Chapter 6. Disorders of Calcium Balance: Hypercalcemia & Hypocalcemia

Essentials of Diagnosis

• Hypercalcemia is usually manifested as a chronic but mildly elevated serum calcium level, although more severe forms that present as hypercalcemic emergencies do exist.
• The symptoms associated with sustained hypercalcemia are relatively nonspecific, but the constellation of symptoms often suggests the diagnosis.
• A combination of neuropsychiatric complaints such as depression, anxiety, cognitive dysfunction, headache, fatigue and even organic brain syndrome, renal complaints including polyuria, polydipsia, nephrogenic diabetes insipidus, nephrolithiasis, nocturia, and renal insufficiency, and gastrointestinal complaints such as constipation, peptic ulcer disease, or a diagnosis of acute pancreatitis would strongly suggest the diagnosis.
• Most patients with hypercalcemia are diagnosed based on data derived from laboratory screening tests.
• The signs and symptoms associated with the underlying disease causing hypercalcemia may dominate the clinical picture.

General Considerations

Calcium in serum exists ionized, bound to organic anions such as phosphate and citrate, and bound to proteins (mainly albumin). Of these, ionized calcium is the physiologically important form. The most common abnormality that distorts the relationship between serum calcium and ionized calcium is hypoalbuminemia. The total serum calcium is lower or higher by 0.8 mg/dL (0.2 mmol/L) for every 1.0 g/dL that the serum albumin is higher or lower, respectively, than 4 g/dL. Thus, patients may have a normal serum ionized calcium but low total calcium if they have hypoalbuminemia due to nephrotic syndrome. Conversely, a patient can have high total calcium, with normal ionized calcium and increased total protein and/or albumin, as in states of severe dehydration.

Hypercalcemia is one of the most common metabolic disorders in malignant diseases and develops in 3–30% of such patients. Hypercalcemia of malignancy is the most common cause of hypercalcemia followed by primary hyperparathyroidism in hospital populations. The most common cause in normal populations is primary hyperparathyroidism followed by transient hypercalcemia.

Pathogenesis

Hypercalcemia can result from increased bone resorption, decreased renal excretion, or increased gastrointestinal absorption. However, bone resorption and intestinal hyperabsorption of calcium are the predominant causes of hypercalcemia. Reduced renal excretion is a permissive factor in all cases of hypercalcemia as in the absence of renal conservation of calcium, any rise in serum calcium would result in the excretion of any excess in the urine and hypercalciuria but not hypercalcemia would ensue.

Typically, the mechanism underlying hypercalcemia is complex and multifactorial. In primary hyperparathyroidism, all three components come into play. High parathyroid hormone (PTH) levels induce bone resorption, increase renal tubular reabsorption, and secondarily increase gastrointestinal calcium absorption as PTH stimulates production of the most active form of vitamin D, calcitriol.

PTH is the master hormone regulating overall calcium metabolism. It is an 84-amino acid hormone that in response to a fall in serum calcium levels raises calcium levels by accelerating osteoclastic bone resorption and increasing renal tubular resorption of calcium. It also increases calcitriol, which indirectly raises serum calcium levels. PTH also induces an increased renal excretion of phosphate. This effect helps to enhance the rise in serum calcium as phosphate tends to coprecipitate with calcium and block the effects of PTH on bone and the effects of PTH on inducing the activation of vitamin D by the kidney.

In primary hyperparathyroidism, there is a fundamental dysregulation of PTH secretion. Normally, the calcium-sensing receptor on the surface of cells in the parathyroid gland senses serum calcium and the release of PTH follows a sigmoidal relationship concentration (see Figure 6–1). The “set point” of this relationship is the serum calcium concentration at which there is half-maximal inhibition of PTH secretion. As seen in Figure 6–1, this relationship is disrupted in primary hyperparathyroidism so that PTH is released even in the face of normally suppressive levels of serum calcium.

Vitamin D is a steroid hormone that may be ingested with the diet but is also produced in the skin by the action of sunlight on metabolic antecedents of vitamin D. Calcitriol, the active form of vitamin D, is derived from the hydroxylation of cholecalciferol, which is first hydroxylated in the liver to 25-hydroxyvitamin D, then in the kidneys to 1,25-dihydroxyvitamin D. Vitamin D has a plethora of actions including altering the growth dynamics of many cell types. Its actions to increase serum calcium are complex and include an increase in the transport of calcium across the gastrointestinal (GI) tract and an increase in calcium release from bone during PTH-induced bone resorption. In the absence of PTH, the GI effect in concert with adequate dietary calcium can maintain normal serum calcium levels and with pharmacologic doses of vitamin D, even induce hypercalcemia.

