Surgery This is controversial. Some clinicians offer surgical removal of pheochro- mocytoma before 24 weeks \200\231 gestation (which is relatively safe following A- and B -blockade) . After 24 weeks \200\231 gestation, surgery should be deferred until fetal maturity, and t hen it can be combined with Cesarean section with removal of the tumor. Ensure adequate adrenergic blockade before surgery. Operate after safe delivery of the fetus. Further reading Hadden DR (1995). Adrenal disorders of pregnancy. Endocrinol Metab Clin Nor th Am 24(1):139 \200\223151. Sam S, Molitch M (2003). Timing and special concerns regarding endocrine surgery during pre g- nancy. Endocrinol Metab Clin North Am 32:337 \200\223354. 64-Draznin-Chap64.indd 364 3/31/2011 3:28:40 PM Part 6 Calcium and bone metabolism Sol Epstein 65 Calcium and bone physiology 66 Investigation of bone 67 Investigation of calcium, phosph ate, 366 369 and magnesium 68 Hypercalcemia 69 Hypocalcemia 70 Rickets and osteomalacia 71 Hypomagnesemi a 72 Osteoporosis 73 Paget \200\231s disease 74 Inherited disorders of bone 373 376 389 396 403 405 421 427 65-Draznin-Chap65.indd 365 3/31/2011 3:29:45 PM CHAPTER 65 Calcium and bone physiology 366 Calcium and bone physiology Bone turnover In order to ensure that bone can undertake its mechanical and metabolic funct ions, it is in a constant state of turnover (see b Fig. 65.1 ). \200 Osteoclasts , derive d from the hematopoetic stem cell series, resorb bone. Osteoblasts , derived from the mesenchymal cell precursors, make bone. Osteocytes , buried osteoblasts, sense mechanical strain and secrete factors important in bone homeostasis. Lining cells Bone lining cells o i d Formation d o s t c Osteoclasts e e r aliz Mineralized bone m i n n U Osteocytes Resorption 21 21 Days of remodeling cycle 100 Fig. 65.1 Bone turnover during remodeling cycle. 65-Draznin-Chap65.indd 366 3/31/2011 3:29:45 PM BONE MASS DURING LIFE 367 Bone mass during life b See Fig. 65.2. Bone is laid down rapidly during skeletal growth at puberty. Following this there is a peri od of stabilization of bone mass in early adult life. After the age of 40, there is a grad ual loss of bone in both sexes. This occurs at the rate of approximately 0.5% annually. However, in women after the menopause there is a period of rapid bone loss. The accelerated loss is maximal immediately after the cessa- tion of ovarian function but remains increase d throughout life. The excess bone loss associated with the menopause is of the order of 10 % of skeletal mass. This menopause-associated loss coupled with lower peak bone mass largely explains why osteo porosis and its associated fractures are more common in women. 120 ) 100 k a e p s s a m e n o B 80 e l a m e f 60 40 % ( 20 0 0 20 40 Age (years) 60 80 Fig. 65.2 Bone mass and age. 65-Draznin-Chap65.indd 367 3/31/2011 3:29:46 PM CHAPTER 65 Calcium and bone physiology 368 Calcium Roles of calcium \200 Skeletal strength \200 Neuromuscular conduction \200 St imulus secretion coupling Calcium in the circulation Circulating calcium exists in several forms ( b see Fig. 65.3 ). \200 Ionized \200\224biologically active \200 Complexed to citrate, phosphate etc. \200\224biologically active \200 Bound to protein, mainly albumin \200\224inactive Ionized Complexed Protein bound 45% 50% 5% Fig. 65.3 Forms of circulating calcium. 65-Draznin-Chap65.indd 368 3/31/2011 3:29:47 PM BONE TURNOVER MARKERS 369 Investigation of bone Bone turnover markers These may be useful in \200 Assessing overall risk of osteoporotic fracture. \200 Judging response to treatments for osteoporosis. Resorption markers Collagen cross-links These make use of the fact that when collagen is laid down in bone, th e \201 bers are held in trimers by covalent links. These links are chemically very stable and are speci \201 c to the type of collagen. The excretion of fragments containing these cross-links is a much better indicator of bone turnover. It can be measured either as the excretion of the linking molecules themselves, known as de oxypyridinoline cross-links , or as small fragments of the ends of the collagen molecule in cluding these cross-links, known as telopeptides . These latter markers can be derived from either the N- or the C-terminal of the collagen molecule, and separate assays are availabl e for each. Assays are available for both blood and urine, although the former are subject to less error and are preferred. Urinary hydroxyproline This relies on the fact that hydroxyproline is unique to collagen, t hus any hydroxyproline in urine must come from collagen breakdown. Unfortunately, this is n ot speci \201 c to bone (type 1) collagen; furthermore, hydroxyproline is variably metabol ized before excretion and so its urinary levels are not a true index of collagen destructio n. It has accordingly