Fwd: Kedar Toraskar has sent you an UpToDate topic
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From: Kedar Toraskar <drke...@hotmail.com>
Date: 23/12/2013 11:25 PM (GMT+05:30)
To: drke...@hotmail.com
Subject: Kedar Toraskar has sent you an UpToDate topic
UpToDate is an online clinical decision support resource featuring over 10,000 clinical topics designed to give immediate answers to clinical questions at the point of care. Visit us on the web at www.uptodate.com.
| ©2013 UpToDate ® |
Ghada El-Hajj Fuleihan, MD, MPH
Shonni J Silverberg, MD
Clifford J Rosen, MD
Jean E Mulder, MD
INTRODUCTION — The diagnosis of hyperparathyroidism is usually first suspected because of the finding of an elevated serum calcium concentration. If hypercalcemia is confirmed on a repeat sample, all of its causes should be considered (table 1). (See "Etiology of hypercalcemia".)
The serum parathyroid hormone (PTH) concentration should then be measured using a two-site immunoradiometric sandwich assay. The diagnosis of primary hyperparathyroidism is usually made by finding a frankly elevated PTH concentration or one that is within the normal range but inappropriately elevated given the patient's hypercalcemia (figure 1).
The diagnosis and differential diagnosis of primary hyperparathyroidism will be discussed here. Other aspects of primary hyperparathyroidism are reviewed elsewhere. (See "Clinical manifestations of primary hyperparathyroidism" and "Pathogenesis and etiology of primary hyperparathyroidism" and "Management of primary hyperparathyroidism" and "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism" and "Parathyroid exploration for primary hyperparathyroidism".)
DIAGNOSIS — The most common clinical presentation of primary hyperparathyroidism is asymptomatic hypercalcemia. The diagnosis of primary hyperparathyroidism is usually made by finding a frankly elevated PTH concentration or one that is within the normal range but inappropriately elevated given the patient's hypercalcemia (figure 1 and algorithm 1).
Measurement of serum calcium — A single elevated serum calcium concentration should be repeated to confirm the presence of hypercalcemia. The total serum calcium concentration should be used for both the initial and the repeat serum calcium measurements. If a laboratory known to measure ionized calcium reliably is available, some authorities prefer to measure the ionized calcium, although this usually adds little in patients with normal serum albumin concentrations and no abnormalities in acid base balance [1]. (See "Diagnostic approach to hypercalcemia", section on 'Interpretation of serum calcium'.)
One circumstance in which ionized calcium measurements may be a useful adjunct to diagnosis is in patients with normocalcemic primary hyperparathyroidism. In one series, 12 of 60 patients had a raised serum concentration of ionized calcium in the presence of a normal total serum calcium concentration [2]. (See 'Normocalcemic primary hyperparathyroidism versus secondary hyperparathyroidism' below.)
If available, previous values for serum calcium should be reviewed. The presence of longstanding asymptomatic hypercalcemia is more suggestive of primary hyperparathyroidism and also raises the possibility of familial hypocalciuric hypercalcemia.
Measurement of PTH — The accurate measurement of serum PTH has been greatly simplified by the use of immunoradiometric (IRMA) and immunochemiluminescent assays [3]. These tests measure intact PTH by using antibodies directed simultaneously at both the N– and the C–terminal regions of the PTH molecule. (See "Parathyroid hormone assays and their clinical use".)
Approximately 80 to 90 percent of patients with primary hyperparathyroidism have high serum PTH concentrations (normal range 10 to 60 pg/mL) (figure 1) [3,4]. In one report, as an example, the average serum calcium and PTH concentrations in patients with asymptomatic hyperparathyroidism were 11 mg/dL (2.8 mmol/L) and 120 pg/mL, respectively [5]. However, 10 to 20 percent of patients have serum PTH values that are only minimally elevated or normal, ranging from 35 to 65 pg/mL [4]. These "normal" values in the presence of hypercalcemia are inappropriately high; normal subjects given calcium intravenously have suppressed serum PTH concentrations (below 10 pg/mL) and patients with nonparathyroid hypercalcemia virtually always have values below 20 to 25 pg/mL (figure 1) [6,7]. Rarely, a patient with proven primary hyperparathyroidism has a serum intact PTH concentration in the lower half of the normal range [8] or one that is undetectable [9]. In the latter report, the patient had a biologically active PTH fragment, which was undetectable with the intact PTH assay. (See "Parathyroid hormone assays and their clinical use", section on 'PTH fragments'.)
The immunoradiometric assays (second generation PTH assays) that replaced older radioimmunoassays (first generation PTH assays) for PTH were touted as measuring "intact" PTH molecule. It is now recognized that second-generation PTH assays detect not only intact 1-84 PTH, but also large carboxyterminal fragments (such as 7-84) of PTH. Some of these fragments may be biologically inactive, while others may inhibit osteoclastic bone resorption, inhibit the formation of mature osteoclasts, and have hypocalcemic properties. (See "Parathyroid hormone assays and their clinical use", section on 'PTH fragments'.)
Newer third-generation assays that detect exclusively the biologically active PTH 1-84 (whole PTH or bioactive PTH) require both the extreme amino-terminal and carboxy-terminal ends of the molecule for detection. Some data suggest these assays may be superior in patients with renal failure, for intraoperative PTH monitoring, and for initial diagnosis in patients with primary hyperparathyroidism and inappropriately "normal" serum PTH concentrations in second generation IRMA assays. (See "Parathyroid hormone assays and their clinical use", section on 'Clinical use of PTH assays'.)
Although limited data [10] suggest that PTH is increased in a higher proportion of patients with primary hyperparathyroidism using the PTH (1-84) assay, several other studies have found no increase in diagnostic utility [11,12]. Thus, either intact PTH (second-generation PTH assay) or PTH (1-84) assays (third generation PTH assays) can be used for diagnosis of hyperparathyroidism [13].
DIFFERENTIAL DIAGNOSIS — Although the most common clinical presentation of primary hyperparathyroidism is asymptomatic hypercalcemia with an elevated or high-normal intact PTH concentration, the presentation may be atypical. Atypical presentations include a spectrum of disturbances in calcium homeostasis, ranging from symptomatic severe hypercalcemia (parathyroid crisis) to normocalcemic primary hyperparathyroidism. Laboratory testing often can distinguish atypical presentations of primary hyperparathyroidism from other diseases, such as malignancy, familial hypocalciuric hypercalcemia (FHH), and secondary hyperparathyroidism (table 2).
In primary hyperparathyroidism and FHH, the calcium and PTH levels are usually simultaneously elevated. Other less common causes of hypercalcemia, including milk-alkali syndrome, granulomatous disease, and hypervitaminosis D, are associated with suppressed rather than elevated PTH concentrations. They are discussed in more detail elsewhere. (See "Etiology of hypercalcemia" and "Diagnostic approach to hypercalcemia".)
Malignancy — Primary hyperparathyroidism and malignancy are the most common causes of hypercalcemia, accounting for more than 90 percent of cases (table 1). It is usually not difficult to differentiate between them. Malignancy is often evident clinically by the time it causes hypercalcemia, and patients with hypercalcemia of malignancy have higher calcium concentrations and are more symptomatic from hypercalcemia than individuals with primary hyperparathyroidism. (See "Hypercalcemia of malignancy".)
However, it may be difficult to differentiate the two problems clinically when the presentation is less typical. As an example, some patients with occult malignancy may present with mild hypercalcemia. Alternatively, patients with hyperparathyroidism can occasionally have acute onset of severe, symptomatic hypercalcemia (parathyroid crisis). In these cases, measurement of intact PTH will usually distinguish the two diseases. Intact PTH concentrations are generally undetectable or very low in hypercalcemia of malignancy and are elevated or high-normal in primary hyperparathyroidism (table 2). It is uncommon for patients with hypercalcemia of malignancy to have elevated PTH levels, but this finding may occur rarely in individuals with hypercalcemia of malignancy and concomitant primary hyperparathyroidism or in individuals with PTH secreting tumors, which are also rare. (See "Hypercalcemia of malignancy", section on 'Ectopic PTH secretion' and "Hypercalcemia of malignancy", section on 'Coexisting primary hyperparathyroidism'.)
