II. A. Trauma, shock, sepsis B. C. III. A. B. IV. A.


InternalMed_Harrison

InternalMed_Harrison. CAuSES of HyPERmAgnESEmiA I. Excessive magnesium intake A. Cathartics, urologic irrigants B. Parenteral magnesium administration II. A. Trauma, shock, sepsis B. C. III. A. B. IV. A. B. C. magnesium. Mild hypermagnesemia due to excessive reabsorption in the cTAL occurs with CaSR mutations in familial hypocalciuric hypercalcemia and has been described in some patients with adrenal insufficiency, hypothyroidism, or hypothermia. Massive exogenous magnesium exposures, usually via the gastrointestinal tract, can overwhelm renal excretory capacity and cause life-threatening hypermagnesemia (Table 423-5). A notable example of this is prolonged retention of even normal amounts of magnesium-containing cathartics in patients with intestinal ileus, obstruction, or perforation. Extensive soft tissue injury or necrosis can also deliver large amounts of magnesium into the ECF in patients who have suffered trauma, shock, sepsis, cardiac arrest, or severe burns.


InternalMed_Harrison

InternalMed_Harrison. Clinical and Laboratory Findings The most prominent clinical manifestations of hypermagnesemia are vasodilation and neuromuscular blockade, which may appear at serum magnesium concentrations >2 mmol/L (>4 meq/L; >4.8 mg/dL). Hypotension that is refractory to vasopressors or volume expansion may be an early sign. Nausea, lethargy, and weakness may progress to respiratory failure, paralysis, and coma, with hypoactive tendon reflexes, at serum magnesium levels >4 mmol/L. Other findings may include gastrointestinal hypomotility or ileus; facial flushing; pupillary dilation; paradoxical bradycardia; prolongation of PR, QRS, and QT intervals; heart block; and, at serum magnesium levels approaching 10 mmol/L, asystole. Hypermagnesemia, acting via the CaSR, causes hypocalcemia and hypercalciuria due to both parathyroid suppression and impaired cTAL calcium reabsorption.


InternalMed_Harrison

InternalMed_Harrison. Hypermagnesemia, acting via the CaSR, causes hypocalcemia and hypercalciuria due to both parathyroid suppression and impaired cTAL calcium reabsorption. Successful treatment of hypermagnesemia generally involves identifying and interrupting the source of magnesium and employing measures to increase magnesium clearance from the ECF. Use of magnesium-free cathartics or enemas may be helpful in clearing ingested magnesium from the gastrointestinal tract. Vigorous IV hydration should be attempted, if appropriate. Hemodialysis is effective and may be required in patients with significant renal insufficiency. Calcium, administered IV in doses of 100–200 mg over 1–2 h, has been reported to provide temporary improvement in signs and symptoms of hypermagnesemia.


InternalMed_Harrison

InternalMed_Harrison. 1,25-Dihydroxyvitamin D (1,25[OH]2D) is the major steroid hormone involved in mineral ion homeostasis regulation. Vitamin D and its metabolites are hormones and hormone precursors rather than vitamins, since in the proper biologic setting, they can be synthesized endogenously (Fig. 423-4). In response to ultraviolet radiation of the 1,25(OH)2D FIGURE 423-4 Vitamin D synthesis and activation. Vitamin D is synthesized in the skin in response to ultraviolet radiation and also is absorbed from the diet. It is then transported to the liver, where it undergoes 25-hydroxylation. This metabolite is the major circulating form of vitamin D. The final step in hormone activation, 1α-hydroxylation, occurs in the kidney.


InternalMed_Harrison

InternalMed_Harrison. skin, a photochemical cleavage results in the formation of vitamin D from 7-dehydrocholesterol. Cutaneous production of vitamin D is decreased by melanin and high solar protection factor sunblocks, which effectively impair skin penetration by ultraviolet light. The increased use of sunblocks in North America and Western Europe and a reduction in the magnitude of solar exposure of the general population over the last several decades has led to an increased reliance on dietary sources of vitamin D. In the United States and Canada, these sources largely consist of fortified cereals and dairy products, in addition to fish oils and egg yolks. Vitamin D from plant sources is in the form of vitamin D2, whereas that from animal sources is vitamin D3. These two forms have equivalent biologic activity and are activated equally well by the vitamin D hydroxylases in humans. Vitamin D enters the circulation, whether absorbed from the intestine or synthesized cutaneously, bound to vitamin D–binding


InternalMed_Harrison

InternalMed_Harrison. and are activated equally well by the vitamin D hydroxylases in humans. Vitamin D enters the circulation, whether absorbed from the intestine or synthesized cutaneously, bound to vitamin D–binding protein, an α-globulin synthesized in the liver. Vitamin D is subsequently 25-hydroxylated in the liver by cytochrome P450–like enzymes in the mitochondria and microsomes. The activity of this hydroxylase is not tightly regulated, and the resultant metabolite, 25-hydroxyvitamin D (25[OH]D), is the major circulating and storage form of vitamin D. Approximately 88% of 25(OH)D circulates bound to the vitamin D–binding protein, 0.03% is free, and the rest circulates bound to albumin. The half-life of 25(OH)D is approximately 2–3 weeks; however, it is shortened dramatically when vitamin D–binding protein levels are reduced, as can occur with increased urinary losses in the nephrotic syndrome.


InternalMed_Harrison

InternalMed_Harrison. 1,25(OH)2D3 Ca2+HPO42– Calcification Ca2+HPO42– KidneyParathyroidglandsBone25(OH)D-1˜-hydroxylaseand other factors PTH PTH Blood calcium IntestinePi /+1,25(OH)2D3 / FIGURE 423-5 Schematic representation of the hormonal control loop for vitamin D metabolism and function. A reduction in the serum calcium below ~2.2 mmol/L (8.8 mg/dL) prompts a proportional increase in the secretion of parathyroid hormone (PTH) and so mobilizes additional calcium from the bone. PTH promotes the synthesis of 1,25(OH)2D in the kidney, which in turn stimulates the mobilization of calcium from bone and intestine and regulates the synthesis of PTH by negative feedback.


InternalMed_Harrison

InternalMed_Harrison. The second hydroxylation, required for the formation of the mature hormone, occurs in the kidney (Fig. 423-5). The 25-hydroxyvitamin D-1α-hydroxylase is a tightly regulated cytochrome P450–like mixed-function oxidase expressed in the proximal convoluted tubule cells of the kidney. PTH and hypophosphatemia are the major inducers of this microsomal enzyme, whereas calcium, FGF23, and the enzyme’s product, 1,25(OH)2D, repress it. The 25-hydroxyvitamin D-1α-hydroxylase is also present in epidermal keratinocytes, but keratinocyte production of 1,25(OH)2D is not thought to contribute to circulating levels of this hormone. In addition to being present in the trophoblastic layer of the placenta, the 1α-hydroxylase is produced by macrophages associated with granulomas and lymphomas. In these latter pathologic states, the activity of the enzyme is induced by interferon γ and TNF-α but is not regulated by calcium or 1,25(OH)2D; therefore, hypercalcemia, associated with elevated levels of


InternalMed_Harrison

InternalMed_Harrison. latter pathologic states, the activity of the enzyme is induced by interferon γ and TNF-α but is not regulated by calcium or 1,25(OH)2D; therefore, hypercalcemia, associated with elevated levels of 1,25(OH)2D, may be observed. Treatment of sarcoidosis-associated hypercalcemia with glucocorticoids, ketoconazole, or chloroquine reduces 1,25(OH)2D production and effectively lowers serum calcium. In contrast, chloroquine has not been shown to lower the elevated serum 1,25(OH)2D levels in patients with lymphoma.