been superseded. Formation markers Total alkaline phosphatase is not speci \201 c; it is also found in the liver, intestine, and placenta. It is relatively insensitive to small changes in bone turno ver and has only found general use in the monitoring of the activity of Paget \200\231s dis ease. Bone-speci \201 c alkaline phosphatase is more speci \201 c but its clinical utility is not yet clear. Osteocalcin is a vitamin K \200\223dependent protein that accounts for about 1% of bone mat rix. The serum level of osteocalcin appears to re \202 ect oste- oblast activity. However, the results obtained with bone-speci \201 c alkaline phosphatase and osteocalcin do not a lways correlate. This is particularly true in Paget \200\231s disease, where the osteocalci n is frequently scarcely ele- vated despite the marked increase in bone turnover. 66-Draznin-Chap66.indd 369 3/31/2011 3:43:44 PM CHAPTER 66 Investigation of bone 370 P1NP is a procollagen fragment released from the N terminal as type 1 collagen is laid down . When measured in the serum it is the most sensi- tive and speci \201 c marker of bone fo rmation, although its clinical utility is as yet unclear. Bone imaging Skeletal radiology This is useful for the following: \200 Diagnosis of fract ure \200 Diagnosis of speci \201 c diseases (e.g., Paget \200\231s disease and osteomala cia) \200 Identi \201 cation of bone dysplasia It is not useful for assessing bone densi ty. Isotope bone scanning Bone-seeking isotopes, particularly 99m technetium-labeled bisphospho - nates, are concentrated in areas of localized i bone cell activity. They are useful for i dentifying localized areas of bone disease such as fracture, metastasis, or Paget \200\231s disease. However, isotope uptake is not selective, and so i activity on a scan does not indicate the nature of the underlying bone disease. Hence, sub- sequent radiology of affected regions i s frequently needed to establish the diagnosis. Isotope bone scans are particularly useful in Paget \200\231s disease to establish the extent of skeletal involvement and the underlying disease activity. 66-Draznin-Chap66.indd 370 3/31/2011 3:43:45 PM BONE MASS MEASUREMENTS 371 Bone mass measurements b See Table 66.1. Interpretation of results The differences in normal ranges between the machines of differen t manufacturers has led to the practice of quoting bone mass measure- ments in terms of the number of standard deviations (SDs) they lie from an expected mean. This can be done in tw o ways: T score and Z score; b see Table 66.2. It is generally accepted that a reduction of 1 SD in bone density will approximately double the risk of fracture. The WHO has developed guidelines for the diagnosis of osteoporosis in postmenopausal women ( b see Table 66.3). No similar criteria have been set in males, but the same thresholds are generally accepted. For some secondary causes of osteoporosis, particularly corticosteroid use, it has been sug gested that the less stringent criterion of T score < \200\2231.5 be used as a treatment in tervention threshold. Table 66.1 Measurement of bone density Technique Site Measures Radiation Reproducibility Spine* Femur* Whole body Forearm Calcaneus Dual energy absorptiometry (DXA) Bone mineral per unit area (g/cm 2 ) 1 Sv per site <1% at spine <2% at femur Quantitative computed tomography (QCT) Spine Forearm True bone mineral density (BMD) (g/cm 3 ) 50 Sv at spine 1% Quantitative ultrasound (QUS) Calcaneus Tibia Fingers Speed of sound or broadband ultrasound attenuation Nil Poor Accepted as gold-standard measurement. 66-Draznin-Chap66.indd 371 3/31/2011 3:43:45 PM CHAPTER 66 Investigation of bone 372 Table 66.2 T score and Z score T score Z score Number of SDs bone density lies from mean density expected for that sex and age De \201 nition Number of SDs bone density lies from peak mean density for that sex Signi \201 cance Age-independent effect on BMD, i.e., secondary osteoporosis Normal range Not applicable \210\2222 to +2 Table 66.3 WHO proposals for diagnosis of postmenopausal osteoporosis T score Fragility fracture Diagnosis (cid:2) \200\223 1 Normal < \200\223 1 but (cid:2) \200\223 2.5 Low bone mass (osteopenia) < \200\223 2.5 No Osteoporosis < \200\223 2.5 Yes Established (severe) osteoporosis Bone biopsy Bone biopsy is occasionally necessary for the diagnosis of dif \201 cult patie nts with metabolic bone disease. This is usually in the context of suspected osteomalacia o r a secondary cause of osteoporosis when the diagnosis is uncertain. Bone biopsy is not indicated for the routine diagnosis of osteoporosis. It is best undertak en in specialist centers and requires \202 uorescent labeling, e.g., tetracycline. 