Familial hypocalciuric hypercalcemia — Familial hypocalciuric hypercalcemia (FHH) is due to an inactivating mutation in the calcium-sensing receptor in the parathyroid glands and the kidneys [14]. A family history of hypercalcemia, especially in young children, and the absence of symptoms and signs of hypercalcemia (such as anorexia, neuromuscular symptoms, and polyuria) are characteristic of this disorder.
Fifteen to 20 percent of patients with FHH may have a mildly elevated PTH concentration [14-17]. In these individuals, it may be difficult to distinguish asymptomatic primary hyperparathyroidism from FHH. It is important to make this distinction, however, because FHH is a benign inherited condition that typically does not require parathyroidectomy, nor will it be cured by it.
The major feature that distinguishes FHH from primary hyperparathyroidism is a low urine calcium excretion and Ca/Cr clearance ratio (table 2). In contrast, most patients with primary hyperparathyroidism have either normal or elevated urinary calcium excretion. Because the calcium-sensing receptor is a cation receptor, urinary magnesium excretion parallels calcium excretion and is therefore low in FHH in contrast to primary hyperparathyroidism. (See 'Measurement of urinary calcium excretion' below and "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Distinction from primary hyperparathyroidism'.)
Drugs — Two drugs deserve special consideration when evaluating a patient for hyperparathyroidism: thiazide diuretics and lithium.
Thiazide diuretics reduce urinary calcium excretion and therefore can cause mild hypercalcemia (up to 11.5 mg/dL [2.9 mmol/L]). (See "Etiology of hypercalcemia".) In addition, some patients with hyperparathyroidism may be prescribed thiazides, which may elevate the serum calcium further and thereby unmask the hyperparathyroidism. Following discontinuation of the drug, these individuals remain hypercalcemic, although perhaps less so, and are found to have surgically proven hyperparathyroidism. Thus, if a patient taking a thiazide is found to be hypercalcemic, the drug should be withdrawn, if possible, and calcium and PTH assessed three months later. Persistent hypercalcemia (with elevated or high-normal PTH) after drug withdrawal suggests that the thiazide has unmasked primary hyperparathyroidism. (See "Pathogenesis and etiology of primary hyperparathyroidism", section on 'Thiazide therapy'.)
Lithium decreases parathyroid gland sensitivity to calcium, shifting the calcium-PTH curve to the right (figure 2). Lithium may also reduce urinary calcium excretion. Lithium is thought to affect calcium-PTH dynamics through an action downstream of the calcium-sensing receptor, but the exact locus is still unknown. Some patients taking lithium develop hypercalcemia and hypocalciuria, and a subset of these individuals has high serum PTH concentrations. If the lithium can be stopped without exacerbating the psychiatric condition, the hypercalcemia may resolve. Following discontinuation, the serum calcium concentration is more likely to normalize if the duration of lithium use had been relatively short, eg, less than a few years, but less likely if it had been longer, eg, more than 10 years. (See "Pathogenesis and etiology of primary hyperparathyroidism", section on 'Lithium therapy' and "Parathyroid hormone secretion and action", section on 'Lithium and PTH secretion'.)
Normocalcemic primary hyperparathyroidism versus secondary hyperparathyroidism — Occasionally, patients with primary hyperparathyroidism have normal total and ionized calcium concentrations (normocalcemic primary hyperparathyroidism). These patients typically come to medical attention in the setting of an evaluation for low bone mineral density. In these cases, it may be difficult to distinguish secondary hyperparathyroidism from early primary hyperparathyroidism because the biochemical findings may be similar.
Secondary hyperparathyroidism — Secondary hyperparathyroidism occurs when the parathyroid gland appropriately responds to a reduced level of extracellular calcium. PTH concentrations rise, and calcium is mobilized by increasing intestinal absorption (via increase in calcitriol) and by increasing bone resorption. Thus, it is characterized biochemically by elevated PTH and normal or low serum calcium concentrations. (See "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients".)
Secondary hyperparathyroidism may occur in patients with renal failure and impaired calcitriol (1,25 dihydroxyvitamin D) production, as well as in individuals with inadequate calcium intake or absorption, as can occur with vitamin D deficiency or with gastrointestinal diseases causing malabsorption (table 3). Assessment of renal function (serum creatinine), vitamin D status (25-hydroxyvitamin D, 25[OH]D), and calcium sufficiency (urinary calcium excretion) may help differentiate normocalcemic primary and secondary hyperparathyroidism. Further assessment and work-up for specific gastrointestinal disorders is generally undertaken only when the clinical suspicion is high.
Some patients may have more than one condition leading to increased PTH secretion. Co-existing primary hyperparathyroidism and vitamin D deficiency is not uncommon. When this occurs, the serum calcium level in the primary hyperparathyroid patient may be reduced (into the normal range in some cases) due to vitamin D deficiency. (See 'Vitamin D metabolites' below.)
Normocalcemic primary hyperparathyroidism — Increasingly, patients undergoing evaluation for low bone density or other conditions may have PTH levels drawn in the absence of hypercalcemia. An international panel of experts recognized a new phenotype of primary hyperparathyroidism in which PTH levels are elevated but serum calcium is normal [18]. In order to make this diagnosis, certain conditions must be met. In particular, all secondary causes for hyperparathyroidism (table 3) must be ruled out, and ionized calcium levels should be normal. The most common explanation for the finding of an elevated PTH and normal serum calcium remains concomitant hypercalcemic primary hyperparathyroidism and vitamin D deficiency.
Patients without an apparent secondary cause may have a "forme fruste" of primary hyperparathyroidism [19,20]. It might be expected that early in the natural history of primary hyperparathyroidism, elevated PTH levels would precede the development of overt hypercalcemia. In these patients, the serum calcium concentration would be expected to rise above the upper limit of normal when followed over time.
In one prospective study of 37 patients with normocalcemic hyperparathyroidism, 41 percent developed evidence for progressive hyperparathyroid disease during a median of three years (range 1 to 8) of observation [21]. However, less than 20 percent of patients became hypercalcemic during the observation period. Instead, some persistently normocalcemic patients developed other indications of progressive disease, such as kidney stones, hypercalciuria, bone loss, and fracture. Furthermore, four individuals with normal serum calcium levels had successful parathyroid surgery.
There are no data to suggest that these patients will ultimately become hypercalcemic, and over what time period. In addition, since most of these patients were identified in the course of an evaluation for osteoporosis, fracture, or low bone density, they may not represent an early form of asymptomatic primary hyperparathyroidism, but could instead represent a unique phenotype of the disease.
Identification of the normocalcemic patients who represent the true clinical precursor of hypercalcemic asymptomatic primary hyperparathyroidism would probably require population screening, which we do not recommend.
TESTS TO CONFIRM PRIMARY HYPERPARATHYROIDISM — Primary hyperparathyroidism is suspected when the intact PTH or PTH (1-84) concentration is elevated or high-normal in the setting of hypercalcemia. Additional tests that can distinguish primary hyperparathyroidism from the diseases described above include measurement of urinary calcium excretion and 25-hydroxyvitamin D (table 2 and algorithm 1).
Measurement of urinary calcium excretion — Measurement of 24-hour urine calcium excretion is required for distinguishing primary hyperparathyroidism from familial hypocalciuric hypercalcemia (FHH). (See 'Familial hypocalciuric hypercalcemia' above.)
Approximately 40 percent of patients with primary hyperparathyroidism are hypercalciuric, and most of the remaining patients have normal values [22]. An elevated urinary calcium concentration essentially excludes FHH. If calcium excretion is low, eg, less than 200 mg/day (5.0 mmol/day), familial hypocalciuric hypercalcemia (FHH, see above) or hyperparathyroidism with concomitant vitamin D deficiency are possibilities; about 75 percent of affected persons with FHH excrete less than 100 mg of calcium in urine daily (algorithm 1) [15].