InternalMed_Harrison

InternalMed_Harrison. The major pathway for inactivation of vitamin D metabolites is an additional hydroxylation step by the vitamin D 24-hydroxylase, an enzyme that is expressed in most tissues. 1,25(OH)2D is the major inducer of this enzyme; therefore, this hormone promotes its own inactivation, thereby limiting its biologic effects. Mutations of the gene encoding this enzyme (CYP24A1) can lead to infantile hypercalcemia and, in those less severely affected, long-standing hypercalciuria, nephrocalcinosis, and nephrolithiasis. Polar metabolites of 1,25(OH)2D are secreted into the bile and reabsorbed via the enterohepatic circulation. Impairment of this recirculation, which is seen with diseases of the terminal ileum, leads to accelerated losses of vitamin D metabolites.


InternalMed_Harrison

InternalMed_Harrison. ACTIONS OF 1,25(OH)2D 1,25(OH)2D mediates its biologic effects by binding to a member of the nuclear receptor superfamily, the vitamin D receptor (VDR). This receptor belongs to the subfamily that includes the thyroid hormone receptors, the retinoid receptors, and the peroxisome proliferator– activated receptors; however, in contrast to the other members of this subfamily, only one VDR isoform has been isolated. The VDR binds to target DNA sequences as a heterodimer with the retinoid X receptor, recruiting a series of coactivators that modify chromatin and approximate the VDR to the basal transcriptional apparatus, resulting in the induction of target gene expression. The mechanism of transcriptional repression by the VDR varies with different target genes but has been shown to involve either interference with the action of activating transcription factors or the recruitment of novel proteins to the VDR complex, resulting in transcriptional repression.


InternalMed_Harrison

InternalMed_Harrison. The affinity of the VDR for 1,25(OH)2D is approximately three orders of magnitude higher than that for other vitamin D metabolites. In normal physiologic circumstances, these other metabolites are not thought to stimulate receptor-dependent actions. However, in states of vitamin D toxicity, the markedly elevated levels of 25(OH)D may lead to hypercalcemia by interacting directly with the VDR and by displacing 1,25(OH)2D from vitamin D–binding protein, resulting in increased bioavailability of the active hormone.


InternalMed_Harrison

InternalMed_Harrison. The VDR is expressed in a wide range of cells and tissues. The molecular actions of 1,25(OH)2D have been studied most extensively in tissues involved in the regulation of mineral ion homeostasis. This hormone is a major inducer of calbindin 9K, a calcium-binding protein expressed in the intestine, which is thought to play an important role in the active transport of calcium across the enterocyte. The two major calcium transporters expressed by intestinal epithelia, TRPV5 and TRPV6 (transient receptor potential vanilloid), are also vitamin D responsive. By inducing the expression of these and other genes in the small intestine, 1,25(OH)2D increases the efficiency of intestinal calcium absorption, and it also has been shown to have several important actions in the skeleton. The VDR is expressed in osteoblasts and regulates the expression of several genes in this cell. These genes include the bone matrix proteins osteocalcin and osteopontin, which are upregulated by 1,25(OH)2D, in


InternalMed_Harrison

InternalMed_Harrison. expressed in osteoblasts and regulates the expression of several genes in this cell. These genes include the bone matrix proteins osteocalcin and osteopontin, which are upregulated by 1,25(OH)2D, in addition to type I collagen, which is transcriptionally repressed by 1,25(OH)2D. Both 1,25(OH)2D and PTH induce the expression of RANK ligand, which promotes osteoclast differentiation and increases osteoclast activity, by binding to RANK on osteoclast progenitors and mature osteoclasts. This is the mechanism by which 1,25(OH)2D induces bone resorption. However, the skeletal features associated with VDR-knockout mice (rickets, osteomalacia) are largely corrected by increasing calcium and phosphorus intake, underscoring the importance of vitamin D action in the gut.


InternalMed_Harrison

InternalMed_Harrison. The VDR is expressed in the parathyroid gland, and 1,25(OH)2D has been shown to have antiproliferative effects on parathyroid cells and to suppress the transcription of the PTH gene. These effects of 1,25(OH)2D on the parathyroid gland are an important part of the rationale for current therapies directed at preventing and treating hyperparathyroidism associated with renal insufficiency. The VDR is also expressed in tissues and organs that do not play a role in mineral ion homeostasis. Notable in this respect is the observation that 1,25(OH)2D has an antiproliferative effect on several cell types, including keratinocytes, breast cancer cells, and prostate cancer cells. The effects of 1,25(OH)2D and the VDR on keratinocytes are particularly intriguing. Alopecia is seen in humans and mice with mutant VDRs but is not a feature of vitamin D deficiency; thus, the effects of the VDR on the hair follicle are ligand-independent.


InternalMed_Harrison

InternalMed_Harrison. The mounting concern about the relationship between solar exposure and the development of skin cancer has led to increased reliance on dietary sources of vitamin D. Although the prevalence of vitamin D deficiency varies, the third National Health and Nutrition Examination Survey (NHANES III) revealed that vitamin D deficiency is prevalent throughout the United States. The clinical syndrome of vitamin D deficiency can be a result of deficient production of vitamin D in the skin, lack of dietary intake, accelerated losses of vitamin D, impaired vitamin D activation, or resistance to the biologic effects of 1,25(OH)2D (Table 423-6). The elderly and nursing home residents are particularly at risk for vitamin D deficiency, since both the efficiency of vitamin D synthesis in the skin and the absorption of vitamin D from the intestine decline with age. Similarly, intestinal malabsorption of dietary fats and short bowel syndrome, including that associated with intestinal bypass surgery, can


InternalMed_Harrison

InternalMed_Harrison. of vitamin D from the intestine decline with age. Similarly, intestinal malabsorption of dietary fats and short bowel syndrome, including that associated with intestinal bypass surgery, can lead to vitamin D deficiency. This is further exacerbated in the presence of terminal ileal disease, which results in impaired enterohepatic circulation of vitamin D metabolites. In addition to intestinal diseases, accelerated inactivation of vitamin D metabolites can be seen with drugs that induce hepatic cytochrome P450 mixed-function oxidases such as barbiturates, phenytoin, and rifampin. Impaired 25-hydroxylation, associated with severe liver disease or isoniazid, is an uncommon cause of vitamin D deficiency. A mutation in the gene responsible for 25-hydroxylation has been identified in one kindred. Impaired 1α-hydroxylation is prevalent in the population with profound renal dysfunction due to an increase in circulating FGF23 levels and a decrease in functional renal mass. Thus, therapeutic