66-Draznin-Chap66.indd 372 3/31/2011 3:43:45 PM BLOOD CONCENTRATION 373 Investigation of calcium, phosphate, and magnesium Blood concentration Calcium The importance of obtaining blood for calcium measurement in th e fasting state with little venous stasis has been overstated. It is, however, impor- tant to collect blood for the estimation of parathyroid hormone (PTH) and phosphate levels after an overnight fast. In most clinical situations, direct measurement of the ionized calcium concentration is not necessary. However, it is important to correct the measured calcium concentration for the prevailing level of albumin ( b see Box 67.1 ). Phosphate and magnesium Measurements of plasma phosphate and magnesium do not normally requ ire to be corrected for plasma proteins. However, phosphate should be measured after an ove rnight fast. Box 67.1 Correction of measured calcium concentration Corrected Ca = measured Ca + 0.02 \227 (40 \200\223 albumin) where calcium is in mmol/L and albumin in g/L 67-Draznin-Chap67.indd 373 4/1/2011 7:02:45 PM CHAPTER 67 Investigation of calcium 374 Urine excretion Calcium A measurement of 24-hour excretion of calcium may be useful for the assessment of the risk of renal stone formation, although the relationship is not that rob ust to show calci \201 cation in states of chronic hypercalcemia. In other circumstances, particularly the assessment of the cause of hypercalcemia (primary hyperparathyroidism vs. familial hypocalciuric hypercalcemia), an estimate of the renal han dling of calcium is more use- ful. This is most commonly estimated from the ratio of the re nal clearance of calcium to that of creatinine in the fasting state ( b see Box 67.2 ). If all values are in mmol/L, the ratio is usually >0.02 in primary hyperparathy- roidism; valu es <0.01 are suggestive of hypocalciuric hypercalcemia. Other causes of hypocalciuria should be excluded, e.g., renal insuf \201 - ciency, vitamin D de \201 ciency, and some drugs. Phosphate A 24-hour measurement of phosphate excretion largely re \202 ects dietary phosph ate intake and has little clinical utility. Box 67.2 Calculation of calcium/creatinine excretion ratio 67-Draznin-Chap67.indd 374 4/1/2011 7:02:45 PM CALCIUM-REGULATING HORMONES 375 Calcium-regulating hormones Parathyroid hormone Reliable immunoassays for PTH are now avail able. In general, these are two-site assays aimed at estimating the concentration of the in tact PTH molecule. PTH is relatively labile and specimens require careful handling, includi ng early separation from the cells and speedy freezing for storage if the assay is not perf ormed immediately. Since PTH secretion is suppressed by calcium ingestion, it should be measured in the fastin g state. The normal range depends on the precise assay employed, but typical values are 10 \200\22360 pg/mL (1 \200\2236 pmol/L). In African Americans, levels are typically higher than in Caucasians. Vitamin D and its metabolites 25OH vitamin D (25OHD) This is the main storage form of vitamin D and the best measure of v ita- min D status. It is relatively stable, and samples do not require as speedy handling a s PTH. In clinical terms, it is the total vitamin D concentration that is important. The conventionally accepted normal range is 5 \200\22330 ng/mL (roughly 12.5 \200\22375 nmo l/L). However, this normal range was set with the idea of avoiding frank osteomalacia. If t he 25OHD is 5 \200\22315 ng/mL, there is likely to be a state of vita- min D insuf \201 ci ency with elevated PTH concentration and i bone turnover. This can be associated with i ris k of fracture, particularly in the elderly. Low levels of 25OHD can result from a variety of causes ( b see vita- min D de \201 ciency , p. 399). Likewise, it is unlikely that serious intoxication will occur unless the 25OHD i s >100 ng/mL. A more pragmatic reference range might be in the region of 20 \200\22380 ng/m L (50 \200\223200 nmol/L). (For con- version from ng/mL to nmol/L, multiply by 2.46.) 1,25( OH) 2 vitamin D (1,25(OH) 2 D) Although this is the active form of vitamin D, measurement o f its concen- tration is less often clinically useful than measurement of 25OHD or PTH. It is sometimes useful as a marker of PTH activity and in diseases such as sarcoidosis where t here is i extrarenal synthesis of 1,25(OH) 2 D. The normal range is generally accepted as 20 \200\22360 pg/mL (50 \200\223125 pmol/L), depending on the assay. Parathyroid hormone \200\223related peptide (PTHrP) It is possible to measure the level of this oncofetoprotein in serum. Although it is raised in many cases of humoral hypercalcemia of malig- nancy, the diagnosis is usually readily made from other sources (i.e., Ca with s uppressed PTH) and this measurement is noncontributory. PTHrP is highly labile. Specimens need to be collected into special pre- servative (Trasylol ), separated, and stored rapidly after venipuncture. Calcitonin Calcitonin assays are available but are limited to diagnosis and monitor- ing of medullary carcinoma of the thyroid. There is no role for calcitonin measurements in routin e investigation of calcium and bone metabolism. 