Hypocalcemia is defined as a total serum calcium concentration < 8.8 mg/dL (< 2.20 mmol/L) in the presence of normal plasma protein concentrations or as a serum ionized calcium concentration < 4.7 mg/dL (< 1.17 mmol/L). Reference ranges for serum calcium vary by age and sex; see Serum Calcium.
Hypocalcemia may be acquired or hereditary. Acquired causes include a variety of illnesses (eg, hypoparathyroidism, hepatic disease, kidney disease), diet, medication, and surgery (see Overview/Etiology).
The presentation of hypocalcemia varies widely, from asymptomatic to life-threatening. Hypocalcemia is frequently encountered in patients who are hospitalized. Depending on the cause, unrecognized or poorly treated hypocalcemic emergencies can lead to significant morbidity or death.[1] Symptomatic patients with classic clinical findings of acute hypocalcemia require immediate resuscitation and evaluation. However, most cases of hypocalcemia are discovered by clinical suspicion and appropriate laboratory testing. (See Presentation and Workup.)
The treatment of hypocalcemia depends on the cause, the severity, the presence of symptoms, and how rapidly the hypocalcemia developed. Most cases of hypocalcemia are clinically mild and require only supportive treatment and further laboratory evaluation. Oral calcium repletion may be indicated for outpatient treatment of mild cases. On occasion, severe hypocalcemia may result in seizures, tetany, refractory hypotension, or arrhythmias that require a more aggressive approach, including intravenous infusions of calcium. (See Treatment and Medication.)
For more information on hypocalcemia in children, see Pediatric Hypocalcemia.
A 70-kg person has approximately 1.2 kg of calcium in the body, more than 99% of which is stored as hydroxyapatite in bones. Less than 1% (5-6 g) is located in the intracellular and extracellular compartments, with only 1.3 g located extracellularly. The total calcium concentration in the plasma is 4.5-5.1 mEq/L (9-10.2 mg/dL). Fifty percent of plasma calcium is ionized, 40% is bound to proteins (90% of which binds to albumin), and 10% circulates bound to anions (eg, phosphate, carbonate, citrate, lactate, sulfate).
At a plasma pH of 7.4, each gram of albumin binds 0.8 mg/dL of calcium. This bond is dependent on the carboxyl groups of albumin and is highly dependent on pH. Acute acidemia decreases calcium binding to albumin, whereas alkalemia increases binding, which decreases ionized calcium. Clinical signs and symptoms are observed only with decreases in ionized calcium concentration (normally 4.5-5.5 mg/dL).[2, 3]
Calcium regulation is critical for normal cell function, neural transmission, membrane stability, bone structure, blood coagulation, and intracellular signaling. The essential functions of this divalent cation continue to be elucidated, particularly in head injury/stroke and cardiopulmonary disorders.
Ionized calcium is the necessary plasma fraction for normal physiologic processes. In the neuromuscular system, ionized calcium facilitates nerve conduction, muscle contraction, and muscle relaxation. Calcium is necessary for bone mineralization and is an important cofactor for hormonal secretion in endocrine organs. At the cellular level, calcium is an important regulator of ion transport and membrane integrity.
Calcium turnover is estimated to be 10-20 mEq/day. Approximately 500 mg of calcium is removed from the bones daily and replaced by an equal amount. Normally, the amount of calcium absorbed by the intestines is matched by urinary calcium excretion. Despite these enormous fluxes of calcium, the levels of ionized calcium remain stable because of the rigid control maintained by parathyroid hormone (PTH), vitamin D, and calcitonin through complex feedback loops. These compounds act primarily at bone, renal, and GI sites. Calcium levels are also affected by magnesium and phosphorus.[4]
PTH stimulates osteoclastic bone reabsorption and distal tubular calcium reabsorption and mediates 1,25-dihydroxyvitamin D (1,25[OH]2 D) intestinal calcium absorption.[5] Vitamin D stimulates intestinal absorption of calcium, regulates PTH release by the chief cells, and mediates PTH-stimulated bone reabsorption. Calcitonin lowers calcium by targeting bone, renal, and GI losses.