A Ca/Cr clearance ratio, which is equivalent to the fractional excretion of calcium, also may be helpful. This ratio is calculated from 24-hour urinary calcium and creatinine and total serum calcium and creatinine concentrations using the following formula:
Ca/Cr clearance ratio = [24 hour Urine Ca x serum Cr] ÷ [serum Ca x 24 hour Urine Cr]
The data establishing the value of the calcium to creatinine clearance ratio in differentiating FHH from primary hyperparathyroidism are based primarily on 24 hour urine collections. While there are insufficient data available to prove that Ca/Cr ratios calculated from spot urines are equivalent to those determined from 24-hour urines, in principle the two should reflect renal calcium handling similarly.
A value below 0.01 in a vitamin D replete individual is highly suggestive of FHH rather than hyperparathyroidism (ratio usually >0.02). In an analysis of five large studies combining 165 patients with FHH and 197 patients with primary hyperparathyroidism, a Ca/Cr clearance ratio <0.01 had a sensitivity for FHH of 85 percent, a specificity of 88 percent, and a positive predictive value of 85 percent; a value >0.02 essentially excluded FHH [14,16]. Due to the difficulty of differentiating FHH from primary hyperparathyroidism when the Ca/Cr clearance ratio is <0.02, some have suggested CaSR mutation analysis for such individuals [23]. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Distinction from primary hyperparathyroidism'.)
Vitamin D metabolites — Patients with primary hyperparathyroidism convert more 25(OH)D (calcidiol) to 1,25 dihydroxyvitamin D (calcitriol) than normal individuals. Serum concentrations of 1,25 dihydroxyvitamin D may therefore be at upper limits of normal or elevated [24,25]. An elevated value is not specific for diagnosis, and measurement of 1,25-dihydroxyvitamin D is not generally needed to confirm the diagnosis.
However, due to the significant prevalence of vitamin D insufficiency in individuals with primary hyperparathyroidism, the Third International Workshop on Asymptomatic Primary Hyperparathyroidism recommends measuring 25(OH)D in all patients with the disease and repleting those with low levels (defined as ≤20 ng/mL [50 nmol/L]) prior to making any management decisions [13]. (See "Management of primary hyperparathyroidism", section on 'Treatment of concomitant vitamin D deficiency' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Coexisting primary hyperparathyroidism'.)
Measurement of vitamin D metabolites is also useful in the following circumstances:
●To differentiate hypervitaminosis D from primary hyperparathyroidism, we typically measure both 1,25-dihydroxyvitamin D and 25(OH)D. (See "Diagnostic approach to hypercalcemia".)
●To differentiate FHH from mild primary hyperparathyroidism with concomitant vitamin D deficiency in individuals with elevated serum PTH and calcium and normal or low 24-hour urinary calcium excretion, we typically measure 25(OH)D. In the latter patients, urinary calcium excretion increases with vitamin D repletion, thereby distinguishing it from FHH.
●To differentiate secondary hyperparathyroidism due to vitamin D deficiency from normocalcemic primary hyperparathyroidism in patients with elevated PTH and normal serum calcium concentrations, we typically measure 25(OH)D, which is low in the former and normal in the latter.
Sometimes patients with presumed secondary hyperparathyroidism have primary hyperparathyroidism with concomitant vitamin D deficiency. In these patients, the diagnosis of mild primary hyperparathyroidism is obscured by vitamin D deficiency (due to poor dietary intake of vitamin D or sunlight exposure) and may not be recognized until vitamin D is repleted and hypercalcemia and/or hypercalciuria develop. Primary hyperparathyroidism with coexisting vitamin D deficiency may be suspected when serum calcium concentrations are in the upper half of the normal range and urinary calcium concentration is normal, despite vitamin D deficiency.
Individuals with normocalcemic hyperparathyroidism and low 25(OH)D concentrations may be repleted with vitamin D. However, vitamin D replacement should be provided cautiously in those with suspected concurrent primary hyperparathyroidism, in particular in those with hypercalciuria, as worsening hypercalcemia and hypercalciuria may develop. (See "Management of primary hyperparathyroidism", section on 'Treatment of concomitant vitamin D deficiency' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Coexisting primary hyperparathyroidism'.)
In contrast, serum and urinary calcium remain normal and PTH normalizes after vitamin D repletion in individuals with vitamin D deficiency-induced secondary hyperparathyroidism.
OTHER TESTS — Other tests that follow are less helpful in confirming the diagnosis of primary hyperparathyroidism but may provide useful clinical information.
Serum phosphorus — The serum phosphorus concentration may be decreased but typically is in the lower range of normal. Some patients have mild hyperchloremic acidosis. (See "Clinical manifestations of primary hyperparathyroidism".)
Serum creatinine — The serum creatinine concentration provides information about renal function, which can be diminished by hypercalcemia. Rather than using serum creatinine alone, the GFR can be estimated in patients with a stable serum creatinine concentration. (See "Clinical manifestations of hypercalcemia" and "Assessment of kidney function", section on 'Estimation equations'.)
An estimated GFR of 60 mL/min is the threshold of chronic kidney disease for deciding which asymptomatic individuals with primary hyperparathyroidism may benefit from early surgical treatment [26]. (See "Management of primary hyperparathyroidism", section on 'Guidelines'.)
Markers of bone turnover — Biochemical markers of bone turnover (collagen crosslinks, osteocalcin, bone-specific alkaline phosphatase) are often at the upper end of normal or mildly elevated in asymptomatic primary hyperparathyroidism. (See "Bone physiology and biochemical markers of bone turnover".) In those with more severe disease, they are typically high. They are only occasionally helpful in the management of hyperparathyroidism and should not be routinely measured [1].
Bone mineral density — Patients with hyperparathyroidism may have decreased bone mineral density (BMD), in particular at more cortical sites (forearm and hip) as compared with more cancellous sites (spine). Although measurement of BMD is not required for the diagnosis of primary hyperparathyroidism, it is an essential part of the management of the disease, and BMD must be measured at the spine, hip, and distal one-third forearm sites. The degree of bone loss is reflective of the severity of hyperparathyroidism and is useful for making recommendations for parathyroid surgery or observation with monitoring. (See "Management of primary hyperparathyroidism", section on 'Bone disease'.)
Renal imaging — Patients with undiagnosed nephrocalcinosis or calcium kidney stones are regarded as having symptomatic disease, regardless of the absence of symptoms. Thus, these patients meet criteria for surgical intervention [26]. Although routine renal imaging at the time of the original evaluation for primary hyperparathyroidism is no longer recommended, renal imaging should be performed if kidney stones are suspected or if there is a history of kidney stones [13]. Ultrasound is typically the imaging modality used.
Localization studies — The diagnosis of primary hyperparathyroidism is established by appropriate biochemical testing. Localization studies with ultrasonography, technetium-99m sestamibi, CT, or MRI scanning should not be used to establish the diagnosis of primary hyperparathyroidism. Their utility is questionable when bilateral neck exploration is planned. However, they are commonly used now, along with intraoperative PTH monitoring, to facilitate unilateral exploration and minimally invasive surgery in those with probable single gland disease. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient information: Primary hyperparathyroidism (The Basics)")
●Beyond the Basics topic (see "Patient information: Primary hyperparathyroidism (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
PTH versus non-PTH mediated hypercalcemia
●The diagnosis of hyperparathyroidism is usually first suspected by the finding of an elevated serum calcium concentration. Measuring intact serum PTH will help distinguish primary hyperparathyroidism from PTH-independent causes of hypercalcemia, such as malignancy. A frankly elevated PTH concentration or a PTH value in the upper half of the normal range in the setting of hypercalcemia is likely the result of primary hyperparathyroidism (algorithm 1). (See 'Diagnosis' above.)