InternalMed_Harrison

InternalMed_Harrison. Impaired 1α-hydroxylation is prevalent in the population with profound renal dysfunction due to an increase in circulating FGF23 levels and a decrease in functional renal mass. Thus, therapeutic interventions should be considered in patients whose creatinine clearance is <0.5 mL/s (30 mL/min). Mutations in the renal 1α-hydroxylase are the basis for the genetic disorder, pseudovitamin D–deficiency rickets. This autosomal recessive disorder presents with the syndrome of vitamin D deficiency in the first year of life. Patients present with growth retardation, rickets, and hypocalcemic seizures. Serum 1,25(OH)2D levels are low despite normal 25(OH)D levels and elevated PTH levels. Treatment with vitamin D metabolites that do not require 1α-hydroxylation results in disease remission, although lifelong therapy is required. A second autosomal recessive disorder, hereditary vitamin D–resistant rickets, a consequence of vitamin D receptor mutations, is a greater therapeutic challenge. These


InternalMed_Harrison

InternalMed_Harrison. lifelong therapy is required. A second autosomal recessive disorder, hereditary vitamin D–resistant rickets, a consequence of vitamin D receptor mutations, is a greater therapeutic challenge. These patients present in a similar fashion during the first year of life, but alopecia often accompanies the disorder, demonstrating a functional role of the VDR in postnatal hair regeneration. Serum levels of 1,25(OH)2D are dramatically elevated in these individuals both because of increased production due to stimulation of 1α-hydroxylase activity as a consequence of secondary hyperparathyroidism and because of impaired inactivation, since induction of the 24-hydroxylase by 1,25(OH)2D requires an intact VDR. Because the receptor mutation results in hormone resistance, daily calcium and phosphorus infusions may be required to bypass the defect in intestinal mineral ion absorption.


InternalMed_Harrison

InternalMed_Harrison. CAuSES of imPAiRED viTAmin D ACTion Accelerated loss of vitamin D 1α-hydroxylase mutation Increased metabolism (barbitu-Oncogenic osteomalacia rates, phenytoin, rifampin) Liver disease, isoniazid


InternalMed_Harrison

InternalMed_Harrison. Regardless of the cause, the clinical manifestations of vitamin D 2465 deficiency are largely a consequence of impaired intestinal calcium absorption. Mild to moderate vitamin D deficiency is asymptomatic, whereas long-standing vitamin D deficiency results in hypocalcemia accompanied by secondary hyperparathyroidism, impaired mineralization of the skeleton (osteopenia on x-ray or decreased bone mineral density), and proximal myopathy. Vitamin D deficiency also has been shown to be associated with an increase in overall mortality, including cardiovascular causes. In the absence of an intercurrent illness, the hypocalcemia associated with long-standing vitamin D deficiency rarely presents with acute symptoms of hypocalcemia such as numbness, tingling, and seizures. However, the concurrent development of hypomagnesemia, which impairs parathyroid function, or the administration of potent bisphosphonates, which impair bone resorption, can lead to acute symptomatic hypocalcemia in vitamin


InternalMed_Harrison

InternalMed_Harrison. development of hypomagnesemia, which impairs parathyroid function, or the administration of potent bisphosphonates, which impair bone resorption, can lead to acute symptomatic hypocalcemia in vitamin D–deficient individuals.


InternalMed_Harrison

InternalMed_Harrison. Rickets and Osteomalacia In children, before epiphyseal fusion, vitamin D deficiency results in growth retardation associated with an expansion of the growth plate known as rickets. Three layers of chondrocytes are present in the normal growth plate: the reserve zone, the proliferating zone, and the hypertrophic zone. Rickets associated with impaired vitamin D action is characterized by expansion of the hyper-trophic chondrocyte layer. The proliferation and differentiation of the chondrocytes in the rachitic growth plate are normal, and the expansion of the growth plate is a consequence of impaired apoptosis of the late hypertrophic chondrocytes, an event that precedes replacement of these cells by osteoblasts during endochondral bone formation. Investigations in murine models demonstrate that hypophosphatemia, which in vitamin D deficiency is a consequence of secondary hyperparathyroidism, is a key etiologic factor in the development of the rachitic growth plate.


InternalMed_Harrison

InternalMed_Harrison. The hypocalcemia and hypophosphatemia that accompany vitamin D deficiency result in impaired mineralization of bone matrix proteins, a condition known as osteomalacia. Osteomalacia is also a feature of long-standing hypophosphatemia, which may be a consequence of renal phosphate wasting or chronic use of etidronate or phosphate-binding antacids. This hypomineralized matrix is biomechanically inferior to normal bone; as a result, patients with vitamin D deficiency are prone to bowing of weight-bearing extremities and skeletal fractures. Vitamin D and calcium supplementation have been shown to decrease the incidence of hip fracture among ambulatory nursing home residents in France, suggesting that undermineralization of bone contributes significantly to morbidity in the elderly. Proximal myopathy is a striking feature of severe vitamin D deficiency both in children and in adults. Rapid resolution of the myopathy is observed upon vitamin D treatment.


InternalMed_Harrison

InternalMed_Harrison. Although vitamin D deficiency is the most common cause of rickets and osteomalacia, many disorders lead to inadequate mineralization of the growth plate and bone. Calcium deficiency without vitamin D deficiency, the disorders of vitamin D metabolism previously discussed, and hypophosphatemia can all lead to inefficient mineralization. Even in the presence of normal calcium and phosphate levels, chronic acidosis and drugs such as bisphosphonates can lead to osteomalacia. The inorganic calcium/phosphate mineral phase of bone cannot form at low pH, and bisphosphonates bind to and prevent mineral crystal growth. Because alkaline phosphatase is necessary for normal mineral deposition, probably because the enzyme can hydrolyze inhibitors of mineralization such as inorganic pyrophosphate, genetic inactivation of the alkaline phosphatase gene (hereditary hypophosphatasia) also can lead to osteomalacia in the setting of normal calcium and phosphate levels.