The parathyroid gland has a remarkable sensitivity to ionized serum calcium changes. These changes are recognized by the calcium-sensing receptor (CaSR), a 7-transmembrane receptor linked to G-protein with a large extracellular amino-terminal region. Binding of calcium to the CaSR induces activation of phospholipase C and inhibition of PTH secretion. On the other hand, a slight decrease in calcium stimulates the chief cells of the parathyroid gland to secrete PTH.
CaSR is crucial in PTH secretion. A loss of CaSR function leads to pathologic states, such as familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. In renal failure, CaSR agonists suppress the progression of hyperparathyroidism and parathyroid gland growth.
Homeostasis is maintained by an extracellular-to-intracellular gradient, which is largely due to abundant high-energy phosphates intracellularly. Intracellular calcium regulates cyclic adenosine monophosphate (cAMP)–mediated messenger systems and most cell organelle functions. Ion pumps control levels. Extracellular calcium levels are maintained at 8.7-10.4 mg/dL. Variations depend on serum pH, protein and anion levels, and calcium-regulating hormone function.
Patients with a decrease in total serum calcium may not have "true" hypocalcemia, which is defined as a decrease in ionized calcium. A reduction in total serum calcium can result from a decrease in albumin secondary to liver disease, nephrotic syndrome, or malnutrition.
Hypocalcemia causes neuromuscular irritability and tetany. Alkalemia induces tetany due to a decrease in ionized calcium, whereas acidemia is protective. This pathophysiology is important in patients with renal failure who have hypocalcemia because rapid correction of acidemia or development of alkalemia may trigger tetany.[6, 7, 8]
The causes of hypocalcemia include the following:
Hypoalbuminemia is the most common cause of hypocalcemia. Causes include cirrhosis, nephrosis, malnutrition, burns, chronic illness, and sepsis. In patients who are critically ill, low calcium levels can be simply due to hypoalbuminemia, which has no clinical significance because the active fraction (ionized) is not affected. However, to prevent missing a second hypocalcemic disorder, measure the ionized calcium level whenever the albumin level is low.
In a patient with hypocalcemia, measurement of the serum albumin is essential to distinguish true hypocalcemia, which involves a reduction in ionized serum calcium, from factitious hypocalcemia, meaning decreased total, but not ionized, calcium. To correct for hypoalbuminemia, add 0.8 mg/dL to the total serum calcium for each 1.0 g/dL decrease in albumin below 4.0 g/dL.
Hypoparathyroidism can be hereditary or acquired. The hereditary and acquired varieties share the same symptoms, although hereditary hypoparathyroidism tends to have a gradual onset.[9]
Acquired hypoparathyroidism may result from the following:
Late-onset hypoparathyroidism can be seen as a part of a complex autoimmune disorder involving ovarian failure and adrenal failure. Mucocutaneous candidiasis, alopecia, vitiligo, and pernicious anemia are associated with this disorder, which is referred to as polyglandular autoimmune disease (PGA I).
Hereditary hypoparathyroidism may be familial or sporadic, and it can occur as an isolated entity or can be associated with other endocrine manifestations. The familial forms include autosomal dominant and autosomal recessive, as well as a sex-linked form of early onset, for which the gene has been located on the long arm of the X chromosome.
Sporadic, late-onset hypoparathyroidism is a feature of several hereditary syndromes. These syndromes, and their associated features, are as follows:
Pseudohypoparathyroidism is characterized by end-organ resistance to the effects of PTH. PTH binds to the PTH receptor, which, in turn, activates cAMP through guanine nucleotide regulatory proteins (Gs). These proteins consist of alpha, beta, and gamma subunits.