PTH-related peptide (PTHrP) is the principal mediator in hypercalcemia associated with solid tumors. Patients with humoral hypercalcemia of malignancy (HHM) constitute about 80% of all patients with hypercalcemia associated with malignancy. PTHrP and PTH share the same molecular region that comprises the receptor-binding domain at the amino terminus. PTHrP binds the PTH receptor and mimics the biologic effects of PTH on bones and the kidneys. PTHrP and PTH share the same receptor, but there are some differences in actions. HHM patients have a greater degree of hypercalciuria than is generally seen in hyperparathyroidism. HHM is usually associated with low serum calcitriol levels, whereas PTH stimulates calcitriol production. Also, PTH stimulates bone resorption and formation, whereas PTHrP stimulates only bone resorption, with very low osteoblastic activity, and thus usually normal alkaline phosphatase levels.

Bone resorption is a key mechanism underlying most cases of hypercalcemia. The skeleton is continually renewed through remodeling, a sequence of events whereby old bone is replaced by new bone (bone turnover). Three types of cells produce and maintain bone. Osteoblasts act at bone surfaces by secreting osteoid, unmineralized collagen, and modulate the crystallization of hydroxyapatite and influence the activity of osteoclasts. Osteoclasts are responsible for the resorption of bone, a process that is necessary for the repair of bone surfaces and the remodeling of bone. Osteocytes are osteoblasts that have become embedded within the mineralized regions of bone.

During bone growth, formation is higher than breakdown. After peak bone mass is achieved, the rates of breakdown and formation are equal and bone mass is thought to remain constant. In hypercalcemic states associated with excess PTH, PTHrP, and other bone-active cytokines, the rate of breakdown increases and exceeds the rate at which bone is formed. If this is coupled with inadequate renal excretion, then hypercalcemia ensues.

Clinical Findings

Primary Hyperparathyroidism

Symptoms and Signs

Primary hyperparathyroidism, the most common cause of hypercalcemia in the outpatient setting, is usually found by routine laboratory screening, as most patients with primary hyperparathyroidism are asymptomatic. When patients are symptomatic, findings may include renal calculi, bone pain, pathologic fractures, and proximal muscle weakness, or nonspecific symptoms such as depression, lethargy, and vague aches and pains. Rarely, full blown psychiatric disorders may be seen. Occasional patients may have a family history of multiple endocrine neoplasia syndromes (type 1 or 2) or a history of preceding head and neck irradiation as a child or an adult for hyperthyroidism treated with radiation modalities. Mental obtundation or coma is an infrequent but life-threatening complication of severe hypercalcemia (hypercalcemic crisis). All patients with calcium-containing renal stones should be evaluated for primary hyperparathyroidism.

Laboratory Findings

Primary hyperparathyroidism is usually diagnosed by demonstrating persistent hypercalcemia in the presence of inappropriately normal or elevated PTH concentrations. Normally, PTH levels are suppressed in the presence of increasing serum calcium levels. Immunoassay of the intact PTH molecule is the preferred method of measurement. Primary hyperparathyroidism may present at an early stage with minimal increases in the serum calcium level in the face of normal or mildly elevated PTH levels. The intact PTH assay uses antibodies to two sites simultaneously (N- and C-terminal) to measure the intact hormone. The normal range for this assay is 18–65 pg/mL. Intact PTH is increased in 80–90% of patients with primary hyperparathyroidism while 10–20% have values in the normal range but that are inappropriately high in the face of hypercalcemia. The intact PTH assay provides good discrimination between parathyroid and nonparathyroid causes of hypercalcemia. This diagnosis should be suspected in patients with renal calculi or reduced bone density who have minimally increased PTH levels and high-normal serum calcium levels (normocalcemic primary hyperparathyroidism). Other findings include mild hypophosphatemia, hypercalciuria, and mild metabolic acidosis as PTH acts on the kidney to promote phosphate and bicarbonate excretion.

Imaging Studies

If a parathyroid adenoma is suspected, the parathyroid glands can be imaged using nuclear medicine techniques. This procedure is based on the differential uptake between normal and abnormal parathyroid glands of the tumor-seeking compound sestamibi, labeled with 99mTc. This material is taken up by both the thyroid and parathyroids and is cleared rapidly from normal tissue but is retained in tumors of the parathyroids. Surgical exploration and the removal of the adenomatous gland constitute the treatment of choice for many patients. Preoperative imaging may not always be necessary since the success rate for parathyroid surgery has been reported to exceed 90%, even in the absence of prior imaging. Localization techniques are more useful in cases of failed primary neck exploration and in cases of postoperative persistent hypercalcemia.