InternalMed_Harrison

InternalMed_Harrison. Diagnosis of Vitamin D Deficiency, Rickets, and Osteomalacia The most specific screening test for vitamin D deficiency in otherwise healthy individuals is a serum 25(OH)D level. Although the normal ranges vary, levels of 25(OH)D <37 nmol/L (<15 ng/mL) are associated with increasing PTH levels and lower bone density. The Institute of Medicine has defined vitamin D sufficiency as a vitamin D level >50 nmol/L (>20 ng/mL), although higher levels may be required to 2466 optimize intestinal calcium absorption in the elderly and those with underlying disease states. Vitamin D deficiency leads to impaired intestinal absorption of calcium, resulting in decreased serum total and ionized calcium values. This hypocalcemia results in secondary hyperparathyroidism, a homeostatic response that initially maintains serum calcium levels at the expense of the skeleton. Due to the PTH-induced increase in bone turnover, alkaline phosphatase levels are often increased. In addition to increasing bone


InternalMed_Harrison

InternalMed_Harrison. maintains serum calcium levels at the expense of the skeleton. Due to the PTH-induced increase in bone turnover, alkaline phosphatase levels are often increased. In addition to increasing bone resorption, PTH decreases urinary calcium excretion while promoting phosphaturia. This results in hypophosphatemia, which exacerbates the mineralization defect in the skeleton. With prolonged vitamin D deficiency resulting in osteomalacia, calcium stores in the skeleton become relatively inaccessible, since osteoclasts cannot resorb unmineralized osteoid, and frank hypocalcemia ensues. Because PTH is a major stimulus for the renal 25(OH)D 1α-hydroxylase, there is increased synthesis of the active hormone, 1,25(OH)2D. Paradoxically, levels of this hormone are often normal in severe vitamin D deficiency. Therefore, measurements of 1,25(OH)2D are not accurate reflections of vitamin D stores and should not be used to diagnose vitamin D deficiency in patients with normal renal function. Radiologic


InternalMed_Harrison

InternalMed_Harrison. Therefore, measurements of 1,25(OH)2D are not accurate reflections of vitamin D stores and should not be used to diagnose vitamin D deficiency in patients with normal renal function. Radiologic features of vitamin D deficiency in children include a widened, expanded growth plate that is characteristic of rickets. These findings not only are apparent in the long bones but also are present at the costochondral junction, where the expansion of the growth plate leads to swellings known as the “rachitic rosary.” Impairment of intramembranous bone mineralization leads to delayed fusion of the calvarial sutures and a decrease in the radiopacity of cortical bone in the long bones. If vitamin D deficiency occurs after epiphyseal fusion, the main radiologic finding is a decrease in cortical thickness and relative radiolucency of the skeleton. A specific radiologic feature of osteomalacia, whether associated with phosphate wasting or vitamin D deficiency, is pseudofractures, or Looser’s zones.


InternalMed_Harrison

InternalMed_Harrison. and relative radiolucency of the skeleton. A specific radiologic feature of osteomalacia, whether associated with phosphate wasting or vitamin D deficiency, is pseudofractures, or Looser’s zones. These are radiolucent lines that occur where large arteries are in contact with the underlying skeletal elements; it is thought that the arterial pulsations lead to the radiolucencies. As a result, these pseudofractures are usually a few millimeters wide, are several centimeters long, and are seen particularly in the scapula, the pelvis, and the femoral neck.


InternalMed_Harrison

InternalMed_Harrison. Based on the Institute of Medicine 2010 report, the recommended daily intake of vitamin D is 600 IU from 1 to 70 years of age, and 800 IU for those over 70. Based on the observation that 800 IU of vitamin D, with calcium supplementation, decreases the risk of hip fractures in elderly women, this higher dose is thought to be an appropriate daily intake for prevention of vitamin D deficiency in adults. The safety margin for vitamin D is large, and vitamin D toxicity usually is observed only in patients taking doses in the range of 40,000 IU daily. Treatment of vitamin D deficiency should be directed at the underlying disorder, if possible, and also should be tailored to the severity of the condition. Vitamin D should always be repleted in conjunction with calcium supplementation because most of the consequences of vitamin D deficiency are a result of impaired mineral ion homeostasis. In patients in whom 1α-hydroxylation is impaired, metabolites that do not require this activation step


InternalMed_Harrison

InternalMed_Harrison. of the consequences of vitamin D deficiency are a result of impaired mineral ion homeostasis. In patients in whom 1α-hydroxylation is impaired, metabolites that do not require this activation step are the treatment of choice. They include 1,25(OH)2D3 (calcitriol [Rocaltrol], 0.25–0.5 μg/d) and 1α-hydroxyvitamin D2 (Hectorol, 2.5–5 μg/d). If the pathway required for activation of vitamin D is intact, severe vitamin D deficiency can be treated with pharmacologic repletion initially (50,000 IU weekly for 3–12 weeks), followed by maintenance therapy (800 IU daily). Pharmacologic doses may be required for maintenance therapy in patients who are taking medications, such as barbiturates or phenytoin, that accelerate metabolism of or cause resistance to 1,25(OH)2D. Calcium supplementation should include 1.5–2 g/d of elemental calcium. Normocalcemia is usually observed within 1 week of the institution of therapy, although increases in PTH and alkaline phosphatase levels may persist for 3–6


InternalMed_Harrison

InternalMed_Harrison. include 1.5–2 g/d of elemental calcium. Normocalcemia is usually observed within 1 week of the institution of therapy, although increases in PTH and alkaline phosphatase levels may persist for 3–6 months. The most efficacious methods to monitor treatment and resolution of vitamin D deficiency are serum and urinary calcium measurements. In patients who are vitamin D replete and are taking adequate calcium supplementation, the 24-h urinary calcium excretion should be in the range of 100–250 mg/24 h. Lower levels suggest problems with adherence to the treatment regimen or with absorption of calcium or vitamin D supplements. Levels >250 mg/24 h predispose to nephrolithiasis and should lead to a reduction in vitamin D dosage and/or calcium supplementation.


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Parathyroid 424 gland and Calcium Homeostasis John T. Potts, Jr., Harald Jpner


InternalMed_Harrison

InternalMed_Harrison. The four parathyroid glands are located posterior to the thyroid gland. They produce parathyroid hormone (PTH), which is the primary regulator of calcium physiology. PTH acts directly on bone, where it induces calcium release; on the kidney, where it enhances calcium reabsorption in the distal tubules; and in the proximal renal tubules, where it synthesizes 1,25-dihydroxyvitamin D (1,25[OH]2D), a hormone that increases gastrointestinal calcium absorption. Serum PTH levels are tightly regulated by a negative feedback loop. Calcium, acting through the calcium-sensing receptor, and vitamin D, acting through its nuclear receptor, reduce PTH release and synthesis. Additional evidence indicates that fibroblast growth factor 23 (FGF23), a phosphaturic hormone, can suppress PTH secretion. Understanding the hormonal pathways that regulate calcium levels and bone metabolism is essential for effective diagnosis and management of a wide array of hyperand hypocalcemic disorders.


InternalMed_Harrison

InternalMed_Harrison. Hyperparathyroidism, characterized by excess production of PTH, is a common cause of hypercalcemia and is usually the result of autonomously functioning adenomas or hyperplasia. Surgery for this disorder is highly effective and has been shown to reverse some of the deleterious effects of long-standing PTH excess on bone density. Humoral hypercalcemia of malignancy is also common and is usually due to the overproduction of parathyroid hormone–related peptide (PTHrP) by cancer cells. The similarities in the biochemical characteristics of hyperparathyroidism and humoral hypercalcemia of malignancy, first noted by Albright in 1941, are now known to reflect the actions of PTH and PTHrP through the same G protein–coupled PTH/PTHrP receptor.