Pseudohypoparathyroidism is classified into types I and II. Type I is further subdivided into Ia, Ib, and Ic.[9]
Type Ia
Type Ia pseudohypoparathyroidism results from a decrease in the Gs-alpha protein. This disorder comprises the biochemical features of pseudohypoparathyroidism along with the following somatic features of Albright hereditary osteodystrophy (AHO):
Laboratory findings in AHO include hypocalcemia, hyperphosphatemia (with normal or high PTH levels), and low calcitriol. Vitamin D may be decreased because of inhibition by elevated levels of phosphorus and by decreased PTH stimulation of 25-hydroxyvitamin D 1-alpha-hydroxylase. The low calcitriol levels, in turn, may cause the resistance to the hypercalcemic effects of PTH in the bone.
The defect of the Gs-alpha protein is not confined to the effects of PTH but also affects other hormonal systems (eg, resistance to glucagon, thyroid-stimulating hormone, gonadotropins). The gene for the Gs-alpha protein is located on chromosome 20. Some family members carry the mutation and display the AHO phenotype but do not have pseudohypoparathyroidism. This is termed pseudo-pseudohypoparathyroidism.
Types Ib and Ic
In type Ib pseudohypoparathyroidism, patients do not present with the somatic features of AHO. These patients have normal Gs-alpha protein, with hormonal resistance to PTH—an impaired cAMP response to PTH, suggesting that the defect lies on the receptor. At what level the receptor is affected is not yet clear.
In type Ic pseudohypoparathyroidism, patients present with resistance to multiple hormonal receptors. However, Gs-alpha protein expression is normal.
Type II
In type II pseudohypoparathyroidism, PTH raises cAMP normally but fails to increase levels of serum calcium or urinary phosphate excretion, suggesting that the defect is located downstream of the generation of cAMP. These patients present with hypocalcemia, hypophosphaturia, and elevated immunoreactive PTH (iPTH) levels. These findings also occur in vitamin D deficiency, but in patients with a vitamin D deficiency, all parameters return to normal after vitamin D administration.
Severe hypomagnesemia can lead to hypocalcemia that is resistant to the administration of calcium and vitamin D. The usual cause of hypomagnesemia is loss via the kidneys (eg, osmotic diuresis, drugs) or the gastrointestinal tract (eg, chronic diarrhea, severe pancreatitis, bypass or resection of small bowel). These patients present with low or inappropriately normal PTH levels in the presence of hypocalcemia.
The mechanism of hypocalcemia includes resistance to PTH in the bone and kidneys, as well as a decrease in PTH secretion. Acute magnesium restoration rapidly corrects the PTH level, suggesting the hypomagnesemia affects the release of PTH, rather than its synthesis.
Vitamin D is a necessary cofactor for the normal response to PTH, and vitamin D deficiency renders PTH ineffective. Poor nutritional intake, chronic renal insufficiency, or reduced exposure to sunlight may cause vitamin D deficiency.
Current Recommended Dietary Allowances (RDAs) for vitamin D are 600 IU of vitamin D per day for adults for individuals from 1 to 70 years of age and 800 IU per day for those over 70 years.[12] Studies have demonstrated that despite adequate intake, that vitamin D insufficiency can still occur and lead to an increased PTH and subsequent bone turnover. Studies have also shown that dietary intake of vitamin D varies greatly by race and age. In a review of National Health and Nutrition Examination Survey (NHANES) III data from 2001-2006, 32% of African-American women were at risk for vitamin D deficiency—defined as serum 25-hydroxyvitamin D (24[OH]D) levels < 30 nmol/L—as compared with only 3% of white women.[13]
An observational study in elderly adults found that 74% of those studied were deficient in vitamin D, defined as 25(OH)D concentrations < 32 ng/mL, despite intake of more than 400-600 IU/d, which was the recommended RDA at the time.[14] The authors of this study suggested that elderly individuals may require as much as 1000 IU per day.