67-Draznin-Chap67.indd 375 4/1/2011 7:02:45 PM CHAPTER 68 Hypercalcemia 376 Hypercalcemia Epidemiology Hypercalcemia is found in 5% of hospital patients but in only 0.5% of the gene ral population. Causes Many different disease states can lead to hypercalcemia. These are listed by order o f importance in hospital practice in Box 68.1. In asymptomatic community-dwelling subjects, the vast majority of hypercalcemia is the result of hyperparathyroidism. Box 68.1 Causes of hypercalcemia Common Hyperparathyroidism \200 Primary \200 Tertiary Malignancy \200 Humoral hyperca lcemia \200 Multiple myeloma \200 Bony metastases Less common \200 Vitamin D intoxication. \200 Familial hypocalciuric hypercalcemia \200 Sarcoidosis and other granulomatous diseases Uncommon \200 Thiazide diuretics \200 Lithium \200 Immobilization (may be more common with Paget \200\231s patients) \200 Hyperthyroidism \200 Renal failure \200 Addison \200\231s disease \200 Vitamin A intoxication 68-Draznin-Chap68.indd 376 3/31/2011 3:48:35 PM CLINICAL FEATURES 377 Clinical features Notwithstanding the underlying cause of hypercalcemia, the clinical featu res are similar. With corrected calcium levels <3.0 mmol/L (<12 mg/ml) it is unlikely that any symptoms will be related to the hypercalcemia itself. With progressive increases in cal cium concentration the likelihood of symptoms increases. The clinical features of hypercalcemia are well recognized (listed in Box 68.2 ). Unfortuna tely, they are nonspeci \201 c and may equally relate to underlying illness. Clinical signs of hypercalcemia are rare. With the exception of band keratopathy, these are not speci \201 c. It is important to seek clinical evidence of underlying causes of hyper calcemia, particularly malignant disease. In addition to these speci \201 c symptoms of hypercalcemia, symptoms of the long-term con sequences of hypercalcemia should be sought. These include the presence of bone pain or fra cture and renal stones. These tend to indicate the presence of chronic hypercalcemia. Investigation of hypercalcemia Con \201 rm the diagnosis \200 Plasma calcium (corrected for albumin) Determine the mech anism \200 i PTH : parathyroid overactivity (can also occur in familial hypocalciuric hyp ercalcemia, tertiary hyperparathyroidism, and in lithium therapy due to faulty calcium sens ing) Box 68.2 Clinical features of hypercalcemia Renal \200 Polyuria \200 Polydipsia Gastrointestinal \200 Anorexia \200 Vomiting \200 Constipation \200 Abdominal pain Central nervous system \200 Confusion \200 Lethargy \200 Depression Other \200 Pruritus \200 Sore eyes 68-Draznin-Chap68.indd 377 3/31/2011 3:48:36 PM CHAPTER 68 Hypercalcemia 378 d PTH : non-parathyroid cause \200 Normal PTH May imply parathyroid overactivity \200\224incomplete suppression \200 May imply altered calcium sensor \200\224familial hypocalciuric hypercalcemia \200\224calcium/creatine excretion ratio will be low \200 Urine calcium to determine calcium/creatinine excretion ratio Seek underlying illness (where indicated) \200 History and examination \200 Chest X-ray \200 FBC and ESR \200 Biochemical pro \201 le (renal and liver function) \200 Thyro id function tests (exclude thyrotoxicosis) \200 25OHD and 1,25(OH) 2 D \200 Plasma and urine protein electrophoresis (exclude myeloma) \200 Serum cortisol (short Synacthen te st [exclude Addison \200\231s disease]) To determine end-organ damage \200 24-hour urine calcium ( urine creatinine for reprodu cibility) \200 Renal tract ultrasound (exclude calculi, nephrocalcinosis) \200 Skeletal radiographs (lateral thoracolumbar spine, hands, knees) \200 BMD \200 Bone turnover ma rkers, to con \201 rm increased bone turnover 68-Draznin-Chap68.indd 378 3/31/2011 3:48:36 PM HYPERPARATHYROIDISM 379 Hyperparathyroidism Primary hyperparathyroidism is present in up to 1 in 500 of the general pop- ulation where it is predominantly a disease of postmenopausal women. The normal physiological response to hypocalcemia is an increase in PTH secretion. This is termed secondary hyperparathyroidism and is not pathological in as much as the PTH secretio n remains under feedback con- trol. Continued stimulation of the parathyroid glands can lea d to autono- mous production of PTH. This in turn causes hypercalcemia, which is termed tertiary hyperpar- athyroidism . This is usually seen in the context of renal disease but can occur in any state of chronic hypocal cemia, such as vitamin D de \201 ciency or malabsorption. Pathology: primary hyperparathyroidism \200 85% single adenoma \200 14% hyperplasia \200 Often associated with other endocrine abnormalities, particularly