●PTH concentrations below 20 to 25 pg/mL in the setting of hypercalcemia are possible but rare in primary hyperparathyroidism and indicate the need for evaluation for other causes of hypercalcemia (table 1). It is uncommon for patients with hypercalcemia of malignancy to have elevated PTH levels, but this finding may occur rarely in individuals with hypercalcemia of malignancy and concomitant primary hyperparathyroidism or in individuals with PTH secreting tumors, which are also rare. If the elevated PTH is exclusively drug-induced, as opposed to unmasked abnormal PTH dynamics by the drug, the hyperparathyroidism and hypercalcemia should reverse with discontinuation of the offending medication, especially in instances of short duration of therapy. (See 'Differential diagnosis' above and "Diagnostic approach to hypercalcemia".)
FHH versus primary hyperparathyroidism
●In some individuals with mildly elevated calcium and PTH concentrations, it may be difficult to distinguish primary hyperparathyroidism from FHH (table 2). In these cases, urinary calcium excretion should be measured. (See 'Tests to confirm primary hyperparathyroidism' above.)
●An elevated urinary calcium concentration or a Ca/Cr clearance ratio >0.02 essentially excludes FHH. (See 'Measurement of urinary calcium excretion' above and 'Familial hypocalciuric hypercalcemia' above.)
●In patients with normal or low urinary calcium concentrations, 25(OH)D concentrations should be measured to distinguish primary hyperparathyroidism with vitamin D deficiency from FHH (algorithm 1). (See 'Vitamin D metabolites' above.)
●In patients with primary hyperparathyroidism and vitamin D deficiency, urinary calcium will increase after vitamin D repletion, thereby differentiating it from FHH. (See 'Vitamin D metabolites' above.)
Normocalcemic hyperparathyroidism
●Patients with normocalcemic hyperparathyroidism (elevated PTH, normal serum calcium) typically come to medical attention in the setting of an evaluation for low bone mineral density. (See 'Normocalcemic primary hyperparathyroidism' above.)
●The differential diagnosis also includes secondary hyperparathyroidism (table 3) and primary hyperparathyroidism with concomitant vitamin D deficiency (table 2).
●Evaluation to rule out causes of secondary hyperparathyroidism, especially vitamin D deficiency or insufficiency, is essential. Patients with true normocalcemic primary hyperparathyroidism may develop symptomatic disease, and therefore require monitoring. (See 'Normocalcemic primary hyperparathyroidism versus secondary hyperparathyroidism' above.)
REFERENCES
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drkedart
-------- Original message --------
From: Kedar Toraskar <drke...@hotmail.com>
Date: 23/12/2013 11:15 PM (GMT+05:30)
To: drke...@hotmail.com
Subject: Kedar Toraskar has sent you an UpToDate topic
UpToDate is an online clinical decision support resource featuring over 10,000 clinical topics designed to give immediate answers to clinical questions at the point of care. Visit us on the web at www.uptodate.com.
| ©2013 UpToDate ® |
Elizabeth Shane, MD
James R Berenson, MD
Clifford J Rosen, MD
Jean E Mulder, MD
INTRODUCTION — Treatment for hypercalcemia should be aimed both at lowering the serum calcium concentration and, if possible, treating the underlying disease. Effective treatments reduce serum calcium by inhibiting bone resorption, increasing urinary calcium excretion, or decreasing intestinal calcium absorption (table 1). The optimal choice varies with the cause and severity of hypercalcemia.
The treatment of hypercalcemia will be reviewed here, with emphasis on the management of hypercalcemia in patients with malignant disease. The modalities described below apply in varying degrees to patients with other causes of hypercalcemia. The clinical manifestations, etiology, and diagnostic approach to hypercalcemia are discussed separately. (See "Clinical manifestations of hypercalcemia" and "Etiology of hypercalcemia" and "Diagnostic approach to hypercalcemia".)
INTERPRETATION OF SERUM CALCIUM — Calcium in serum is bound to proteins, principally albumin. As a result, total serum calcium concentrations in patients with low or high serum albumin levels may not accurately reflect the physiologically important ionized (or free) calcium concentration. As an example, in patients with hypoalbuminemia, total serum calcium concentration may be normal when serum ionized calcium is elevated.
Alternatively, patients with hyperalbuminemia due to severe volume depletion and rare patients with multiple myeloma, who have a calcium-binding paraprotein, have increased protein binding of calcium. This can cause an elevation in the serum total calcium concentration without any rise in the serum ionized calcium concentration. This phenomenon is called pseudohypercalcemia (or factitious hypercalcemia), since the patient has a normal ionized serum calcium concentration.
In patients with hypoalbuminemia or hyperalbuminemia, the measured serum calcium concentration should be corrected for the abnormality in albumin (calculator 1) or for standard units (calculator 2). If a laboratory known to measure ionized calcium reliably is available, some authorities prefer to measure the serum ionized calcium in this situation. (See "Relation between total and ionized serum calcium concentration".)
INDICATIONS FOR TREATMENT — Hypercalcemia may be associated with a spectrum of clinical manifestations, ranging from few or no symptoms in patients with mild chronic hypercalcemia to severe obtundation and coma. (See "Clinical manifestations of hypercalcemia".) The degree of hypercalcemia, along with the rate of rise of serum calcium concentration, often determines symptoms and the urgency of therapy. The therapeutic approach should reflect these differences [1,2].
Patients with asymptomatic or mildly symptomatic (eg, constipation) hypercalcemia (calcium <12 mg/dL [3 mmol/L]) do not require immediate treatment. (See 'Preferred approach' below.) Similarly, a serum calcium of 12 to 14 mg/dL (3 to 3.5 mmol/L) may be well-tolerated chronically, and may not require immediate treatment. However, an acute rise to these concentrations may cause marked changes in sensorium, which requires more aggressive measures. In addition, patients with a serum calcium concentration >14 mg/dL (3.5 mmol/L) require treatment, regardless of symptoms.
SALINE HYDRATION — Initial therapy of severe hypercalcemia includes the simultaneous administration of saline, calcitonin, and a bisphosphonate. (See 'Severe hypercalcemia' below.) Isotonic saline corrects possible volume depletion due to hypercalcemia-induced urinary salt wasting and, in some cases, vomiting. Hypovolemia exacerbates hypercalcemia by impairing the renal clearance of calcium (table 1) [3].
The rate of saline infusion depends upon several factors, including the severity of hypercalcemia, the age of the patient, and presence of comorbid conditions, particularly underlying cardiac or renal disease. A reasonable regimen, in the absence of edema, is the administration of isotonic saline at an initial rate of 200 to 300 mL/hour that is then adjusted to maintain the urine output at 100 to 150 mL/hour.
Saline therapy requires careful monitoring, since it can lead to fluid overload in patients who cannot excrete the administered salt because of impaired renal function, which can be induced by hypercalcemia or heart failure. The saline infusion should be stopped in patients who develop edema and a loop diuretic may be used as necessary.
Saline therapy rarely normalizes the serum calcium concentration in patients with more than mild hypercalcemia [3]. In the past, administration of a loop diuretic was initiated routinely once fluid repletion had been achieved to further increase urinary calcium excretion. However, this practice was based upon an approach that involved intensive administration of furosemide (80 to 100 mg every one to two hours) with aggressive fluid hydration (10 liters daily) [4].
Saline therapy beyond that necessary to restore euvolemia has fallen out of favor for two reasons [5,6]:
- The availability of drugs such as the bisphosphonates and calcitonin that inhibit bone resorption, which is primarily responsible for the hypercalcemia.
- The requirement for careful monitoring because of the potential fluid and electrolyte complications resulting from a massive saline infusion and furosemide-induced diuresis such as hypokalemia, hypomagnesemia, and volume depletion if the diuretic-induced losses are not replaced.
Concurrent treatment with bisphosphonates with or without calcitonin is typically required to treat moderate to severe hypercalcemia. (See 'Preferred approach' below.)
CALCITONIN — Pharmacologic doses of calcitonin reduce the serum calcium concentration by increasing renal calcium excretion and, more importantly, by decreasing bone resorption via interference with osteoclast function [7,8]. Salmon calcitonin (4 international units/kg) is usually administered intramuscularly or subcutaneously every 12 hours; doses can be increased up to 6 to 8 international units/kg every six hours. Nasal application of calcitonin is not efficacious for treatment of hypercalcemia [9].