Mild hypovitaminosis D may not be trivial. In an elderly population with an increased PTH and osteoporosis, response to alendronate was attenuated. This attenuation was improved when vitamin D was administered.[15, 16]
Impaired absorption
Numerous conditions can impair the absorption of vitamin D. Small bowel diseases, such as celiac disease, gastric bypass (particularly long limb Roux-en-Y gastric bypass), steatorrhea, and pancreatic diseases can all lead to low vitamin D levels.[17]
Pseudovitamin D deficiency rickets
This condition is secondary to an autosomal mutation of the 1-hydroxylase gene. Ultimately, calcidiol is not hydroxylated to calcitriol, and calcium is not absorbed appropriately. This condition is considered a pseudovitamin D deficiency because high doses of vitamin D can overcome the clinical and biochemical findings of this disease.
Hereditary vitamin D resistance rickets
This condition is extremely rare and is caused by a mutation in the vitamin D receptor. Typically, this condition presents within the first 2 years of life.
Liver disease with decreased synthetic function can cause vitamin D deficiency from several sources, as follows:
Patients with cirrhosis and osteomalacia have low or normal levels of calcitriol, suggesting that other factors may interfere with vitamin D function or are synergistic with malabsorption or decreased sun exposure. These patients require administration of calcidiol or calcitriol for the treatment of hypocalcemia.
Chronic kidney disease leads to a decrease in the conversion of 25-hydroxyvitamin D to its active form 1,25-dihydroxyvitamin D, particularly when the glomerular filtration rate (GFR) falls below 30 mL/min. This results in an increase in PTH. Ultimately, the increased absorption of phosphorus and calcium can lead to calcium-phosphorus mineral deposition in the soft tissues. In the early stages of renal failure, hypocalcemia can occur because of the decrease in calcitriol production and a subsequent decrease in the intestinal absorption of calcium.
Surgical correction of primary or secondary hyperparathyroidism may be associated with severe hypocalcemia due to a rapid increase in bone remodeling. Hypocalcemia results if the rate of skeletal mineralization exceeds the rate of osteoclast-mediated bone resorption.
A less severe picture is also observed after correction of thyrotoxicosis, after institution of vitamin D therapy for osteomalacia, and with tumors associated with bone formation (eg, prostate, breast, leukemia). All of these disease states result in hypocalcemia due to mineralization of large amounts of unmineralized osteoid.[18]
Pancreatitis can be associated with tetany and hypocalcemia. It is caused primarily by precipitation of calcium soaps in the abdominal cavity, but glucagon-stimulated calcitonin release and decreased PTH secretion may play a role.
When the pancreas is damaged, free fatty acids are generated by the action of pancreatic lipase. Insoluble calcium salts are present in the pancreas, and the free fatty acids avidly chelate the salts, resulting in calcium deposition in the retroperitoneum. In addition, hypoalbuminemia may be a part of the clinical picture, resulting in a reduction in total serum calcium. In patients with concomitant alcohol abuse, a poor nutritional intake of calcium and vitamin D, as well as accompanying hypomagnesemia, may predispose these patients to hypocalcemia.[19]
Hyperphosphatemia may be seen in critical illness and in patients who have ingested phosphate-containing enemas. Phosphate binds calcium avidly, causing acute hypocalcemia. Acute hypocalcemia secondary to hyperphosphatemia may also result from renal failure or excess tissue breakdown because of rhabdomyolysis or tumor lysis.
In acute hyperphosphatemia, calcium is deposited mostly in the bone but also in the extraskeletal tissue. In contrast, in chronic hyperphosphatemia, which is nearly always from chronic renal failure, calcium efflux from the bone is inhibited and the calcium absorption is low, because of reduced renal synthesis of 1,25-dihydroxyvitamin D. However, other consequences of renal failure, including a primary impairment in calcitriol synthesis, also contribute to hypocalcemia.