InternalMed_Harrison

InternalMed_Harrison. The genetic basis of multiple endocrine neoplasia (MEN) types 1 and 2, familial hypocalciuric hypercalcemia (FHH), different forms of pseudohypoparathyroidism, Jansen’s syndrome, disorders of vitamin D synthesis and action, and the molecular events associated with parathyroid gland neoplasia have provided new insights into the regulation of calcium homeostasis. PTH and possibly some of its analogues are promising therapeutic agents for the treatment of postmenopausal or senile osteoporosis, and calcimimetic agents, which activate the calcium-sensing receptor, have provided new approaches for PTH suppression.


InternalMed_Harrison

InternalMed_Harrison. The primary function of PTH is to maintain the extracellular fluid (ECF) calcium concentration within a narrow normal range. The hormone acts directly on bone and kidney and indirectly on the intestine through its effects on synthesis of 1,25(OH)2D to increase serum calcium concentrations; in turn, PTH production is closely regulated by the concentration of serum ionized calcium. This feedback system is the critical homeostatic mechanism for maintenance of ECF calcium. Any tendency toward hypocalcemia, as might be induced by calciumor vitamin D–deficient diets, is counteracted by an increased secretion of PTH. This in turn (1) increases the rate of dissolution of bone mineral, thereby increasing the flow of calcium from bone into blood; (2) reduces the renal clearance of calcium, returning more of the calcium and phosphate filtered at the glomerulus into ECF; and (3) increases the efficiency of calcium absorption in the intestine by stimulating the production of 1,25(OH)2D. Immediate


InternalMed_Harrison

InternalMed_Harrison. more of the calcium and phosphate filtered at the glomerulus into ECF; and (3) increases the efficiency of calcium absorption in the intestine by stimulating the production of 1,25(OH)2D. Immediate control of blood calcium is due to PTH effects on bone and, to a lesser extent, on renal calcium clearance. Maintenance of steady-state calcium balance, on the other hand, probably results from the effects of 1,25(OH)2D on calcium absorption (Chap. 423). The renal actions of the hormone are exerted at multiple sites and include inhibition of phosphate transport (proximal tubule), augmentation of calcium reabsorption (distal tubule), and stimulation of the renal 25(OH)D-1α-hydroxylase. As much as 12 mmol (500 mg) of calcium is transferred between the ECF and bone each day (a large amount in relation to the total ECF calcium pool), and PTH has a major effect on this transfer. The homeostatic role of the hormone can preserve calcium concentration in blood at the cost of bone demineralization.


InternalMed_Harrison

InternalMed_Harrison. PTH has multiple actions on bone, some direct and some indirect. PTH-mediated changes in bone calcium release can be seen within minutes. The chronic effects of PTH are to increase the number of bone cells, both osteoblasts and osteoclasts, and to increase the remodeling of bone; these effects are apparent within hours after the hormone is given and persist for hours after PTH is withdrawn. Continuous exposure to elevated PTH (as in hyperparathyroidism or long-term infusions in animals) leads to increased osteoclast-mediated bone resorption. However, the intermittent administration of PTH, elevating hormone levels for 1–2 h each day, leads to a net stimulation of bone formation rather than bone breakdown. Striking increases, especially in trabecular bone in the spine and hip, have been reported with the use of PTH in combination with estrogen. PTH(1–34) as monotherapy caused a highly significant reduction in fracture incidence in a worldwide placebo-controlled trial.


InternalMed_Harrison

InternalMed_Harrison. Osteoblasts (or stromal cell precursors), which have PTH/PTHrP receptors, are crucial to this bone-forming effect of PTH; osteoclasts, which mediate bone breakdown, lack such receptors. PTH-mediated stimulation of osteoclasts is indirect, acting in part through cytokines released from osteoblasts to activate osteoclasts; in experimental studies of bone resorption in vitro, osteoblasts must be present for PTH to activate osteoclasts to resorb bone (Chap. 423).


InternalMed_Harrison

InternalMed_Harrison. PTH is an 84-amino-acid single-chain peptide. The amino-terminal portion, PTH(1–34), is highly conserved and is critical for the biologic actions of the molecule. Modified synthetic fragments of the amino-terminal sequence as small as PTH(1–11) are sufficient to activate the PTH/PTHrP receptor (see below). The carboxyl-terminal region of the full-length PTH(1–84) molecule also can bind to a separate binding protein/receptor (cPTH-R), but this receptor has been incompletely characterized. Fragments shortened at the amino-terminus possibly by binding to cPTH-R can reduce, directly or indirectly, some of the biologic actions of full-length PTH(1–84) and of PTH(1–34).


InternalMed_Harrison

InternalMed_Harrison. BIOSYNTHESIS, SECRETION, AND METABOLISM Synthesis Parathyroid cells have multiple methods of adapting to increased needs for PTH production. Most rapid (within minutes) is secretion of preformed hormone in response to hypocalcemia. Second, within hours, PTH mRNA expression is induced by sustained hypocalcemia. Finally, protracted challenge leads within days to cellular replication to increase parathyroid gland mass. PTH is initially synthesized as a larger molecule (preproparathyroid hormone, consisting of 115 amino acids). After a first cleavage step to remove the “pre” sequence of 25 amino acid residues, a second cleavage step removes the “pro” sequence of 6 amino acid residues before secretion of the mature peptide comprising 84 residues. Mutations in the preprotein region of the gene can cause hypoparathyroidism by interfering with hormone synthesis, transport, or secretion.


InternalMed_Harrison

InternalMed_Harrison. Transcriptional suppression of the PTH gene by calcium is nearly maximal at physiologic calcium concentrations. Hypocalcemia increases transcriptional activity within hours. 1,25(OH)2D strongly suppresses 2467 PTH gene transcription. In patients with renal failure, IV administration of supraphysiologic levels of 1,25(OH)2D or analogues of this active metabolite can dramatically suppress PTH overproduction, which is sometimes difficult to control due to severe secondary hyperparathyroidism. Regulation of proteolytic destruction of preformed hormone (posttranslational regulation of hormone production) is an important mechanism for mediating rapid (within minutes) changes in hormone availability. High calcium increases and low calcium inhibit the proteolytic destruction of stored hormone.


InternalMed_Harrison

InternalMed_Harrison. Regulation of PTH Secretion PTH secretion increases steeply to a maximum value of about five times the basal rate of secretion as the calcium concentration falls from normal to the range of 1.9–2.0 mmol/L (7.6–8.0 mg/dL; measured as total calcium). However, the ionized fraction of blood calcium is the important determinant of hormone secretion. Severe intracellular magnesium deficiency impairs PTH secretion (see below).