Familial Hypocalciuric Hypercalcemia

Familial hypocalciuric hypercalcemia is characterized by benign asymptomatic hypercalcemia. It is an autosomal dominant condition in which the genetic abnormality leads to a loss of function mutation of the calcium-sensing receptor that exists on the c-cells of the parathyroid glands. This inactive receptor necessitates higher serum calcium levels in order to suppress PTH. Because the calcium-sensing receptor also exists within the kidney and regulates calcium reabsorption in the thick ascending loop of Henle, the defect in the protein structure leads to increased renal tubular calcium reabsorption and reduced excretion. Apparently many of the symptoms associated with hypercalcemia require activation of the calcium-sensing receptor as patients with this condition are remarkably free of symptoms. It is therefore important to inquire about familial hypercalcemia in any hypercalcemic patients and to assess urinary calcium excretion.

Laboratory Findings

Strikingly low urinary calcium excretion (<100 mg/24 hours) is seen in the majority of patients, despite hypercalcemia and iPTH levels in the normal range in 80–85% of patients.

Hypercalcemia of Malignancy

Hypercalcemia of malignancy occurs in 10–20% of patients with cancer and the hypercalcemia is usually severe and of relatively short duration. The tumors that manifest in this disorder most commonly are breast, lung cancer, and multiple myeloma. The condition is induced by a number of humoral mediators: PTHrP is the most common and is found in 80–90% of cases and in both carcinomas and lymphomas. In multiple myeloma, the mediator is osteoclast-activating factor. In those patients with Hodgkin's disease and a substantial fraction of those with non-Hodgkin's lymphomas who develop hypercalcemia, high levels of calcitriol are found. The malignant cells are capable of enzymatically activating 25-hydroxyvitamin D to its more active metabolite calcitriol. In patients with osteolytic metastases, a variety of cytokines released by the tumor cells including tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and PTHrP may each lead to activation of bone resorption and, ultimately, hypercalcemia.

Laboratory Findings

Generally, patients with HHM manifest higher levels of serum calcium than those with primary hyperparathyroidism. Also, serum phosphate and bicarbonate levels tend to be higher. However, specific laboratory tests are rarely required for the diagnosis of HHM since patients with malignancy almost always have other signs or symptoms of their malignancy when hypercalcemia is found. However, assays for iPTH and for PTHrP are available and finding an elevated PTHrP is specific for HHM.

Granulomatous Diseases

Hypercalcemia occurs in most granulomatous disorders. High serum calcium levels are seen in about 10% of patients with sarcoidosis; hypercalciuria is about three times more frequent. Tuberculosis, fungal diseases including histoplasmosis, cocidioidomycosis, and berylliosis, and some lymphomas, particularly those associated with human immunodeficiency viruses, are other conditions that are associated with disorders of calcium metabolism. These abnormalities of calcium metabolism are due to production of calcitriol by activated macrophages either in pulmonary alveoli or in granulomatous inflammation. Macrophages have the enzymatic capacity to convert 25-hydroxyvitamin D3 to calcitriol. As this condition is associated with suppressed PTH levels, hypercalciuria is a prominent feature of this form of hypercalcemia.

Milk-Alkali Syndrome

The milk-alkali syndrome became rare with the advent of modern gastric ulcer therapy with antibiotics. However, the growing popularity of the use of calcium carbonate as an antacid or as calcium supplementation to prevent osteoporosis has led to a reappearance of this problem. Patients with this syndrome typically ingest massive quantities of calcium and absorbable alkali and are unaware of the toxic effects of these compounds. They present with the triad of hypercalcemia, metabolic alkalosis, and renal failure that is occasionally so severe that dialysis is necessary. The serum parathyroid hormone or calcitriol levels are appropriately decreased in response to the hypercalcemia. Since both physicians and patients are often unaware of the calcium and alkali content of many nonprescription medicines, the diagnosis of the milk-alkali syndrome, a reversible cause of renal failure, can be missed if a detailed history of such intake is not elicited.