Patients receiving the calcimimetic agent cinacalcet to help control secondary hyperparathyroidism in renal failure may experience hypocalcemia as a result of acute inhibition of PTH release. Clinically significant hypocalcemia occurs in approximately 5% of patients treated with cinacalcet.[20]
Hypocalcemia can also occur in patients treated with some chemotherapeutic drugs. For example, cisplatin can induce hypocalcemia by causing hypomagnesemia, and combination therapy with 5-fluorouracil and leucovorin can cause mild hypocalcemia (65% of patients in one series), possibly by decreasing calcitriol production.[21] In addition, acute kidney injury and hypocalcemia have been reported as adverse effects in patients receiving the programmed cell death protein 1 (PD-1) inhibitors nivolumab and pembrolizumab.[22]
Hypocalcemia may result from the treatment of hypercalcemia with bisphosphonates, particularly zoledronic acid, which is significantly more potent than other bisphosphonates in suppressing the formation and function of osteoclasts. Patients who are affected appear to lack an adequate PTH response to decreasing serum calcium levels.[23]
Hypocalcemia and osteomalacia have been described with prolonged therapy with anticonvulsants (eg, phenytoin, phenobarbital).[24] The mechanisms differ according to the class of anticonvulsants; for example, phenytoin induces cytochrome P450 enzymes and enhances vitamin D catabolism.
Foscarnet is a drug used to treat refractory cytomegalovirus and herpes infections in patients who are immunocompromised, and it complexes ionized calcium and, therefore, lowers ionized calcium concentrations, potentially causing symptomatic hypocalcemia. Therefore, the ionized calcium concentration should be measured at the end of an infusion of foscarnet.
Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappaB ligand (RANKL), an osteoclast differentiating factor. It inhibits osteoclast formation, decreases bone resorption, increases bone mineral density (BMD), and reduces the risk of fracture. See the Fracture Index WITH known Bone Mineral Density (BMD) calculator.
In the denosumab trials, all women were supplemented with daily calcium (1000 mg) and vitamin D (400-800 U). A small proportion of women in the denosumab trials had a decrease in the serum calcium level to less than 8.5 mg/dL. However, in patients with conditions that predispose to hypocalcemia, such as chronic kidney disease, malabsorption syndromes, or hypoparathyroidism, symptomatic hypocalcemia may occur. The nadir in serum calcium occurs approximately 10 days after administration. Thus, denosumab should not be given to patients with preexisting hypocalcemia until it is corrected. In addition, patients with conditions predisposing to hypocalcemia (ie, chronic kidney disease and creatinine clearance < 30 mL/min) should be monitored for hypocalcemia.[25]
Symptomatic hypocalcemia during transfusion of citrated blood or plasma is rare, because healthy patients rapidly metabolize citrate in the liver and kidney. However, a clinically important fall in serum ionized calcium concentration can occur if citrate metabolism is impaired due to hepatic or renal failure or if large quantities of citrate are given rapidly, for example, during plasma exchange or massive blood transfusion.
Sodium phosphate preparations, which come in aqueous and tablet forms, are used to cleanse the bowel prior to GI procedures such as colonoscopy. In certain populations, these agents can lead to acute hyperphosphatemia and subsequent hypocalcemia.[26, 27] Risk factors include the following:
Some radiographic contrast dyes may contain ethylenediaminetetraacetic acid (EDTA), which chelates calcium in serum, thereby reducing serum ionized calcium concentration, resulting in hypocalcemia. Gadolinium-based contrast material can falsely lower serum calcium levels and should be considered if levels are drawn shortly after magnetic resonance imaging.
Rarely, an excess intake of fluoride can cause hypocalcemia; this effect is presumably mediated by inhibition of bone resorption. Overfluorinated public water supplies and ingestion of fluoride-containing cleaning agents have been associated with low serum calcium levels. In this case, hypocalcemia is thought to be due to excessive rates of skeletal mineralization secondary to formation of calcium difluoride complex.
Proton pump inhibitors (PPIs) and histamine-2 receptor blockers (eg, cimetidine) reduce gastric acid production; this slows fat breakdown, which is necessary to complex calcium for gut absorption. An association with these medicines and an increased risk for hip fractures in elderly patients has been made because of decreased calcium absorption.
Other medication effects that may lead to hypocalcemia are as follows:
Protein binding is enhanced by elevated pH and free fatty acid release in high catecholamine states. Anion chelation is seen in high phosphate states (eg, renal failure, rhabdomyolysis, mesenteric ischemia, oral administration of phosphate-containing enemas); high citrate states (eg, massive blood transfusion, radiocontrast dyes); and high bicarbonate, lactate, and oxalate levels.