Calcitonin is safe and relatively nontoxic (other than mild nausea and the rare hypersensitivity reaction). Although a relatively weak agent, it works rapidly, lowering the serum calcium concentration by a maximum of 1 to 2 mg/dL (0.3 to 0.5 mmol/L) beginning within four to six hours (table 1) [1,10-12]. Thus, it is useful in combination with hydration for the initial management of severe hypercalcemia.
The efficacy of calcitonin is limited to the first 48 hours, even with repeated doses, indicating the development of tachyphylaxis, perhaps due to receptor downregulation [1,8,13,14]. Because of its limited duration of effect, calcitonin is most beneficial in symptomatic patients with calcium >14 mg/L (3.5 mmol/L), when combined with hydration and bisphosphonates. Calcitonin and hydration provide a rapid reduction in serum calcium concentration, while a bisphosphonate provides a more sustained effect.
BISPHOSPHONATES — The bisphosphonates are nonhydrolyzable analogs of inorganic pyrophosphate that adsorb to the surface of bone hydroxyapatite and inhibit calcium release by interfering with osteoclast-mediated bone resorption [15]. They are effective in treating hypercalcemia resulting from excessive bone resorption of any cause (table 1). (See "Pharmacology of bisphosphonates".)
All of the bisphosphonates are relatively nontoxic compounds and they are more potent than calcitonin and saline for patients with moderate or severe hypercalcemia [1,16-22]. As a result, they have become the preferred agents for management of hypercalcemia due to excessive bone resorption from a variety of causes, including malignancy-related hypercalcemia [22-24]. Their maximum effect occurs in two to four days, so that they are usually given in conjunction with saline and/or calcitonin, which reduce calcium concentration more rapidly. (See 'Preferred approach' below.)
Although bisphosphonates are most commonly used to treat established hypercalcemia, they have also been given to prevent hypercalcemia and adverse skeletal events, particularly in patients with metastatic cancer to bone. The use of bisphosphonates to improve outcomes for patients with cancer is discussed separately. (See "Bisphosphonates and denosumab in patients with metastatic cancer".)
Among the currently available agents for the treatment of malignancy-associated hypercalcemia (pamidronate, zoledronic acid, ibandronate, clodronate, and etidronate), intravenous zoledronic acid (ZA) or pamidronate are our bisphosphonates of choice. ZA is favored by some because it is more potent than pamidronate [21] and can be administered over a shorter time period (15 minutes compared to two hours).
Repetitive IV use of bisphosphonates has been associated with risk of developing osteonecrosis of the jaw in patients with multiple myeloma or metastatic bone disease. Some data suggest a higher risk of osteonecrosis of the jaw following the repeated use of ZA. As a result, some groups favor use of pamidronate over ZA in particular cancer patients, such as those with multiple myeloma. However, osteonecrosis of the jaw is a complication of long-term, high dose IV bisphosphonate therapy. Therefore, concerns about the risk of osteonecrosis of the jaw are of limited relevance in the management of acute hypercalcemia. (See 'Side effects and precautions' below and "The use of bisphosphonates in patients with multiple myeloma", section on 'Choice of agent'.)
Alendronate and risedronate are potent-third generation bisphosphonates that can be given orally. However, neither is used for the treatment of severe or acute hypercalcemia.
Pamidronate — A number of observational studies and some randomized trials have demonstrated the efficacy of intravenous pamidronate for the treatment of hypercalcemia due to excessive bone resorption from a variety of causes, including malignancy, acute primary hyperparathyroidism, immobilization, hypervitaminosis D, and sarcoidosis [1,18,25-34].
Early trials showed pamidronate (60 mg over 24 hours) was more effective in ameliorating hypercalcemia of malignancy than intravenous etidronate (70 percent versus 41 percent) [18] or clodronate [31]. Subsequent trials showed that shorter infusion times (two to four hours) were safe and effective, maintaining normocalcemia for two or more weeks [19,32].
The maximal calcium response occurs at 90 mg IV [33]. However, many clinicians vary the usual initial dose of pamidronate according to the degree of hypercalcemia: 60 mg if the serum calcium concentration is up to 13.5 mg/dL (3 to 3.4 mmol/L) and 90 mg for higher levels. Serum calcium concentrations begin to decrease in one or two days. Doses should not be repeated sooner than a minimum of seven days.
Intravenous pamidronate is well tolerated, with a low incidence of fever being the main side effect. A less favorable response may be seen in patients with humoral hypercalcemia of malignancy, a paraneoplastic syndrome typically resulting from autonomous production of parathyroid hormone-related protein (PTHrP) by the tumor [35-37]. (See "Hypercalcemia of malignancy", section on 'PTH-related protein'.) Such patients may have a better response to zoledronic acid.
Zoledronic acid — Zoledronic acid (ZA) is considered by many the agent of choice for malignancy-associated hypercalcemia because it is more potent and effective than pamidronate. Although it can be administered over a shorter time period (15 minutes as compared with two hours), which may be more convenient, this may not be as important in the setting of hypercalcemia since many of these patients require hospitalization. ZA is currently approved by the United States Food and Drug Administration for treatment of hypercalcemia of malignancy at a dose of 4 mg IV over at least 15 minutes.
In a pooled analysis of two separate phase III trials involving a total of 275 patients with tumor-induced hypercalcemia, a single dose of ZA (either 4 mg or 8 mg) normalized the corrected serum calcium concentration in 87 to 88 percent of patients, compared with only 70 percent of those receiving pamidronate (90 mg) [21]. In addition, the median duration of serum calcium control was longer for those receiving ZA (32 to 43 versus 18 days).
Although renal events were reported more frequently with ZA than with pamidronate in trials evaluating chronic use of these drugs to treat patients with metastatic bone disease, there was no difference in the frequency of grade 3 or 4 renal toxicity with either drug. The efficacy of the 4 and 8 mg ZA doses were similar, but the 4 mg dose was recommended because there was greater renal toxicity with the 8 mg dose (5.2 versus 2.3 percent with 4 mg) and higher all-cause mortality (33 versus 19 percent) [38]. (See 'Dosing in renal impairment' below.)
Ibandronate — Ibandronate effectively treats hypercalcemia of malignancy. In combined trials with over 320 patients, ibandronate doses of 2 mg IV administered over two hours normalized serum calcium in up to 67 percent of patients, and doses up to 6 mg were safe and well tolerated [39,40]. The frequency of response was significantly higher with 4 or 6 mg than with 2 mg (76 to 77 versus 50 percent), but the duration of response was not dose-dependent [40].
Ibandronate appears to be as effective as pamidronate. Ibandronate (2 or 4 mg IV) was directly compared with pamidronate (15 to 90 mg IV) in a randomized trial involving 72 patients with hypercalcemia of malignancy [41]. The number of patients responding to both agents was similar (77 and 76 percent for ibandronate and pamidronate, respectively) but the median time until the serum calcium began to rise again was significantly longer with ibandronate (14 versus 4 days). However, four days is an unusually short duration of effect for pamidronate and may reflect inadequate dosing or the small size of the clinical trial.
Clodronate and etidronate — Clodronate and etidronate are first generation bisphosphonates that were introduced over 20 years ago. They are relatively weak inhibitors of bone resorption compared with the newer agents. Clodronate is widely available outside the United States.
In randomized trials of patients with multiple myeloma or metastatic breast cancer, the administration of oral clodronate to decrease skeletal complications was associated with fewer episodes of severe hypercalcemia. (See "The use of bisphosphonates in patients with multiple myeloma", section on 'Oral bisphosphonates' and "Overview of the use of osteoclast inhibitors in early breast cancer".)
However, the poor oral bioavailability of clodronate, the size of the tablets, and the need to take them on an empty stomach with nothing to eat for one hour afterward increases the risk of noncompliance [22]. As a result, IV clodronate is often preferred at the onset of therapy [42], with oral clodronate being used for maintenance therapy.