Medication-Induced Hypercalcemia

Vitamin D usage is an important cause of hypercalcemia. To diagnose vitamin D intoxication, it is necessary to consider it in the differential diagnosis and obtain a history of vitamin D intake in patients with hypercalcemia, azotemia, and anemia. The renal disease is reversible if the use of vitamin D is stopped. Hypervitaminosis D is characterized by high serum levels of 25-hydroxyvitamin D, hypercalcemia, hypercalciuria, and hyperphosphatemia but normal levels of calcitriol and suppressed parathyroid hormone. The pattern of vitamin D metabolites seen is the result of unregulated production of 25-hydroxyvitamin D but inhibition of activity of the renal 1-hydroxylase enzyme in the face of suppressed PTH and hyperphosphatemia.

Thiazide diuretics increase renal calcium reabsorption and may cause mild hypercalcemia. Typically, hypercalcemia induced by thiazide diuretic therapy unmasks other underlying disorders that predispose to hypercalcemia including primary hyperparathyroidism and vitamin D usage. Lithium use can cause hypercalcemia by increasing the calcium set point for secretion of PTH requiring a higher serum calcium level to suppress PTH secretion. Large doses of vitamin A and its analogs, including Retin-A, the antiacne agent, can cause hypercalcemia, which appears to be mediated through increased bone resorption.

Immobilization

Immobilization leads to an increase in bone resorption. Bone mineral density tests have shown evidence of bone resorption from prolonged immobilization after a variety of diseases including spinal injury and stroke. The mechanism is unknown and hypercalcemia usually develops after 4 weeks of immobilization. Hypercalciuria may result from the combination of hypercalcemia and suppressed PTH secretion may attenuate hypercalcemia and even maintain normocalcemia. In fact, patients can have a negative calcium balance as a result of urine calcium losses, which can last for months. If an impairment in renal function occurs, however, hypercalcemia may ensue. Children are at particular risk from this complication.

Differential Diagnosis

If hypercalcemia is detected on a routine screening test, then the approach to diagnosis is to first exclude familial hypocalciuric hypercalcemia (FHH) with a careful family history looking for a pattern that has an autosomal dominant inheritance. A low urinary calcium excretion (<100 mg/24 hours in 75% of patients) and normal PTH level are typically seen. Second, the clinician must exclude hypercalcemia of malignancy. In that instance, cancer is usually clinically evident by the time it causes hypercalcemia and PTH levels are generally <25 pg/mL, unless the patient has coexistent primary hyperparathyroidism (which is somewhat increased in the setting of hypercalcemia of malignancy). If those entities are excluded, and a careful history reveals no intake of medications known to induce hypercalcemia, then a normal or elevated PTH in the face of hypercalcemia is almost certainly the result of primary hyperparathyroidism. If PTH levels are reduced upon testing, then the presence of a granulomatous disease such as sarcoidosis or tuberculosis should be considered.

Treatment

General Principles

In patients with fairly acute, symptomatic, or severe hypercalcemia (>12 mg/dL) the initial approach is to dilute the level of extracellular calcium and enhance renal calcium excretion by correcting extracellular volume contraction with isotonic saline, thereby inhibiting tubular sodium and calcium reabsorption, and then adding a loop diuretic to inhibit thick ascending limb calcium reabsorption, after volume depletion has been corrected. Next, agents to suppress osteoclastic bone resorption should be used. They include calcitonin, a hormone with a rapid onset of action (within 2 hours) to suppress bone resorption. Unfortunately it is effective in only 60–70% of patients and even if effective, typically induces tachyphylaxis. After calcitonin infusion, pamidronate, alendronate, or zolendronic acid, drugs of the bisphosphonate class, should be used. They have a somewhat delayed onset of action (24–48 hours) but they are highly effective and will maximally reduce calcium levels in 3–4 days and have a persisting effect for up to 1 month (mean 15 days). In those patients with severe renal insufficiency, it may be necessary to remove calcium directly from the blood by hemodialysis. With chronic hypercalcemia, the specific underlying disease or cause for the hypercalcemia should also be treated or corrected if possible.

Primary Hyperparathyroidism

First-line treatment of symptomatic (ie, renal stones, renal insufficiency, neuromuscular symptoms, bone fractures) primary hyperparathyroidism is surgical removal of a parathyroid adenoma or removal of a large fraction of parathyroid tissue if there is diffuse parathyroid hyperplasia. In asymptomatic primary hyperparathyroidism a National Institutes of Health workshop suggested that surgery was recommended for patients with the following: (1) serum calcium >1 mg/dL (0.25 mmol/L) above the upper limit of normal, (2) urinary calcium excretion >400 mg/24 hours, (3) impaired renal function (creatinine clearance reduced by 30% from age-matched healthy patients), (4) T-score less than −2.5 (matching the World Health Organization definition of osteoporosis), and (5) age younger than 50 years. Follow-up is likely to be unreliable.