Multifactorial causes are probably the most clinically relevant in hypocalcemic emergencies in the emergency department (ED). These include the following:
Acute illness may lead to hypocalcemia for multiple reasons. In one study, the 3 most common factors identified in patients with hypocalcemia associated with acute illness were hypomagnesemia, acute renal failure, and transfusions.
In gram-negative sepsis, there is a reduction in total and ionized serum calcium. The mechanism for this remains unknown, but it appears to be associated with multiple factors, including elevated levels of cytokines (eg, interleukin-6, interleukin-1, TNF-alpha), hypoparathyroidism, and vitamin D deficiency or resistance.
Mortality rates are increased in patients with sepsis and hypocalcemia, compared with patients who are normocalcemic.[29, 30] However, there is no clear evidence that treating critically ill patients with supplemental calcium alters outcomes.[31]
The following surgical procedures may result in hypocalcemia:
Epidemiologic studies of hypocalcemia versus other electrolyte abnormalities have not been performed. During the last 20 years, laboratory tests have quantified serum and ionized calcium and PTH levels, enabling easier diagnosis. The incidence of ionized hypocalcemia is difficult to quantify. In intensive care patients, reported rates have ranged from 15-88%.[33] A systematic review and meta-analysis of hypocalcemia after thyroidectomy found that the median incidence of transient hypocalcaemia was 27% (range, 19-38%) and that of permanent hypocalcemia was 1% (range, 0-3%).[34] In a series of 500 postsurgical patients operated on for hyperparathyroidism, 2% had permanent hypocalcemia.[35]
In order of frequency, hypocalcemia occurs in the following settings:
Death is rare but has been reported. The disease causing hypocalcemia may have greater impact on morbidity than hypocalcemia itself.
Complications of chronic hypocalcemia predominantly are those of bone disease. In addition, severe hypocalcemia may result in cardiovascular collapse, hypotension unresponsive to fluids and vasopressors, and dysrhythmias. Some patients may manifest digitalis insensitivity. Neurologic complications of hypocalcemia include acute seizures or tetany, basal ganglia calcification, parkinsonism, hemiballismus, and choreoathetosis. Although some patients with hypocalcemia may improve with treatment, the calcification typically is not reversible.
The age distribution of hypocalcemia is contingent on the underling disorder. In children, nutritional deficiencies are more frequent; in adults, renal failure predominates. However, the recognition of the high prevalence of vitamin D deficiency, particularly in elderly patients, may change the understanding of hypocalcemia in the general population.
In neonates, hypocalcemia is more likely to occur in infants born of diabetic or preeclamptic mothers. Hypocalcemia also may occur in infants born to mothers with hyperparathyroidism.
Clinically evident hypocalcemia generally presents in milder forms and is usually the result of a chronic disease state. In emergency department patients, chronic or subacute complaints secondary to mild or moderate hypocalcemia are more likely to be a chief complaint than severe symptomatic hypocalcemia.
Once laboratory results demonstrate hypocalcemia, the first question is whether the hypocalcemia is true—that is, whether it is representative of a decrease in ionized calcium. The presence of chronic diarrhea or intestinal disease (eg, Crohn disease, sprue, chronic pancreatitis) suggests the possibility of hypocalcemia due to malabsorption of calcium and/or vitamin D.
The patient's past medical history should be explored for pancreatitis, anxiety disorders, renal or liver failure, gastrointestinal disorders, and hyperthyroidism or hyperparathyroidism. Previous neck surgery suggests hypoparathyroidism; a history of seizures suggests hypocalcemia secondary to anticonvulsants. The patient may have a recent history of thyroid, parathyroid, or bowel surgeries or recent neck trauma.
The length of time that a disorder is present is an important clue. Hypoparathyroidism and pseudohypoparathyroidism are lifelong disorders. Instead, acute transient hypocalcemia may be associated with acute gastrointestinal illness, nutritional deficiency, or acute or chronic renal failure.