InternalMed_Harrison

InternalMed_Harrison. ECF calcium controls PTH secretion by interaction with a calcium-sensing receptor (CaSR), a G protein–coupled receptor (GPCR) for which Ca2+ ions act as the primary ligand (see below). This receptor is a member of a distinctive subgroup of the GPCR superfamily that mediates its actions through the alpha-subunits of two related signaling G proteins, namely Gq and G11, and is characterized by a large extracellular domain suitable for “clamping” the small-molecule ligand. Stimulation of the CaSR by high calcium levels suppresses PTH secretion. The CaSR is present in parathyroid glands and the calcitonin-secreting cells of the thyroid (C cells), as well as in multiple other sites, including brain and kidney. Genetic evidence has revealed a key biologic role for the CaSR in parathyroid gland responsiveness to calcium and in renal calcium clearance. Heterozygous loss-of-function mutations in CaSR cause the syndrome of FHH, in which the blood calcium abnormality resembles that observed in


InternalMed_Harrison

InternalMed_Harrison. responsiveness to calcium and in renal calcium clearance. Heterozygous loss-of-function mutations in CaSR cause the syndrome of FHH, in which the blood calcium abnormality resembles that observed in hyperparathyroidism but with hypocalciuria; two more recently defined variants of FHH, FHH2 and FHH3, are caused either by heterozygous mutations in G11, one of the signaling proteins downstream of the CaSR, or by hetero zygous mutations in AP2S1. Homozygous loss-of-function mutations in the CaSR are the cause of severe neonatal hyperparathyroidism, a disorder that can be lethal if not treated within the first days of life. On the other hand, heterozygous gain-of-function mutations cause a form of hypocalcemia resembling hypoparathyroidism (see below).


InternalMed_Harrison

InternalMed_Harrison. Metabolism The secreted form of PTH is indistinguishable by immunologic criteria and by molecular size from the 84-amino-acid peptide (PTH[1–84]) extracted from glands. However, much of the immunoreactive material found in the circulation is smaller than the extracted or secreted hormone. The principal circulating fragments of immunoreactive hormone lack a portion of the critical amino-terminal sequence required for biologic activity and, hence, are biologically inactive fragments (so-called middle and carboxyl-terminal fragments). Much of the proteolysis of the hormone occurs in the liver and kidney. Peripheral metabolism of PTH does not appear to be regulated by physiologic states (high versus low calcium, etc.); hence, peripheral metabolism of hormone, although responsible for rapid clearance of secreted hormone, appears to be a high-capacity, metabolically invariant catabolic process.


InternalMed_Harrison

InternalMed_Harrison. The rate of clearance of the secreted 84-amino-acid peptide from blood is more rapid than the rate of clearance of the biologically inactive fragment(s) corresponding to the middle and carboxyl-terminal regions of PTH. Consequently, the interpretation of results obtained with earlier PTH radioimmunoassays was influenced by the nature of the peptide fragments detected by the antibodies. Although the problems inherent in PTH measurements have been largely circumvented by use of double-antibody immunometric assays, it is now known that some of these assays detect, besides the intact molecule, large amino-terminally truncated forms of PTH, which are present in normal and uremic individuals in addition to PTH(1–84). The concentration of these fragments relative to that of intact PTH(1–84) is higher with induced hypercalcemia than in eucalcemic


InternalMed_Harrison

InternalMed_Harrison. Disorders of the Parathyroid Gland and Calcium Homeostasis 2468 or hypocalcemic conditions and is higher in patients with impaired especially of the squamous cell type as well as renal cell carcinomas, renal function. PTH(7–84) has been identified as a major component lead to massive overproduction of the hormone and hypercalcemia. of these amino-terminally truncated fragments. Growing evidence suggests that the PTH(7–84) (and probably related amino-terminally PTH AND PTHrP HORMONE ACTION truncated fragments) can act, through yet undefined mechanisms, Both PTH and PTHrP bind to and activate the PTH/PTHrP receptor.as an inhibitor of PTH action and may be of clinical significance, The PTH/PTHrP receptor (also known as the PTH-1 receptor, PTH1R) particularly in patients with chronic kidney disease. In this group of belongs to a subfamily of GPCRs that includes the receptors for calcitopatients, efforts to prevent secondary hyperparathyroidism by a variety nin, glucagon, secretin,


InternalMed_Harrison

InternalMed_Harrison. disease. In this group of belongs to a subfamily of GPCRs that includes the receptors for calcitopatients, efforts to prevent secondary hyperparathyroidism by a variety nin, glucagon, secretin, vasoactive intestinal peptide, and other peptides.of measures (vitamin D analogues, higher calcium intake, higher dialy-Although both ligands activate the PTH1R, the two peptides induce sate calcium, phosphate-lowering strategies, and calcimetic drugs) distinct responses in the receptor, which explains how a single receptorcan lead to oversuppression of the parathyroid glands since some without isoforms can serve two biologic roles. The extracellular regions amino-terminally truncated PTH fragments, such as PTH(7–84), react of the receptor are involved in hormone binding, and the intracellularin many immunometric PTH assays (now termed second-generation domains, after hormone activation, bind G protein subunits to trans-assays; see below under “Diagnosis”), thus overestimating the levels duce


InternalMed_Harrison

InternalMed_Harrison. immunometric PTH assays (now termed second-generation domains, after hormone activation, bind G protein subunits to trans-assays; see below under “Diagnosis”), thus overestimating the levels duce hormone signaling into cellular responses through the stimulationof biologically active, intact PTH. Such excessive parathyroid gland of second messenger formation. A second receptor that binds PTH,suppression in chronic kidney disease can lead to adynamic bone originally termed the PTH-2 receptor (PTH2R), is primarily expresseddisease (see below), which has been associated with further impaired in brain, pancreas, and testis. Different mammalian PTH1Rs respondgrowth in children and increased bone fracture rates in adults, and can equivalently to PTH and PTHrP, at least when tested with traditionalfurthermore lead to significant hypercalcemia. The measurement of assays, whereas only the human PTH2R responds efficiently to PTHPTH with newer third-generation immunoassays, which use detection


InternalMed_Harrison

InternalMed_Harrison. lead to significant hypercalcemia. The measurement of assays, whereas only the human PTH2R responds efficiently to PTHPTH with newer third-generation immunoassays, which use detection (but not to PTHrP). PTH2Rs from other species show little or no stimuantibodies directed against extreme amino-terminal PTH epitopes and lation of second-messenger formation in response to PTH or PTHrP.thus detect only full-length PTH(1–84), may provide some advantage The endogenous ligand of the PTH2R was shown to be a hypothalamicto prevent bone disease in chronic kidney disease. peptide referred to as tubular infundibular peptide of 39 residues, TIP39, that is distantly related to PTH and PTHrP. The PTH1R and the PTH2R can be traced backward in evolutionary time to fish; in fact, the zebrafish genome contains, in addition to the PTH1R and the PTH2R orthologs, a PTHrP is responsible for most instances of humoral hypercalcemia third receptor, the PTH3R, that is more closely related to the fish PTH1R of


InternalMed_Harrison

InternalMed_Harrison. in addition to the PTH1R and the PTH2R orthologs, a PTHrP is responsible for most instances of humoral hypercalcemia third receptor, the PTH3R, that is more closely related to the fish PTH1R of malignancy (Chap. 121), a syndrome that resembles primary than to the fish PTH2R. The evolutionary conservation of structure and hyperparathyroidism but without elevated PTH levels. Most cell types function suggests important biologic roles for these receptors, even in normally produce PTHrP, including brain, pancreas, heart, lung, fish, which lack discrete parathyroid glands but produce two molecules mammary tissue, placenta, endothelial cells, and smooth muscle. In that are closely related to mammalian PTH. fetal animals, PTHrP directs transplacental calcium transfer, and Studies using the cloned PTH1R confirm that it can be coupled high concentrations of PTHrP are produced in mammary tissue and to more than one G protein and second-messenger pathway, apparsecreted into milk, but the biologic