Nonsurgical treatment of primary hyperparathyroidism is less than optimal, but the following have been studied. Estrogens and bisphosphonates have been used as medical treatments for primary hyperparathyroidism. High-dose estrogen modestly reduces serum calcium levels by about 0.5 mg/dL predominantly by reducing bone resorption as opposed to a reduction in PTH. The well-known adverse effects of combined estrogen–progesterone treatment on breast cancer risk and cardiovascular disease preclude its use in most patients.

Bisphosphonates, inhibitors of osteoclastic bone resorption, have not proven to be successful in reducing hypercalcemia in primary hyperparathyroidism although treatment with alendronate for 2 years does improves bone mineral density and may therefore be indicated in patients with a clinically significant reduction in bone mass but are not candidates for surgical therapy. Failure of bisphosphonates is likely due to stimulation of further increases in PTH levels as inhibition of bone resorption tends to reduce serum calcium transiently.

Calcimimetic agents, a new class of drugs that increases the sensitivity of the calcium-sensing receptor in the parathyroid gland, have been found to be effective in controlling PTH levels and serum calcium levels in primary hyperparathyroidism in early studies. They may become a viable alternative to surgery in some patients.

Hypercalcemia of Malignancy

Table 6–1 presents a summary of the various treatments available for hypercalcemia associated with malignancy.

Granulomatous Diseases

Treatment of the hypercalcemia or hypercalciuria associated with granulomatous diseases such as sarcoidosis is aimed at reducing intestinal calcium absorption and calcitriol synthesis. Reduction of calcium absorption requires reducing intake to less than 400 mg/day and eliminating dietary sources of vitamin D. In addition, low-dose glucocorticoid therapy (10–30 mg/day of prednisone) will usually be adequate in sarcoidosis, although somewhat higher doses may be required for patients with hypercalcemia associated with lymphoma. The full hypocalcemic response usually requires 7–10 days of glucocorticoid therapy. Glucocorticoids probably act by inhibiting calcitriol synthesis by the activated macrophage cells within the granulomatous tissue.

Prognosis

The outcome of treatment of hypercalcemia is dependent on the underlying disease responsible for the disorder. In all circumstances except for familial hypocalciuric hypocalcemia, long-standing hypercalcemia and hypercalciuria may lead to renal failure secondary to complications of nephrolithiasis or secondary to nephrocalcinosis. In addition, vascular calcifications may induce cardiovascular diseases such as coronary artery disease and stroke.

If hypercalcemia is caused by hyperparathyroidism, then disturbances of bone including pathologic fractures may be seen. Hypercalcemia of malignancy is often a terminal event and patients rarely survive 1 year following its onset.

Essentials of Diagnosis

• Hypocalcemia usually results from a failure of mobilization of calcium from bone, which typically involves a defect or deficiency in the PTH or vitamin D axis.
• Tissue deposition of calcium or the complexing of calcium with other ions such as phosphate can lead to hypocalcemia if these processes occur more rapidly than calcium can be mobilized from bone.
• Transient hypocalcemia is common in critical care medicine while sustained hypocalcemia is uncommon, with the exception of patients with chronic renal insufficiency where abnormalities of PTH and vitamin D activity are invariably found.

Pathogenesis

Hypoparathyroidism

Hypoparathyroidism may be a primary disorder due to surgery, autoimmunity, or genetic abnormalities or it may be a functional and reversible phenomenon resulting from medications or hypomagnesemia. Postsurgical hypoparathyroidism is a rare (1–2%) but devastating complication of total thyroidectomy. It may also result from exploration of the parathyroid glands or following radical neck dissection for cancers of the head and neck. Hypocalcemia in this setting may be intermittent or permanent.

Hypoparathyroidism induced by autoimmune mechanisms may be associated with other endocrine deficiencies termed polyglandular autoimmune syndrome type I. This condition is associated with adrenal insufficiency and mucocutaneous candidiasis, which reflect defects in thymic development. Patients may also develop anemia due to vitamin B12 deficiency as a result of autoantibodies to gastric parietal cells and subsequent achlorhydria. In some patients, there may be autoantibodies to the calcium-sensing receptor on the surface of parathyroid cells. These antibodies may activate the receptor and mimic the effects of calcium, thereby reducing PTH secretion.