multiple endocrine neoplasia (MEN) types I and II ( b see Chapter 91, MEN type 1, p. 499; C hapter 92, MEN type 2, p. 503). <1% carcinoma Clinical features \200 Most patients are asymptomatic. \200 Features of hypercalcemia \200 End-organ damage \200\224 b see Box 68.3. Natural history In most patients without end-organ damage disease is benign and stable. A signi \201 cant minority (2 \200\2233% per annum, depending on the series) will develop new indications for surgery. Excess deaths are due to diabetes and vascular diseases. Investigation (Box 68.4) Potential diagnostic pitfalls are as follows: \200 Familial hypo calciuric hypercalcemia (FHH) \200\224differentiate with calcium/creatine excretion ratio ( b see Familial hypocalciuric hypercalcemia, p. 387) (<0.01 in FHH, >0.02 in hyperparathyro idism) Long-standing vitamin D de \201 ciency in which the concomitant osteomalacia and calcium malabsorption can mask hypercalcemia, which becomes apparent only after vitamin D repletion. Consider other causes of a raised PTH (Box 68.5.) Drugs associated with hypercalcemia (e.g., thiazides and lithium) Investigation is, therefo re, aimed primarily at determining the presence of end-organ damage from the hypercalcemia to determine whether opera- tive intervention is indicated. 68-Draznin-Chap68.indd 379 3/31/2011 3:48:36 PM CHAPTER 68 Hypercalcemia 380 Box 68.3 End-organ damage in hyperparathyroidism Bone Osteoporosis \200 Common \200 Affects all sites but predominant loss is in periphe ral cortical bone Radiographic changes \200 Uncommon \200 Include subperiosteal resorption, abnormal skul l vault, eroded lamina dura (around teeth), and bone cysts Osteitis \201 brosa cystica \200 Rare \200 Usually with tertiary hyperparathyroidism Kidneys \200 Renal calculi \200 Nephrocalcinosis \200 Renal impairment Joints \200 Chondrocalcinosis \200 Pseudogout Pancreatitis Box 68.4 Diagnosis of primary hyperparathyroidism \200 Ca >2.65 mmol (corrected) repeated ; however, this depends on the lab normal values Urea and electrolytes normal \200 Not on lithium or thiazide diuretic \200 PTH >3.0 pmo l (depending on the normal lab values) \200 Urine Ca >2.5 mmol/day Box 68.5 Causes of a secondary raised PTH \200 GI disorders, e.g., malabsorption \200 R enal insuf \201 ciency \200 Vitamin D de \201 ciency (25 OHD <20 ng/mL) \200 Renal hy percalcemia \200 Drugs (e.g., lithium, thiazides) 68-Draznin-Chap68.indd 380 3/31/2011 3:48:36 PM HYPERPARATHYROIDISM 381 Exclusion of underlying condition Primary hyperparathyroidism (PHP) can be associated with genetic abnor- malities, especially MEN I and II, as well as familial hyperparathyroidism. These conditions should be sought in patients presenting with PHP and a family history in ( cid:2)1 \201 rst-degree relative, or at a young age (<40 years). Localization of abnormal parathyroid glands This should only form part of a preoperative as sessment and is not indi- cated in the initial diagnosis of hyperparathyroidism. Localization with two separate techniques (usually US and 99m Tc-ses- tamibi) is usual befo re performing minimally invasive parathyroidectomy. Otherwise, bilateral neck exploration b y an experienced surgeon is opti- mal in the \201 rst instance. After failed neck exploration, other techniques may be needed: 99m Tc-sestamibi \200 \200\223thallium/technetium subtraction scanning (less sensitive) \200 CT \200 US Following failed neck exploration, it is often useful to undertake angi ogra- phy with selective venous sampling. This should be con \201 ned to specialist center s. 68-Draznin-Chap68.indd 381 3/31/2011 3:48:36 PM CHAPTER 68 Hypercalcemia 382 Treatment Surgery This should be done only by an experienced surgeon (>20 procedures per ye ar). \200 Adenoma : remove affected gland \200 Hyperplasia : either Partial parathyroidectomy (perhaps with reimplantation of tissue in more accessible site), or Total parathyroidectomy with medical treatment for hypoparathyroidism Observation This approach is suitable for patients with mild disease with no evidence of en d-organ damage. Such patients can continue for many years without deterioration. They require follow up: \200 Annual plasma calcium \200 Creatinine annually \200 Ever y 1 \200\2232 years BMD Any signi \201 cant deterioration is an indication for surgery. Medical management This is only indicated if the patient is not suitable for surgery. Hormone replacement therapy \200 Reduces plasma and urine calcium \200 Preserves bone m ass Consider the long-term risks (breast cancer, venous thrombosis, heart disease, and stro ke). Bisphosphonates \200 Only transient effect on plasma and urine calcium \200 Preserve bo ne mass Calcium-sensing receptor agonists Cinacalcet (30 mg tid) will reduce plasma, but no t urinary, calcium concen- trations. It increases the sensitivity