InternalMed_Harrison

InternalMed_Harrison. PTH1R confirm that it can be coupled high concentrations of PTHrP are produced in mammary tissue and to more than one G protein and second-messenger pathway, apparsecreted into milk, but the biologic significance of the very high con-ently explaining the multiplicity of pathways stimulated by PTH. centrations of this hormone in breast milk is unknown. PTHrP also Activation of protein kinases (A and C) and calcium transport chanplays an essential role in endochondral bone formation and in branch-nels is associated with a variety of hormone-specific tissue responses. ing morphogenesis of the breast, and possibly in uterine contraction These responses include inhibition of phosphate and bicarbonate and other biologic functions. transport, stimulation of calcium transport, and activation of renal


InternalMed_Harrison

InternalMed_Harrison. PTH and PTHrP, although products of different genes, exhibit con-1α-hydroxylase in the kidney. The responses in bone include effects siderable functional and structural homology (Fig. 424-1) and have on collagen synthesis, alkaline phosphatase, ornithine decarboxylase, evolved from a shared ancestral gene. The structure of the gene encod-citrate decarboxylase, and glucose-6-phosphate dehydrogenase activiing human PTHrP, however, is more complex than that of PTH, con-ties; phospholipid synthesis; and calcium and phosphate transport. taining multiple additional exons, which can undergo alternate splic-Ultimately, these biochemical events lead to an integrated hormonal ing patterns during formation of the mature mRNA. Protein products response in bone turnover and calcium homeostasis. PTH also actiof 139, 141, and 173 amino acids are produced, and other molecular vates Na+/Ca2+ exchangers at renal distal tubular sites and stimulates forms may result from tissue-specific degradation at


InternalMed_Harrison

InternalMed_Harrison. also actiof 139, 141, and 173 amino acids are produced, and other molecular vates Na+/Ca2+ exchangers at renal distal tubular sites and stimulates forms may result from tissue-specific degradation at accessible internal translocation of preformed calcium transport channels, moving them cleavage sites. The biologic roles of these various molecular species and from the interior to the apical surface to increase tubular uptake of the nature of the circulating forms of PTHrP are unclear. In fact, it is calcium. PTH-dependent stimulation of phosphate excretion (reducuncertain whether PTHrP circulates at any significant level in adults. ing reabsorption—the opposite effect from actions on calcium in As a paracrine factor, PTHrP may be produced, act, and be destroyed the kidney) involves the downregulation of two sodium-dependent locally within tissues. In adults, PTHrP appears to have little influence phosphate co-transporters, NPT2a and NPT2c, and their expression on calcium homeostasis,


InternalMed_Harrison

InternalMed_Harrison. of two sodium-dependent locally within tissues. In adults, PTHrP appears to have little influence phosphate co-transporters, NPT2a and NPT2c, and their expression on calcium homeostasis, except in disease states, when large tumors, at the apical membrane, thereby reducing phosphate reabsorption in


InternalMed_Harrison

InternalMed_Harrison. FIGURE 424-1 Schematic diagram to illustrate similarities and differences in structure of human parathyroid hormone (PTH) and human PTH-related peptide (PTHrP). Close structural (and functional) homology exists between the first 30 amino acids of hPTH and hPTHrP. The PTHrP sequence may be ≥144 amino acid residues in length. PTH is only 84 residues long; after residue 30, there is little structural homology between the two. Dashed lines in the PTHrP sequence indicate identity; underlined residues, although different from those of PTH, still represent conservative changes (charge or polarity preserved). Ten amino acids are identical, and a total of 20 of 30 are homologues.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 424-2 Dual role for the actions of the PTH/PTHrP receptor (PTH1R). Parathyroid hormone (PTH; endocrine-calcium homeostasis) and PTH-related peptide (PTHrP; paracrine–multiple tissue actions including growth plate cartilage in developing bone) use the single receptor for their disparate functions mediated by the amino-terminal 34 residues of either peptide. Other regions of both ligands interact with other receptors (not shown). the proximal renal tubules. Similar mechanisms may be involved in other renal tubular transporters that are influenced by PTH. Recent studies reaffirm the critical linkage of blood phosphate lowering to net calcium entry into blood by PTH action and emphasize the participation of bone cells other than osteoclasts in the rapid calcium-elevating actions of PTH.


InternalMed_Harrison

InternalMed_Harrison. PTHrP exerts important developmental influences on fetal bone development and in adult physiology. A homozygous ablation of the gene encoding PTHrP (or disruption of the PTH1R gene) in mice causes a lethal phenotype in which animals are born with pronounced acceleration of chondrocyte maturation that resembles a lethal form of chondrodysplasia in humans that is caused by homozygous or compound heterozygous, inactivating PTH1R mutations (Fig. 424-2). Heterozygous PTH1R mutations in humans furthermore can be a cause of delayed tooth eruption, and mice that are heterozygous for ablation of the PTHrP gene display reduced mineral density consistent with osteoporosis. Experiments with these mouse models point to a hitherto unappreciated role of PTHrP as a paracrine/autocrine factor that modulates bone metabolism in adults as well as during bone development.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 408) Calcitonin is a hypocalcemic peptide hormone that in several mammalian species acts as an indirect antagonist to the calcemic actions of PTH. Calcitonin seems to be of limited physiologic significance in humans, at least with regard to calcium homeostasis. It is of medical significance because of its role as a tumor marker in sporadic and hereditary cases of medullary carcinoma and its medical use as an adjunctive treatment in severe hypercalcemia and in Paget’s disease of bone.


InternalMed_Harrison

InternalMed_Harrison. The hypocalcemic activity of calcitonin is accounted for primarily by inhibition of osteoclast-mediated bone resorption and secondarily by stimulation of renal calcium clearance. These effects are mediated by receptors on osteoclasts and renal tubular cells. Calcitonin exerts additional effects through receptors present in the brain, the gastrointestinal tract, and the immune system. The hormone, for example, exerts analgesic effects directly on cells in the hypothalamus and related structures, possibly by interacting with receptors for related peptide hormones such as calcitonin gene–related peptide (CGRP) or amylin. Both of these ligands have specific high-affinity receptors that share considerable structural similarity with the PTH1R and can also bind to and activate calcitonin receptors. The calcitonin receptor shares considerable structural similarity with the PTH1R.


InternalMed_Harrison

InternalMed_Harrison. The thyroid is the major source of the hormone, and the cells 2469 involved in calcitonin synthesis arise from neural crest tissue. During embryogenesis, these cells migrate into the ultimobranchial body, derived from the last branchial pouch. In submammalian vertebrates, the ultimobranchial body constitutes a discrete organ, anatomically separate from the thyroid gland; in mammals, the ultimobranchial gland fuses with and is incorporated into the thyroid gland. The naturally occurring calcitonins consist of a peptide chain of 32 amino acids. There is considerable sequence variability among species. Calcitonin from salmon, which is used therapeutically, is 10–100 times more potent than mammalian forms in lowering serum calcium.