Hypoparathyroidism on a genetic basis is a rare condition that is the result of mutations of the gene for the calcium-sensing receptor that activate the receptor at low levels of calcium, which thereby leads to reduced PTH secretion despite hypocalcemia. The condition is associated with normal but inappropriately low PTH secretion, hypercalciuria, and nephrolithiasis and nephrocalcinosis. DiGeorge's syndrome, a genetic disorder leading to maldevelopment of the third and fourth branchial pouches, is associated with absence of parathyroid glands and an associated aplasia of the thymus as well as cardiac malformations.

Hypomagnesemia

Hypomagnesemia results in a syndrome characterized by hypocalcemia, hypomagnesemia, and hypokalemia. It typically requires a rather severe degree of hypomagnesemia (serum magnesium <0.8 mEq/L or 1 mg/dL) for all of the manifestations to be observed. As noted, magnesium deficiency has multiple effects including reduction of PTH release, inhibition of PTH action on bone, and possibly an action to block bone resorption that may be direct and unrelated to changes in PTH. All abnormalities rapidly resolve if magnesium is infused, but calcium administration does not correct the hypocalcemia until serum magnesium levels are restored to normal.

Pseudohypoparathyroidism

Pseudohypoparathyroidism is a rare set of disorders characterized by normal PTH responsiveness to hypocalcemia but failure of PTH action on target-organs of bone and kidney or some combination of the two. Patients manifest the clinical features of hypoparathyroidism, but PTH levels are elevated yet hypocalcemia persists. In Type 1, binding of the PTH receptor fails to elicit the generation of cyclic AMP as there is inactivation mutation of the gene for the G protein mutation. In Type 2 pseudohypoparathyroidism, the receptor is normal but the cellular response to cyclic AMP is deficient.

Vitamin D Deficiency

Reduced vitamin D intake or production in skin can occur in areas in which there is minimal sun exposure or in individuals in whom exposure of the skin is minimal and whose dietary intake of vitamin D-containing foods is low, particularly if foods are not fortified with vitamin D.

Malabsorption syndromes induced by postsurgical gastrectomy state, celiac sprue, inflammatory bowel disease, cystic fibrosis, or chronic pancreatitis may be associated with either reduced absorption of dietary sources of vitamin D or defects in the enterohepatic circulation leading to decreased reabsorption of secreted calcidiol.

In addition to reduced endogenous production of vitamin D in elderly individuals, vitamin D intake is often low as it is for most Americans. This may contribute to the risk for osteoporosis. Dietary vitamin D deficiency can occur in children and results in hypocalcemia as well as abnormal bone formation and development (rickets).

Patients with chronic kidney disease are usually considered to have 1,25-dihydroxyvitamin D (calcitriol) deficiency due to reduced renal synthesis of the active hormone. Diminished availability of calcidiol in patients with severe liver disease and those taking drugs that increase the activity of P-450 enzymes that metabolize vitamin D to inactive forms, such as anticonvulsants (phenobarbital, phenytoin, carbamazepine), alcohol, isoniazid, theophylline, and rifampin, may lead to vitamin D deficiency associated with calcidiol deficiency.

Genetic Abnormalities of Vitamin D Metabolism

Vitamin D-dependent rickets refers to two autosomal recessive syndromes characterized by hypocalcemia, hypophosphatemia, and rickets. Type 1 vitamin D-dependent rickets, also called pseudovitamin D deficiency rickets, is characterized by an inability to produce calcitriol due to an inactivating mutation in the 1-hydroxylase gene. Type 2 vitamin D-dependent rickets is an autosomal recessive disorder due to hereditary resistance to vitamin D. It is usually caused by mutations in the gene encoding the vitamin D receptor.

In nephrotic syndrome, there may be excessive urinary loss of vitamin D-binding protein and bound vitamin D leading to vitamin D deficiency but rarely to clinically significant hypocalcemia.

Intravascular and Tissue Complexation of Calcium Hyperphosphatemia

Intravascular and tissue complexation of calcium hyperphosphatemia induces hypocalcemia through several mechanisms including formation of deposits of calcium phosphate in bone and soft tissue when the product of the serum calcium (mg/dL) and phosphate (mg/dL) is higher than 55 mg2/dL2. This may occur as phosphate infusions or oral or rectal administration for bowel cleansing or as laxatives. Also, phosphate release from cells during chemotherapy of a variety of tumors or leukemia or during rhabdomyolysis may produce the same disturbance. Intravascular precipitation may occur if the hyperphosphatemia is acute. Intravascular complexation may also occur if patients receive large amount of citrate in blood products such as may occur with plasma exchange or massive blood transfusion. In this setting, ionized calcium must be measured, as total serum calcium will include the portion bound to citrate and total calcium will be in the normal range while ionized calcium will be reduced.