of calcium-sensing recept ors decreasing PTH secretion. It is licensed for use in secondary hyperparathyroidism and parathyroid carcinoma. It is not licensed for use in primary hyperparathyroidism. Indications for surgery in primary hyperparathyroidism It is generally accepted that all pa tients with symptomatic hyperparathy- roidism or evidence of end-organ damage should be con sidered for par- athyroidectomy. This would include the following: \200 De \201 nite sym ptoms of hypercalcemia. There is less good evidence that nonspeci \201 c symptoms such as abdominal pain, tiredness, or mild cognitive impairm ent bene \201 t from surgery. Impaired renal function 68-Draznin-Chap68.indd 382 3/31/2011 3:48:36 PM TREATMENT 383 Renal stones (symptomatic or on radiograph) \200 Parathyroid bone disease, especially ost eitis \201 brosis cystica (low BMD T score <2.5 and/or previous fragility fracture) Pancreatitis Surgery may also be indicated when medical surveillance is neither desired nor required. Guidelines for the management of asymptomatic hyperparathyroidism have been produced on the basis of a consensus development conference in the United States. 1 Indications for surger y in asymptomatic patients are presented in Table 68.1. Conservative management Patients not managed with surgery require regular follow-up (see Ta ble 68.2). Table 68.1 Indications for parathyroidectomy in asymptomatic patients in the U.S.* Plasma calcium (>upper limit of normal) 1.0 mg /dL (0.25 mmol/L) 24-hour urine calcium Not indicated Creatinine clearance (calculated) Reduced to less than 60 ml/min BMD T score < \200\223 2.5 at any site and/or previous fracture fragility Age >50 years Surgery may also be indicated in patients in whom medical surveillance is neither desired n or possible. Source : Bilezekeian JP, Kahn AA, Potts JT, et al. (2009). Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Third In ternational Workshop. J Clin Endocrinol Metab 94(2):335 \200\223339. Table 68.2 Management recommendations for patients Plasma calcium 12 months Plasma creatinine 12 months Urine calcium Not recommended Creatinine clearance (24-hour collection) Not recommended BMD 12 months Abdominal X-ray/US Not recommended 1 Bilezikian, JP, Khan AA, Potts JT, et al. (2009). The diagnosis and management of asympto matic primary hyperparathyroidism revisited. J Clin Endocrinol Metab 94(2):335 \200\223339. 68-Draznin-Chap68.indd 383 3/31/2011 3:48:36 PM CHAPTER 68 Hypercalcemia 384 Complications of parathyroidectomy Mechanical Vocal cord paresis \200 Usually transient \200 May be permanent with extensive explorat ion, particularly repeated surgery May require Te \202 on injection of vocal cord Tracheal compression from hematoma Metabolic (hypocalcemia) Transient \200 Due to suppression of remaining glands \200 Usually causes little proble m \200 May sometimes require oral therapy with calcium vitamin D metabolites Severe \200 Due to hungry bones (calcitriol 1 mcg/day and oral calcium, e.g., calcium cit rate 1200 mg daily may be required for several weeks) Occurs in patients with pre-existing bone disease \200 Prevent postoperative hypocalcemia or hungry bone disease through pretreatment with calcium and vitamin D (1 g and 20 mcg [800 IU], respectively, daily) for several weeks. Vitamin D insuf \201 ciency is common in primary hyperparathyroidism. Serum calcium must be monitored while on vitamin D replacement therapy. May settle with oral therapy but often requires IV calcium. Outcome after surgery Less than 10% fail to become normocalcemic; of these, half will respo nd to a second operation. Relapse occurs in 1/20 patients with adenoma but in 1/6 with hype rplasia. All patients with parathyroid hyperplasia (including MEN) need inde \201 - nite follow-up. If the patient is rendered hypoparathyroid by surgery, they will need lifelong supplements of calcium active metabolites of vitamin D. This can lead to hypercalciuria, and the ris k of stone formation may still be present in these patients. 68-Draznin-Chap68.indd 384 3/31/2011 3:48:36 PM OTHER CAUSES OF HYPERCALCEMIA 385 Other causes of hypercalcemia Hypercalcemia of malignancy Mechanism ( b See Table 68.3) Clinical features Hypercalcemia is usually a late manifestation of malignant disease and fr e- quently indicates the presence of an untreatable tumor load (50% due within 30 days). On e exception to this is in small endocrine tumors such as carcinoids and islet cell tumors, which can produce humoral mediators of hypercalcemia (PTHrP) in the absence of signi \201 cant spread. Hypercalcemic symptoms are nonspeci \201 c and frequently dif \201 cult to dis- tinguish from those of the underlying disease. Investigation b See investigation of hypercalcemia in Clinical features, p. 377. Factors suggesting hypercalcemia of malignancy include the