When used for treatment of malignancy-associated hypercalcemia, etidronate must be given intravenously (7.5 mg/kg in 250 mL of saline over four hours) for at least three consecutive days [16-18]. Prolonging treatment to five days increases responsiveness from 60 percent to almost 100 percent of patients. Other effective treatment schedules include a single 24-hour infusion (30 mg/kg) or 4.3 mg/kg IV daily for seven consecutive days [43,44]. Serum calcium levels may not decrease until approximately four days after treatment is started.
Prolonged administration of etidronate has been associated with hyperphosphatemia due to increased tubular reabsorption of phosphate. The dose of etidronate should be reduced by 50 percent in patients with impaired renal function because it is excreted in the urine.
The inconvenience of prolonged intravenous treatment and the relatively weak potency has diminished the utility of etidronate, and it is not generally recommended unless other bisphosphonates are not available [23].
Side effects and precautions — Although intravenous bisphosphonates are generally well tolerated, side effects may include flu-like symptoms (fever, arthralgias, myalgia, fatigue, bone pain), ocular inflammation (uveitis), hypocalcemia, hypophosphatemia, impaired renal function, nephrotic syndrome, and osteonecrosis of the jaw [45,46]. These side effects are discussed in detail elsewhere; the incidence varies somewhat with the indication for use due in part to the higher doses used in cancer patients compared to those with osteoporosis. (See "Risks of therapy with bone modifying agents in patients with advanced malignancy" and "The use of bisphosphonates in postmenopausal women with osteoporosis", section on 'Adverse effects'.)
Dosing in renal impairment — As mentioned in the preceding section, bisphosphonates have potential nephrotoxicity. A separate issue is dosing of bisphosphonates in patients with underlying renal disease.
In clinical trials of ZA for the treatment of hypercalcemia of malignancy, patients with serum creatinine concentrations as high as 4.5 mg/dL (400 micromol/L) were eligible for participation [21]. In addition, there are case reports of successful use of ibandronate and pamidronate for patients with renal failure and multiple myeloma [47], renal insufficiency (creatinine ≥1.5 mg/dL [133 micromol/L]) [48], and in hemodialysis patients with severe hypercalcemia [49,50]. However, we suggest caution when using intravenous bisphosphonates to treat hypercalcemia in patients with impaired renal function (creatinine >4.5 mg/dL). Adequate hydration with saline and treatment with a reduced dose and/or slower infusion rate (4 mg ZA over 30 to 60 minutes, 30 to 45 mg pamidronate over four hours, 2 mg ibandronate over one hour) may minimize risk.
GLUCOCORTICOIDS — Increased absorption of dietary calcium is primarily, but not completely, responsible for the hypercalcemia associated with the excess administration or ingestion of vitamin D, or with the endogenous overproduction of calcitriol (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D). Increased calcitriol production can occur in patients with chronic granulomatous diseases (eg, sarcoidosis) and in occasional patients with lymphoma. In such patients, glucocorticoids (eg, prednisone in a dose of 20 to 40 mg/day) will usually reduce serum calcium concentrations within two to five days by decreasing calcitriol production by the activated mononuclear cells in the lung and lymph nodes. (See "Hypercalcemia in granulomatous diseases".)
GALLIUM NITRATE — The calcium-lowering effects of gallium nitrate were initially discovered when hypocalcemia developed in patients undergoing gallium imaging who previously had normal serum calcium levels [51]. Gallium inhibits osteoclastic bone resorption, in part via inhibition of an ATPase dependent proton pump on the osteoclast ruffled membrane, without being directly cytotoxic or acting as a metabolic toxin to bone cells [52]. Gallium also inhibits PTH secretion from parathyroid cells in vitro [53].
Unlike bisphosphonates, gallium appears to be effective in both PTHrP-mediated, and non-PTHrP-mediated hypercalcemia [51,54-56]. Preliminary data from clinical trials indicated that it is more potent than etidronate, pamidronate, and calcitonin alone [54-56].
The efficacy of gallium was more rigorously examined in a trial of 64 patients with malignancy-associated hypercalcemia (serum calcium ≥12 mg/dL [3 mmol/L] after intravenous hydration) [56]. Patients were randomly assigned to daily intravenous gallium nitrate (200 mg/m2) daily for five days or pamidronate (60 mg, or 90 mg if initial calcium ≥13.5 mg/dL [3.8 mmol/L]) for one day followed by four days of placebo infusions.
Normocalcemia (serum calcium ≤10.5 mg/dL [2.7 mmol/L]) was achieved within 10 days in 69 and 56 percent of the gallium and pamidronate treated patients, respectively, and the estimated duration of normocalcemia in responders was 14 and 10 days, respectively. The disadvantages of gallium include its potential for nephrotoxicity, and the need for continuous infusion over five days [57]. Therefore, for the treatment of hypercalcemia due to excessive bone resorption, we prefer to use bisphosphonates rather than gallium nitrate.
OTHER THERAPIES
Calcimimetics — Primary hyperparathyroidism is the most common outpatient cause of hypercalcemia. The elevation in serum calcium is usually mild and treatment is typically directed at correcting the hyperparathyroidism. (See "Management of primary hyperparathyroidism".)
However, a calcimimetic agent (only cinacalcet is currently available) reduces the serum calcium concentration in patients with severe hypercalcemia due to parathyroid carcinoma and in hemodialysis patients with an elevated calcium-phosphorous product and secondary hyperparathyroidism. Calcimimetics have also been evaluated in patients with primary hyperparathyroidism, but are not standard therapy. (See "Parathyroid carcinoma", section on 'Calcimimetics' and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients", section on 'Calcimimetics' and "Management of primary hyperparathyroidism", section on 'Calcimimetics'.)
Dialysis — Hemodialysis with little or no calcium in the dialysis fluid and peritoneal dialysis (though it is slower) are both effective therapies for hypercalcemia, and are considered treatments of last resort. Dialysis may be indicated in patients with severe malignancy-associated hypercalcemia and renal insufficiency or heart failure, in whom hydration cannot be safely administered [58].
The use of hemodialysis for patients with hypercalcemia but without renal failure may require alterations in the composition of conventional dialysis solutions in order to avoid an exacerbation or induction of other metabolic abnormalities, particularly hypophosphatemia. As an example, hemodialysis with a dialysis solution enriched with phosphorus (final phosphorous concentration of 4 mg/dL) resulted in rapid correction of all abnormalities in one patient in whom medical therapy had failed to reverse hypercalcemia, mental status changes, and hypophosphatemia due to primary hyperparathyroidism [59].
PREFERRED APPROACH
Mild hypercalcemia — Patients with asymptomatic or mildly symptomatic hypercalcemia (calcium <12 mg/dL [3 mmol/L]) do not require immediate treatment. However, they should be advised to avoid factors that can aggravate hypercalcemia, including thiazide diuretics and lithium carbonate therapy, volume depletion, prolonged bed rest or inactivity, and a high calcium diet (>1000 mg/day). Adequate hydration (at least six to eight glasses of water per day) is recommended to minimize the risk of nephrolithiasis. Additional therapy depends mostly upon the cause of the hypercalcemia. (See 'Other' below.)
Moderate hypercalcemia — Asymptomatic or mildly symptomatic individuals with chronic moderate hypercalcemia (calcium between 12 and 14 mg/dL [3 to 3.5 mmol/L]) may not require immediate therapy. However, they should follow the same precautions described above for mild hypercalcemia.
It is important to note that an acute rise to these concentrations may cause marked changes in sensorium, which requires more aggressive therapy. In these patients, we typically treat with saline hydration and bisphosphonates, as described for severe hypercalcemia (below).
Severe hypercalcemia — Patients with calcium >14 mg/dL (3.5 mmol/L) require more aggressive therapy. The acute therapy of such patients consists of a three-pronged approach [1,2,11]:
- Volume expansion with isotonic saline at an initial rate of 200 to 300
mL/hour that is then adjusted to maintain the urine output at 100 to 150
mL/hour. (See 'Saline hydration' above.)