In an elderly patient, a nutritional deficiency may be associated with a low intake of vitamin D. A history of alcoholism can help diagnose hypocalcemia due to magnesium deficiency, malabsorption, or chronic pancreatitis.
Inquire about recent use of drugs associated with hypocalcemia, including the following:
Other considerations in the history include the following:
Acute hypocalcemia may lead to syncope, chronic heart failure (CHF), and angina due to the multiple cardiovascular effects.[36] Neuromuscular and neurologic symptoms may also occur.[37] Neuromuscular symptoms include the following[38] :
Neurologic symptoms of hypocalcemia include the following[39] :
Chronic hypocalcemia may produce the following dermatologic manifestations:
Neuromuscular and cardiovascular findings predominate. Neural hyperexcitability due to acute hypocalcemia causes smooth and skeletal muscle contractions. In addition, patients may appear confused or disoriented and may exhibit signs of dementia or overt psychosis. Irritability, confusion, hallucinations, dementia, extrapyramidal manifestations, and seizures may occur.
On head and neck examination, the hair may appear coarse, and alopecia may be present. Signs of recent trauma or of surgery of the neck (eg, scars over the thyroid region) should be noted. Perioral anesthesia may be present, and adults with chronic (since childhood) hypocalcemia may be at an increased risk for dental caries and enamel hypoplasia. On eye examination, subcapsular cataracts or papilledema may be seen.
On respiratory examination, inspiratory or expiratory wheezes may be present. Smooth muscle contraction may lead to laryngeal stridor, dysphagia, and bronchospasm. On cardiac examination, bradycardia, tachycardia, S3, and signs of heart failure may be present.[40]
Dry skin or patches of psoriasis and eczema may be present, particularly in patients with chronic hypocalcemia. Excoriations as a result of pruritus may be noted. Test for Chvostek sign by tapping the skin over the facial nerve about 2 cm anterior to the external auditory meatus. Ipsilateral contraction of the facial muscles is a positive sign. Depending on the calcium level, a graded response will occur: twitching first at the angle of the mouth, then by the nose, the eye, and the facial muscles. Up to 10% of the population will have a positive Chvostek sign in the absence of hypocalcemia; thus, this test, while suggestive, is not diagnostic of hypocalcemia.
Test for the Trousseau sign by placing a blood pressure cuff on the patient’s arm and inflating to 20 mm Hg above systolic blood pressure for 3-5 minutes. This increases the irritability of the nerves, and a flexion of the wrist and metacarpal phalangeal joints can be observed with extension of the interphalangeal joints and adduction of the thumb (carpal spasm). The Trousseau sign is more specific than the Chvostek sign but has incomplete sensitivity.
Movement abnormalitiesassociated with hypocalcemia include the following:
Peripheral nervous system findings include tetany, focal numbness, and muscle spasms. Smooth muscle contraction causes biliary colic, intestinal colic, and dysphagia. Seizures often occur in individuals with preexistent epileptic foci when the excitation threshold is lowered.
Symptomatic patients with classic clinical findings of acute hypocalcemia require immediate resuscitation and evaluation. However, most cases of hypocalcemia are discovered by clinical suspicion and appropriate laboratory testing. Albumin, liver function studies, and coagulation parameters should be obtained to assess liver dysfunction and hypoalbuminemia. Blood urea nitrogen (BUN) and serum creatinine should be measured, as elevated levels may indicate renal dysfunction.
In a patient with hypocalcemia, measurement of the serum albumin is essential to distinguish true hypocalcemia, which involves a reduction in ionized serum calcium, from factitious hypocalcemia, meaning decreased total, but not ionized, calcium. To correct for hypoalbuminemia, add 0.8 mg/dL to the total serum calcium for each 1.0 g/dL decrease in albumin below 4.0 g/dL.
The parathyroid hormone (PTH) level should be checked as early as possible. Vitamin D should be measured if deficiency is suspected. In patients with PTH deficiencies, alkaline phosphatase levels tend to be normal or slightly decreased, whereas these levels frequently are elevated in patients with osteomalacia and rickets. If the diagnosis of osteomalacia is suspected, a bone biopsy can determine the final diagnosis.