following: i Calcium \200 d PTH \200 Other features of malignant disease \200 i PTHrP \200\224no t usually measured in clinical practice Treatment Frequently, patients requiring treatment will have severe symptomatic hypercalcemia. Often emergency treatment is necessary to stabi lize the patient before con \201 rmation of the diagnosis of the underlying malignant stat e can be con \201 rmed. Table 68.3 Types of hypercalcemia associated with cancer Bone metastases Causing agent Type Frequency Tumor type Local osteolytic 20 Common Extensive Cytokines Chemokines PTHrP Breast Myeloma Lymphoma Humoral 80 Minimal PTHrP Sqamous carcinoma Renal Ovarian Endometrial Breast HTLV Lymphoma 1,25OH vitamin D <1 Variable 1,25(OH) 2 D Lymphoma, granulomatous diseases Ectopic PTH <1 Variable PTH Variable 68-Draznin-Chap68.indd 385 3/31/2011 3:48:36 PM CHAPTER 68 Hypercalcemia 386 In such circumstances, the principles of management are the same as those for severe hypercalcemia from any cause ( b see Box 68.6 ). Box 68.6 Management of severe hypercalcemia 1. Stabilization Stabilize the level of hypercalcemia and prevent any further decline in re nal function. This requires the IV infusion of large quantities of 0.9% saline, frequently 3 \200\2236 L over the \201 rst 24 hours. If there is a danger of salt and water retention, a loop diuretic should be added. This is the only role of diuretics in the management of hyper- calcemia. There is no evidence that they lead to sustained reduction in plasma calcium. As they cause intravascular volume depl etion, they can worsen the situation and so should otherwise be avoided. In very severe renal impairment, dialysis might help both stabilize the \202 uid balance and assist in the removal of calcium from the plasma. 2. Treating hypercalcemia Once the patient is volume replete, it is necessary to treat the cause of the hypercalcemia. The most effective therapy available for this is IV bisphos- ph onate. Although these agents are speci \201 c inhibitors of bone resorption, they are ofte n bene \201 cial when hypercalcemia is the result of i tubular reabsorption of calcium bro ught about by PTHrP production. \200 Vigorous rehydration 200 \200\223500 mL/hr \200 Ca lciuresis with loop diuretics when normovolemia \200 Disodium pamidronate 60 \200\22390 m g. Zoledronic acid 5 mg IV infusion over 20 minutes, but creatinine clearance should be above 35 mL/min Calcium falls within 12 hours nadix 4 \200\2237 days \200 Remains normal for 1 \200\2233 weeks. IV bisphosphonate therapy is generally well tolerated, but a minority of patient may develo p i bone pain or a transient pyrexia and \202 u-like symptoms. Rarer complications includ e rashes and iritis. Bisphosphonates have been associated with deterioration in renal function. For this reason, they should not be given to patients until ade- quate rehydration has been administered. I n addition, dose reduction should be considered for patients with GFR <30 mL/min. 3. Treatment of resistant hypercalcemia Although most patients will respond to IV bisphosph onates, not all will do so. In such cases, treatment with calcitonin may be helpful. This i s usually given as salmon calcitonin and may need to be given as high doses of up to 400 IU by IM injection every 6 hours. In addition to the large volume of injection required, this is frequently poorly tolerated, with side effects such as \202 ushing and nausea. Some cases of resistant hypercalcemia will respond to corticosteroid therapy, which needs t o be given in high doses, such as prednisolone 40 mg daily. 68-Draznin-Chap68.indd 386 3/31/2011 3:48:36 PM VITAMIN D INTOXICATION 387 Familial hypocalciuric hypercalcemia (FHH) FHH is also known as familial benign hypercalcem ia. \200 2% of all asymptomatic hypercalcemia \200 Autosomal dominant with virtually co mplete penetrance \200 Mutation occurs in the calcium-sensing receptor that reduces its s ensitivity such that the body behaves as if it were experiencing normocalcemia, even though the plasma calcium level is elevated. \200 Generally benign and is not usually associate d with symptoms or adverse effects such as renal stones or bone disease Does not usually show any sustained bene \201 t from parathyroidectomy \200 A few adults with FHH have had recurrent pancreatitis. In such cases, parathyroidectomy may reduce the frequency of attacks. The homozygous state produces severe life-threatening hypercalcemia soon after birth (neona tal severe hyperparathyroidism). In such cases, total parathyroidectomy is life saving. Patients have low urine calcium excretion (24 hours <2.5 mmol, fasting calcium/creatine excretion ration <0.01; b see Box 68.2 , p. 377). Further Reading Pallais JC, Kifor O, Chen YB, et al. (2004). Acquired hypocalciuric hyperca lcemia due to autoanti- bodies against the