In the absence of renal failure or heart failure, loop diuretic therapy to directly increase calcium excretion is not recommended because of potential complications and the availability of drugs that inhibit bone resorption, which is primarily responsible for the hypercalcemia. - Administration of salmon calcitonin (4 international units/kg) and repeat measurement of serum calcium in several hours. If a hypocalcemic response is noted, then the patient is calcitonin-sensitive and the calcitonin can be repeated every 6 to 12 hours (4 to 8 international units/kg). We typically administer calcitonin (along with a bisphosphonate) in patients with calcium >14 mg/dL who are also symptomatic.
- The concurrent administration of zoledronic acid (4 mg IV over 15 minutes) or pamidronate (60 to 90 mg over two hours), preferably zoledronic acid, because it is superior to pamidronate in reversing hypercalcemia related to malignancy.
The administration of calcitonin plus saline should result in substantial reduction in serum calcium concentrations within 12 to 48 hours. The bisphosphonate will be effective by the second to fourth day, thereby maintaining control of the hypercalcemia.
Follow-up therapy is aimed at preventing recurrence of hypercalcemia. In patients with hypercalcemia of malignancy, progressive hypercalcemia will inevitably accompany tumor progression, and therefore the underlying disease causing the hypercalcemia should be treated, if at all possible. Many patients with malignancy may also have metastatic bone disease and will receive intravenous ZA or pamidronate every three to four weeks as part of their treatment to prevent skeletal complications. As a result, recurrent hypercalcemia will be prevented.
Additional, more aggressive measures are necessary in the rare patient with very severe, symptomatic hypercalcemia. Hemodialysis should be considered, in addition to the above treatments, in patients who have serum calcium concentrations in the range of 18 to 20 mg/dL (4.5 to 5 mmol/L) and neurologic symptoms but a stable circulation.
Other — The modalities described above apply in varying degrees to patients with all causes of hypercalcemia. The treatment of some disorders is discussed in detail in other topic reviews. Summarized briefly:
- Hyperparathyroidism is the most common outpatient cause of mild hypercalcemia. The treatment is typically directed at correcting the hyperparathyroidism or monitoring for complications of primary hyperparathyroidism. (See "Management of primary hyperparathyroidism".)
- Patients with lymphoma, sarcoidosis or other granulomatous causes of hypercalcemia have enhanced intestinal calcium absorption due to increased endogenous calcitriol production. The major modalities of therapy are a low calcium diet, corticosteroids, and treatment of the underlying disease. (See "Hypercalcemia in granulomatous diseases".)
- Hypercalcemia due to ingestion of calcitriol as treatment for hypoparathyroidism or for the hypocalcemia and hyperparathyroidism of renal failure usually lasts only one to two days because of the relatively short biologic half-life of calcitriol. Thus,
stopping the calcitriol, increasing salt and fluid intake, or perhaps hydration with intravenous saline may be the only therapy that is needed.
Hypercalcemia caused by vitamin D or calcidiol lasts longer, so that more aggressive therapy such as glucocorticoids and pamidronate may be necessary [29]. - Hypercalcemia is typically not treated in patients with familial hypocalciuric hypercalcemia because the elevation in serum calcium is typically mild and produces few if any symptoms. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
SUMMARY AND RECOMMENDATIONS
- Patients with asymptomatic or mildly symptomatic hypercalcemia (calcium <12 mg/dL [3 mmol/L]) do not require immediate treatment. However, they should be advised to avoid factors that can aggravate hypercalcemia, including thiazide diuretic and lithium carbonate therapy, volume depletion, prolonged bed rest or inactivity, and a high calcium diet (>1000 mg/day). (See 'Preferred approach' above.)
- Asymptomatic or mildly symptomatic individuals with chronic moderate hypercalcemia (calcium between 12 and 14 mg/dL [3 to 3.5 mmol/L]) may not require immediate therapy. However, an acute rise to these levels may cause gastrointestinal side effects and changes in sensorium, which requires treatment as described for severe hypercalcemia. (See 'Moderate hypercalcemia' above.)
- Patients with more severe (calcium >14 mg/dL [3.5 mmol/L]) or symptomatic hypercalcemia are usually dehydrated and require saline hydration as initial therapy. A reasonable regimen is the administration of isotonic saline at an initial rate of 200 to 300 mL/hour that is then adjusted to maintain the urine output at 100 to 150 mL/hour. (See 'Saline hydration' above.)
- In patients with hypercalcemia receiving saline hydration, we suggest not routinely using a loop diuretic (Grade 2C). However, in individuals with renal insufficiency or heart failure, careful monitoring and judicious use of loop diuretics may be required to prevent fluid overload. (See 'Saline hydration' above.)
- For immediate short-term management of hypercalcemia, we suggest administration of calcitonin (in addition to saline hydration) only in patients with calcium >14 mg/dL (3.5 mmol/L) who are also symptomatic (Grade 2B). (See 'Calcitonin' above.)
- For longer-term control of hypercalcemia in patients with more severe (calcium >14 mg/dL) or symptomatic hypercalcemia due to excessive bone resorption, we suggest the addition of a bisphosphonate rather than gallium nitrate (Grade 2B). (See 'Bisphosphonates' above and 'Gallium nitrate' above.)
- Among intravenous bisphosphonates, we suggest zoledronic acid (Grade 2B). Pamidronate is an alternative option when zoledronic acid is not available. (See 'Bisphosphonates' above.)
- Glucocorticoids are effective in treating hypercalcemia due to some lymphomas, sarcoid, or other granulomatous diseases. (See 'Glucocorticoids' above.)
- Dialysis is generally reserved for those with severe hypercalcemia. (See 'Severe hypercalcemia' above.)
REFERENCES
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Zalman S Agus, MD
Stanley Goldfarb, MD
Mitchell Geffner, MD
John P Forman, MD, MSc
INTRODUCTION — The plasma (or serum) calcium concentration measured in the laboratory is usually reported in units of mg/dL in the United States, in mmol/L in many other countries, and in meq/L in some laboratories. The relationship between these units is defined by the following equations:
mmol/L = [mg/dL x 10] ÷ mol wt
meq/L = mmol/L x valence
Since the molecular weight of calcium is 40 and the valence is +2, 1 mg/dL is equivalent to 0.25 mmol/L and to 0.5 meq/L. Thus, the normal range of total serum calcium concentration of 8.8 to 10.3 mg/dL is equivalent to 2.2 to 2.6 mmol/L and 4.4 to 5.2 meq/L.
DETERMINANTS OF THE SERUM CALCIUM CONCENTRATION — The total serum calcium concentration consists of three fractions [1,2]:
- Approximately 15 percent is bound to multiple organic and inorganic anions such as sulfate, phosphate, lactate, and citrate.
- Approximately 40 percent is bound to albumin in a ratio of 0.8 mg/dL (0.2 mmol/L or 0.4 meq/L) of calcium per 1.0 g/dL (10 g/L) of albumin.
- The remaining 45 percent circulates as physiologically active ionized (or free) calcium. The ionized serum calcium concentration is tightly regulated by parathyroid hormone and vitamin D, and can be modified by a variety of factors. (See 'Change in ionized fraction but not total calcium' below.)
The wide range in the normal total serum calcium concentration is probably due to variations in the serum concentration of albumin among normal healthy individuals and occasionally to variations in the state of hydration that can alter the serum albumin concentration.
Thus, measurement of the total serum calcium concentration alone is sometimes misleading, since this parameter can change without affecting the concentration of ionized calcium [3]. In addition, the ionized fraction can change without an alteration in the total serum calcium concentration.
Change in total but not ionized calcium — An abnormal total serum calcium concentration in the absence of an abnormal ionized calcium concentration can occur in patients with hypoalbuminemia, hyperalbuminemia, and multiple myeloma. If the total serum calcium is low but the ionized calcium is normal, it is called pseudohypocalcemia. If the total serum calcium is high in the setting of a normal ionized calcium, it is called pseudohypercalcemia.
Hypoalbuminemia — The total serum calcium concentration will change in parallel to the albumin concentration. Thus, hypoalbuminemia due to hepatic or renal disease is associated with hypocalcemia. In comparison, globulins only minimally bind calcium and changes in the globulin level are usually not associated with changes in the calcium concentration with the occasional exception of marked hyperglobulinemia in multiple myeloma.