“Hungry bone” syndrome refers to the rapid uptake of calcium and phosphate into bone after parathyroidectomy, particularly in patients who have had long-standing primary or secondary hyperparathyroidism and who have severe degrees of bone resorption. The syndrome typically occurs in the first few hours after parathyroidectomy and may persist for several days. A similar phenomenon may be seen in patients with certain tumors such as prostate cancer who develop osteoblastic metastasis.

Soft tissue complexation also occurs in acute pancreatitis as calcium may combine with circulating and with tissue fats and form “soap” at the sites of precipitation. Calcium may also be deposited in the damaged muscle of patients suffering from rhabdomyolysis.

Other Causes of Hypocalcemia

Other causes of hypocalcemia include sepsis where multiple abnormalities including hypoalbuminemia, lactic acidosis, hypomagnesemia, and a primary impairment of PTH secretion may occur. During infusions of magnesium in women treated for preeclampsia, the calcium-sensing receptor may be bound by and activated by magnesium resulting in a transient reduction in PTH secretion and hypocalcemia. Typically patients are not symptomatic from hypocalcemia because of the concurrent hypermagnesemia. Finally, cinacalcet, a drug in the new class of calcimimetic agents, will induce hypocalcemia as it acts to increase the sensitivity of the calcium-sensing receptor to calcium and thereby leads to inhibition of PTH secretion in the face of hypocalcemia.

Pseudohypocalcemia has recently been described as certain gadolinium-based contrast agents used in magnetic resonance imaging, gadodiamide and gadoversetamide, may bind to the indicator reagents used in colorimetric assays for calcium and produce a false low value. This may be a particular problem in patients with renal insufficiency receiving these agents as they are renally excreted.

Clinical Findings

Symptoms and Signs

The clinical manifestations of hypocalcemia are rather specific and relate to the neuromuscular actions of hypocalcemia. Tetany is the hallmark of hypocalcemia and results from increased neuromuscular irritability after stimulation. It consists of a set of symptoms including circumoral and acral paresthesias. The signs of hypocalcemia include muscle spasms and specifically carpopedal spasm (adduction of thumb, flexion of wrists and metacarpals, and extension of fingers). The manifestations of hypocalcemia can be elicited during the physical examination and include Trousseau's sign (elicited by inflating a sphygmomanometer cuff above systolic pressure for 3 minutes and finding carpopedal spasm of the affected limb) or Chvostek's sign (twitching of facial muscles after tapping on the facial nerve anterior to the ear). While these findings are relatively specific for hypocalcemia, they are also found in hypomagnesemic patients. However, hypomagnesemia induces hypocalcemia, so that if tetany is found, it is usually in the setting of hypocalcemia as well. These signs of neuromuscular irritability may herald grand mal seizures and therefore represent a medical emergency when seen. Cardiac abnormalities including arrhythmias, particularly in patients on digitalis, and hypotension may be seen as well, particularly in the critical care setting. These abnormalities are typically seen when patients have a serum calcium level that is 30% or greater lower than normal.

It should be noted that occasionally patients with acute, severe respiratory alkalosis will manifest tetany as the acute alkalemia itself induces neuromuscular irritability and alkalemia decreases ionized calcium by increasing the negative charges on albumin and thereby increasing albumin binding of ionized calcium.

Some patients with chronic hypocalcemia may have neuropsychiatric manifestations including dementia or mental retardation in children and other psychiatric syndromes including depression and anxiety. In addition, idiopathic hypoparathyroidism, an important cause of chronic hypocalcemia, may be associated paradoxically with intracerebral calcifications, particularly in the basal ganglia, and a Parkinsonian syndrome may result from basal ganglia damage.

Differential Diagnosis

The diagnosis of hypocalcemia rests with a measurement of serum calcium as either a screening test or in response to the symptomatology described above. As the physiologically active fraction of calcium is ionized and closely regulated yet the standard measure of serum calcium includes a major fraction bound to albumin and other anions, it is important to consider the relation of total serum calcium to the bound fraction. Total serum calcium falls approximately 0.8 mg/dL for every 1 g/dL decrement in the concentration of serum albumin. Serum ionized calcium can also be measured directly by an ion electrode.