calcium-sensing receptor. N Engl J Med 351(4):36 2 \200\223369. Vitamin D intoxication The diagnosis is established by the presence of greatly elevated con centra- tions of 25OHD (>100 ng/mL) and 1,25(OH) 2 D together with suppressed PTH. If calci triol or alfacalcidol is the offending compound, then 25OHD levels will not be elevated. In mild cases, particularly when the active vitamin D metabolites are involved, the only tr eatment necessary is to withdraw the offending treatment and let the calcium levels settle. If the longer-acting vitamin D metabolites are involved, active treatment may be necessary depending on the level of increased calcium. Patients should \201 rst be stabilized with a saline infusion ( b see Box 68.4 , p. 380). Following this, the traditional management has been to give high-dose oral corticosteroids such as prednisolone 40 mg daily. This reduces the vitamin D \200\223stimulated calcium abs orption and may have bene \201 cial effects on vitamin D metabolism following intoxication . However, there is now emerging evidence to suggest that bisphospho- nates given as for hypercalcemia of malignancy are equally effective. 68-Draznin-Chap68.indd 387 3/31/2011 3:48:36 PM CHAPTER 68 Hypercalcemia 388 Sarcoidosis Together with other granulomatous disorders, sarcoidosis causes hyper- calcemia by extrarenal production of 1,25(OH) 2 D in granulomata. This process is not under feedbac k inhibition, but is substrate regulated. The hypercalcemia is therefore dependent on vitam in D supply. Patients frequently present with hypercalcemia in the summer or fol- lowing foreign holiday s when endogenous production of vitamin D is maximal. The biochemical picture is of normal 25OHD, raised 1,25(OH) 2 D, and suppressed PTH. In add ition, other markers of sarcoid activity, such as raised angiotensin-converting enzyme (ACE ) activity, are frequently present. Treatment with high-dose corticosteroids as in vitamin D intoxication is generally recommen ded to control sarcoid activity and to minimize the GI effects of the excess 1,25(OH) 2 D. The antifungal ketoconazole and the antimalarial chloroquine (or its derivative, hydroxychl oroquine) modulate vitamin D metabolism and have been reported to reduce hypercalcemia in p atients with sarcoidosis. If the calcium levels do not respond to these, there is evidence that bisphosphonates might be useful in this situation. Further reading Bilezikian JP, Watts JT Jr, Fuleihan Gel-H, et al. (2002). Summary statemen t from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st c entury. J Clinl Endocrinol Metab 87(12):5353 \200\2235361. Palazzo FF, Sadler GP (2004). Minimally invasive parathyroidectomy. BMJ 328(7444):849 \200 \223850. Peacock M, Bilezikian JP, Klassen PS, et al. (2005). Cinacalcet hydrochloride maintains lon g-term normocalcemia in patients with primary hyperthyroidism. J Clin Endocrinol Metab 90(1 ):135 \200\223141. Stewart AE (2005). Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 35 2(4):373 \200\223379. 68-Draznin-Chap68.indd 388 3/31/2011 3:48:36 PM CAUSES 389 Hypocalcemia Causes Although hypocalcemia can result from failure of any of the mechanisms by which plas ma calcium concentration is maintained, it is usually the result of either failure of PTH s ecretion or the inability to release calcium from bone. These causes are summarized in Box 69.1. Box 69.1 Causes of hypocalcemia Hypoparathyroidism Destruction of parathyroid glands \200 Autoimmune \200 Surgical \200 Radiation \200 In \201 ltration Failure of parathyroid development \200 Isolated, e.g., X-linked \200 With other abnormalities, e.g., DiGeorge syndrome (with thymic aplasia, immunode \201 ciency, and cardiac anomalies) Failure of PTH secretion \200 Magnesium de \201 ciency \200 Overactivity of calcium se nsing receptor Failure of PTH action \200 Pseudohypoparathyroidism \200\224due to G prote in abnormality Failure of 1,25(OH) 2 D levels \200 Drugs, e.g., ketoconazole \200 Acute pancreatitis \200 Acute systemic illness Failure of release of calcium from bone Osteoma lacia \200 Vitamin D de \201 ciency \200 Vitamin D resistance \200 Renal failure Inhibition of bone resorption \200 Hypocalcemic drugs, e.g., cisplatin, calcitonin, oral phosphate, bisphosphonates, rankl inhibitors 69-Draznin-Chap69.indd 389 3/31/2011 3:47:37 PM CHAPTER 69 Hypocalcemia 390 Box 69.1 (Contd.) i Uptake of calcium into bone \200 Osteoblastic metastases (e.g., prost ate) \200 Hungry bone syndrome Complexing of calcium from the circulation \200 i Albumi n binding in alkalosis \200 Acute pancreatitis Formation of calcium soaps from autodigestion of fat \200 Abnormal PTH and vitamin D meta bolism \200 Phosphate infusion \200 Multiple blood transfusion \200\224complexing by ci trate 69-Draznin-Chap69.indd 390 3/31/2011 3:47:37 PM CLINICAL FEATURES 391