In general, the serum calcium concentration falls by 0.8 mg/dL (0.2 mmol/L) for every 1.0 g/dL (10 g/L) fall in the serum albumin concentration. Thus, the measured serum calcium concentration can be corrected for the presence of hypoalbuminemia from the following equation:
Corrected [Ca] = Measured total [Ca] + (0.8 x (4.5 - [alb]))
where the serum calcium and albumin concentrations are measured in units of mg/dL and g/dL, respectively. A calculator is available to correct the calcium concentration for hypoalbuminemia using mg/dL (calculator 1), and mmol/L (calculator 2). As an example, if the measured values for total serum calcium and albumin are 7.6 mg/dL and 2.5 g/dL, respectively, then:
Corrected [Ca] = 7.6 + (0.8 x 2) = 9.2 mg/dL
Hyperalbuminemia — An elevation in serum albumin, leading to a rise in serum calcium, can be induced by extracellular volume depletion or by fluid movement out of the vascular space due, for example, to a tight tourniquet [4]. Hyperalbuminemia has also been reported in athletes who consume very high protein diets (more than 2 g of protein per kg of body weight per day) [5].
Multiple myeloma — Myeloma can induce pseudohypercalcemia by a mechanism other than hyperalbuminemia. Rarely, a monoclonal myeloma protein binds calcium with high affinity, potentially leading to a marked elevation in the total serum calcium concentration [6-8]. The absence of hypercalcemic symptoms is the major clue suggesting that the ionized fraction is normal in this setting and that therapy aimed at correcting the hypercalcemia is not indicated.
The hyperproteinemia in myeloma can also cause a spurious elevation in the serum phosphate concentration [9]. The mechanism is uncertain but may involve interference with the normal assay used to measure to serum phosphate concentration.
Change in ionized fraction but not total calcium — Physiologically important changes in the ionized calcium concentration may occur without an alteration in the total serum calcium concentration.
Acid-base disorders — Acid-base disorders can lead to changes in the ionized calcium concentration. An elevation in extracellular pH (alkalemia) increases the binding of calcium to albumin, thereby lowering the serum ionized calcium concentration [10]. The fall in ionized calcium with acute respiratory alkalosis is approximately 0.16 mg/dL (0.04 mmol/L or 0.08 meq/L) for each 0.1 unit increase in pH [10]. Thus, acute respiratory alkalosis, as in the hyperventilation syndrome, can induce symptoms of hypocalcemia, including cramps, paresthesias, tetany, and seizures although the alkalosis is likely to be of primary importance. The same relationship is true in vitro when the pH is changed in specimens of whole blood or serum [11].
There is also a significant fall in the ionized calcium concentration in chronic respiratory alkalosis. However, the fall in ionized calcium in this setting is not due to increased calcium binding, since the renal adaptation lowers the serum bicarbonate concentration and minimizes the rise in extracellular pH. The hypocalcemia in this setting is due both to relative hypoparathyroidism and to renal resistance to PTH, with resultant hypercalciuria [12]. Why these changes occur is not well understood. (See "Simple and mixed acid-base disorders".)
In chronic metabolic acidosis, the increase in ionized calcium due to less albumin binding may not be recognized by measurement of total calcium concentrations [13,14]. In one study, for example, the total serum calcium underestimated the diagnosis of hypercalcemia in incident renal transplant recipients [14]. This was explained primarily by the high prevalence of metabolic acidosis in these patients.
The binding of calcium to albumin that is induced by an elevation in extracellular pH may be important in patients with severe chronic kidney disease who often have both hypocalcemia and metabolic acidosis, which will tend to raise the ionized calcium concentration. Treatment of the metabolic acidosis with bicarbonate therapy or dialysis can lower the ionized calcium concentration [15,16], which may exacerbate preexisting hypocalcemia and precipitate symptoms such as tetany [16].
Parathyroid hormone — Parathyroid hormone (PTH) may decrease the binding of calcium to albumin and therefore increase ionized calcium at the expense of the protein-bound fraction, resulting in an increased ratio of ionized to total calcium in patients with elevated levels of PTH [17]. On the other hand, the sensitivities of ionized and total calcium concentrations in the diagnosis of primary hyperparathyroidism were identical in a large cohort of patients [18], suggesting that this effect of PTH on protein binding of calcium does not have diagnostic implications. (See "Diagnosis and differential diagnosis of primary hyperparathyroidism", section on 'Normocalcemic primary hyperparathyroidism'.)
Hyperphosphatemia — Acute hyperphosphatemia (as with phosphate release from cells due to a marked increase in cell breakdown) can reduce the ionized serum calcium concentration by binding to circulating calcium. The total serum calcium concentration will also fall in a short period of time as the calcium-phosphate precipitates and is deposited in soft tissues. (See "Etiology of hypocalcemia in adults".)
MEASURING THE SERUM CALCIUM IN PATIENTS WITH CKD — In patients with a reduced glomerular filtration rate (GFR less than 60 mL/min per 1.73m2), the total serum calcium concentration does not reliably predict the ionized calcium concentration, even if the total serum calcium is corrected for a low serum albumin [13,14]. This was best shown in 691 consecutive patients with CKD who had simultaneous measurement of total serum calcium, ionized calcium, and serum albumin [13]. The total serum calcium failed to identify 44 of the 109 (40 percent) patients who had low ionized calcium levels, and also failed to identify 6 of the 28 (21 percent) patients who had a high ionized calcium. In addition, 11 percent of patients with normal ionized calcium concentrations were mistakenly identified as having either hypocalcemia or hypercalcemia by using the total serum calcium. Correcting the total calcium for the serum albumin did not substantially improve the reliability of the total serum calcium.
Two major factors contributed to the unreliability of the total serum calcium [13]:
- Patients with CKD often have metabolic acidosis, which can lead to an underestimate of the ionized calcium concentration when only the total serum calcium is measured. (See 'Acid-base disorders' above.)
- The standard equations used to correct for a low serum albumin frequently overestimated the ionized calcium.
Thus, in patients with reduced GFR who have a low serum bicarbonate and/or a low serum albumin, measuring the ionized calcium is preferable to measuring the total calcium in order to diagnose hypocalcemia or hypercalcemia.
SUMMARY
- The total serum calcium concentration consists of three fractions: (See 'Determinants of the serum calcium concentration' above.)
- 15 percent is bound to organic and inorganic anions.
- 40 percent is bound to albumin.
- 45 percent is physiologically active ionized (or free) calcium.
- Measurement of the total serum calcium concentration alone is sometimes misleading, since this parameter can change without affecting the concentration of ionized calcium, such as with:
- Hypoalbuminemia, because a large fraction of calcium circulates bound to albumin. The total serum calcium can be adjusted for the concentration of albumin using the following equation: (See 'Hypoalbuminemia' above.)
Corrected [Ca] = Measured total [Ca] + (0.8 x (4.5 - [alb])) (calculator 1 and calculator 2) - Hyperalbuminemia, as may occur with extracellular volume depletion or by fluid movement out of the vascular space due to a tight tourniquet, and can also result from a very high protein diet.
- Some cases of multiple myeloma, in which calcium binds to the monoclonal immunoglobulin. (See 'Multiple myeloma' above.)
- The ionized fraction can change without an alteration in the total serum calcium concentration, as with:
- Acid-base disorders, in which an increase in blood pH may enhance binding of calcium to albumin, thereby decreasing the ionized fraction. (See 'Acid-base disorders' above.)
- Hyperparathyroidism, which increases the ionized calcium at the expense of that bound to albumin. (See 'Parathyroid hormone' above.)
- Hyperphosphatemia, which increases the fraction bound to inorganic anions, decreasing ionized calcium. (See 'Hyperphosphatemia' above.)
- In patients who have CKD and a low serum bicarbonate, a low serum albumin, or both, measuring the ionized calcium is preferable to measuring the total calcium in order to diagnose hypocalcemia or hypercalcemia. (See 'Measuring the serum calcium in patients with CKD' above.)
REFERENCES