Since hypocalcemia is found only in the setting of disorders of PTH and vitamin D or as a result of tissue deposition or complexation, a variety of other assays should be made in order to diagnose the underlying disturbance. First, serum phosphate should be measured, as an elevated value might suggest kidney disease, hypoparathyroidism, or release of cellular stores of phosphate such as occurs in rhabdomyolysis or when a large tumor burden is suddenly reduced by lytic therapies such as chemotherapy for leukemia.

Serum magnesium should be measured as severe hypomagnesemia (<1 mg/dL) is associated with a failure of PTH secretion and/or a failure of bone to respond normally to circulating PTH. As chronic kidney disease reduces calcitriol levels and induces hyperphosphatemia, serum creatinine should be measured in all hypocalcemic patients.

If the diagnosis is not apparent from the patient's history, physical examination, and the above noted assays, the next step is to measure immunoreactive intact PTH levels. In diseases associated with secondary hyperparathyroidism and in defective tissue response to PTH (pseudohypoparathyroidism), the PTH level will be high in hypocalcemia. In idiopathic or postsurgical hypoparathyroidism, PTH levels will be low in hypocalcemia, although normal PTH levels may be inappropriately low if hypocalcemia is found.

If secondary hyperparathyroidism is found, then vitamin D metabolites should be measured. Low levels of 25-hydroxyvitamin D (calcidiol) suggest chronic vitamin D deficiency, usually due to decreased intake or abnormal GI absorption of vitamin D as calcidiol levels are reflective of intake and not subject to physiologic regulation. However, low or low-normal levels of calcitriol with normal calcidiol levels in hypocalcemia is a pattern seen in renal failure.

Treatment

Symptomatic Hypocalcemia

Since there are multiple systems designed to maintain the serum calcium level and there is a large store of calcium in bone, hypocalcemia will not be successfully treated in a sustained manner by calcium infusions alone. Typically, calcium infusions may correct the symptoms of acute or chronic hypocalcemia, but sustained therapy usually requires either correction of the underlying cause of hypocalcemia or use of vitamin D supplementation.

The most appropriate treatment for patients with symptomatic hypocalcemia, either acute or chronic, is intravenous calcium, in the form of 100–200 mg (2.5–5 mmol) of elemental calcium (1–2 g of calcium gluconate) in 10–20 minutes. This should be followed by a slow infusion of calcium as the serum calcium will rapidly return to low levels under most circumstances. The dose of the slow infusion should be 1.0 mg/kg/hour as 10% calcium gluconate (90 mg of elemental calcium per 10-mL ampoule). Some postparathyroidectomy patients may require prolonged, massive calcium therapy due to hungry bone disease.

If hypomagnesemia is the cause of hypocalcemia, 2 g (16 mEq) of magnesium sulfate should be infused as a 10% solution over 10 minutes, followed by 1 g (8 mEq) in 100 mL of fluid per hour until serum magnesium remains normal. Patients with hypocalcemia and severe acute hyperphosphatemia due to tumor lysis syndrome require hemodialysis to correct hyperphosphatemia. This will typically ameliorate hypocalcemia.

Chronic Hypocalcemia Induced by Hypoparathyroidism

Both oral calcium and vitamin D supplementation are usually required to correct the hypocalcemia of chronic hypoparathyroidism. The target serum calcium level should be approximately 8.0 mg/dL and at that level, most patients will be asymptomatic. If serum calcium is maintained at a higher level, patients will develop hypercalciuria because of the lack of PTH to enhance calcium reabsorption across the distal nephron. Chronic hypercalciuria may lead to development of nephrocalcinosis, nephrolithiasis, and renal insufficiency.

Occasionally in mild hypoparathyroidism 2 g of oral calcium supplements will achieve normal calcium levels. If this fails, vitamin D should be added. The usual initial daily dose is 50,000 international units of ergocalciferol (vitamin D2) or 0.25–0.5 μg of calcitriol. Appropriate doses of calcium and vitamin D are established by gradual titration. If hypercalciuria is detected, a thiazide diuretic may be added to the regimen. This will result in diminished calciuria and a further increase in the serum calcium level. Serum and urine calcium levels must be monitored carefully, as the main complications of the treatment of hypoparathyroidism are inadvertent hypercalcemia and/or hypercalciuria.

With the recent availability of a synthetic PTH preparation (1-34 PTH, teriparatide) using twice-daily subcutaneous administration has led to correction of hypocalcemia with lower risk of hypercalciuria.

Renal Failure

While hypocalcemia is highly prevalent in patients with chronic renal failure, symptomatic hypocalcemia is rare. The approach to hypocalcemia in renal failure is primarily to lower serum phosphorus and supplement patients with active forms of vitamin D.