InternalMed_Harrison

InternalMed_Harrison. There are two calcitonin genes, α and β; the transcriptional control of these genes is complex. Two different mRNA molecules are transcribed from the α gene; one is translated into the precursor for calcitonin, and the other message is translated into an alternative product, CGRP. CGRP is synthesized wherever the calcitonin mRNA is expressed (e.g., in medullary carcinoma of the thyroid). The β, or CGRP-2, gene is transcribed into the mRNA for CGRP in the central nervous system (CNS); this gene does not produce calcitonin, however. CGRP has cardiovascular actions and may serve as a neurotransmitter or play a developmental role in the CNS.


InternalMed_Harrison

InternalMed_Harrison. The circulating level of calcitonin in humans is lower than that in many other species. In humans, even extreme variations in calcitonin production do not change calcium and phosphate metabolism; no definite effects are attributable to calcitonin deficiency (totally thyroidectomized patients receiving only replacement thyroxine) or excess (patients with medullary carcinoma of the thyroid, a calcitonin secreting tumor) (Chap. 408). Calcitonin has been a useful pharmacologic agent to suppress bone resorption in Paget’s disease (Chap. 426e) and osteoporosis (Chap. 425) and in the treatment of hypercalcemia of malignancy (see below). However, bisphosphonates are usually more effective, and the physiologic role, if any, of calcitonin in humans is uncertain. On the other hand, ablation of the calcitonin gene (combined because of the close proximity with ablation of the CGRP gene) in mice leads to reduced bone mineral density, suggesting that its biologic role in mammals is still not fully


InternalMed_Harrison

InternalMed_Harrison. calcitonin gene (combined because of the close proximity with ablation of the CGRP gene) in mice leads to reduced bone mineral density, suggesting that its biologic role in mammals is still not fully understood.


InternalMed_Harrison

InternalMed_Harrison. (See also Chap. 65) Hypercalcemia can be a manifestation of a serious illness such as malignancy or can be detected coincidentally by laboratory testing in a patient with no obvious illness. The number of patients recognized with asymptomatic hypercalcemia, usually hyperparathyroidism, increased in the late twentieth century. Whenever hypercalcemia is confirmed, a definitive diagnosis must be established. Although hyperparathyroidism, a frequent cause of asymptomatic hypercalcemia, is a chronic disorder in which manifestations, if any, may be expressed only after months or years, hypercalcemia can also be the earliest manifestation of malignancy, the second most common cause of hypercalcemia in the adult. The causes of hypercalcemia are numerous (Table 424-1), but hyperparathyroidism and cancer account for 90% of all cases.


InternalMed_Harrison

InternalMed_Harrison. Before undertaking a diagnostic workup, it is essential to be sure that true hypercalcemia, not a false-positive laboratory test, is present. A false-positive diagnosis of hypercalcemia is usually the result of inadvertent hemoconcentration during blood collection or elevation in serum proteins such as albumin. Hypercalcemia is a chronic problem, and it is cost-effective to obtain several serum calcium measurements; these tests need not be in the fasting state.


InternalMed_Harrison

InternalMed_Harrison. Clinical features are helpful in differential diagnosis. Hypercalcemia in an adult who is asymptomatic is usually due to primary hyperparathyroidism. In malignancy-associated hypercalcemia, the disease is usually not occult; rather, symptoms of malignancy bring the patient to the physician, and hypercalcemia is discovered during the evaluation. In such patients, the interval between detection of hypercalcemia and death, especially without vigorous treatment, is often <6 months. Accordingly, if an asymptomatic individual has had hypercalcemia or some manifestation of hypercalcemia such as kidney stones for more than 1 or 2 years, it is unlikely that malignancy Disorders of the Parathyroid Gland and Calcium Homeostasis ClASSifiCATion of CAuSES of HyPERCAlCEmiA I. Parathyroid-Related A. Primary hyperparathyroidism 1. 2. 3. B. Lithium therapy C. Familial hypocalciuric hypercalcemia II. Malignancy-Related A. Solid tumor with metastases (breast)


InternalMed_Harrison

InternalMed_Harrison. I. Parathyroid-Related A. Primary hyperparathyroidism 1. 2. 3. B. Lithium therapy C. Familial hypocalciuric hypercalcemia II. Malignancy-Related A. Solid tumor with metastases (breast) B. Solid tumor with humoral mediation of hypercalcemia (lung, kidney) C. Hematologic malignancies (multiple myeloma, lymphoma, leukemia) III. Vitamin D–Related A. Vitamin D intoxication B. ↑ 1,25(OH)2D; sarcoidosis and other granulomatous diseases C. ↑ 1,25(OH)2D; impaired 1,25(OH)2D metabolism due to 24-hydroxylase deficiency IV. Associated with High Bone Turnover A. Hyperthyroidism B. Immobilization C. Thiazides D. Vitamin A intoxication E. Fat necrosis V. Associated with Renal Failure A. Severe secondary hyperparathyroidism B. Aluminum intoxication


InternalMed_Harrison

InternalMed_Harrison. A. Hyperthyroidism B. Immobilization C. Thiazides D. Vitamin A intoxication E. Fat necrosis V. Associated with Renal Failure A. Severe secondary hyperparathyroidism B. Aluminum intoxication C. Milk-alkali syndrome is the cause. Nevertheless, differentiating primary hyperparathyroidism from occult malignancy can occasionally be difficult, and careful evaluation is required, particularly when the duration of the hypercalcemia is unknown. Hypercalcemia not due to hyperparathyroidism or malignancy can result from excessive vitamin D action, impaired metabolism of 1,25(OH)2D, high bone turnover from any of several causes, or renal failure (Table 424-1). Dietary history and a history of ingestion of vitamins or drugs are often helpful in diagnosing some of the less frequent causes. Immunometric PTH assays serve as the principal laboratory test in establishing the diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Hypercalcemia from any cause can result in fatigue, depression, mental confusion, anorexia, nausea, vomiting, constipation, reversible renal tubular defects, increased urine output, a short QT interval in the electrocardiogram, and, in some patients, cardiac arrhythmias. There is a variable relation from one patient to the next between the severity of hypercalcemia and the symptoms. Generally, symptoms are more common at calcium levels >2.9–3.0 mmol/L (11.6–12.0 mg/dL), but some patients, even at this level, are asymptomatic. When the calcium level is >3.2 mmol/L (12.8 mg/dL), calcification in kidneys, skin, vessels, lungs, heart, and stomach occurs and renal insufficiency may develop, particularly if blood phosphate levels are normal or elevated due to impaired renal excretion. Severe hypercalcemia, usually defined as ≥3.7–4.5 mmol/L (14.8–18.0 mg/dL), can be a medical emergency; coma and cardiac arrest can occur.


InternalMed_Harrison

InternalMed_Harrison. Acute management of the hypercalcemia is usually successful. The type of treatment is based on the severity of the hypercalcemia and the nature of associated symptoms, as outlined below.