An electrocardiogram (ECG) is indicated. Imaging studies may include plain radiography or computed tomography (CT) scans. On radiographs, disorders associated with rickets or osteomalacia present with the pathognomonic Looser zones, which are better observed in the pubic ramus, upper femoral bone, and ribs. Radiography will also disclose osteoblastic metastases from certain tumors (eg, breast, prostate, lung), which can cause hypocalcemia. CT scans of the head may show basal ganglia calcification and extrapyramidal neurologic symptoms (in idiopathic hypoparathyroidism).
Ionized calcium is the definitive method for diagnosing hypocalcemia. A serum calcium level less than 8.5 mg/dL or an ionized calcium level less than 1.0 mmol/L is considered hypocalcemia.
Analysis for the ionized calcium level must be performed rapidly with whole blood to avoid changes in pH and anion chelation. Blood should be drawn in an unheparinized syringe for best results.
Falsely elevated calcium levels may be seen with elevated acetaminophen levels, alcohol, hydralazine, and hemolysis. Falsely depressed levels can be seen with heparin, oxalate, citrate, or hyperbilirubinemia.
In healthy kidneys, parathyroid hormone (PTH) stimulates phosphate excretion. The combination of hypocalcemia and elevated phosphorus levels typically suggests hypoparathyroidism or pseudohypoparathyroidism.
Patients with renal failure and hypocalcemia usually present with hyperphosphatemia and high PTH levels. Hypophosphatemia develops in patients with vitamin D deficiency and hungry bone disease.
The serum magnesium level should always be checked to determine its potential contribution to the hypocalcemia. Occasionally, inadequate dietary magnesium intake leads to hypomagnesemia, hypophosphatemia, and hypocalcemia.[1]
The parathyroid hormone level should be checked as early as possible. This test is an antibody-mediated radioimmunoassay. Low-to-normal PTH levels occur in patients with hereditary or acquired hypoparathyroidism and in patients with severe hypomagnesemia.
Patients with ineffective PTH have elevated PTH levels. The PTH elevation is a result of hypocalcemia.
If vitamin D deficiency is suspected, measurements of 25(OH) D and 1,25(OH)2 D should be performed. A low 25(OH) D level suggests vitamin D deficiency from poor nutritional intake, lack of sunlight, or malabsorption. Low levels of 1,25(OH)2 D in association with high PTH suggest ineffective PTH from a lack of vitamin D, as observed in patients with chronic renal failure, vitamin D–dependent rickets type I (VDDR-I), and pseudohypoparathyroidism.
Urinary cyclic adenosine monophosphate (cAMP) may help differentiate hypoparathyroidism from pseudohypoparathyroidism types I and II. Urinary cAMP levels are generally elevated in hypoparathyroidism.
Acute hypocalcemia causes prolongation of the QT interval, which may lead to ventricular dysrhythmias (see the image below). It also causes decreased myocardial contractility, which can lead to heart failure, hypotension, and angina. Cardiomyopathy and ventricular tachycardia may be reversible with treatment.
 View Image | Electrocardiogram (ECG) findings in severe hypocalcemia. |
The treatment of hypocalcemia depends on the cause, the severity, the presence of symptoms, and how rapidly the hypocalcemia developed.[37] Hypocalcemia generally results from another disease process. Awareness of the diseases that cause hypocalcemia is important so that the cause can be identified and managed early.
Most hypocalcemic emergencies are mild and require only supportive treatment and further laboratory evaluation. On occasion, severe hypocalcemia may result in seizures, tetany, refractory hypotension, or arrhythmias that require a more aggressive approach.
In the emergency department, magnesium and calcium (in their many different forms) are the only medications necessary to treat hypocalcemic emergencies. The consulting endocrinologist may choose to prescribe any of the various vitamin D supplements depending on laboratory workup findings, and oral calcium supplementation for outpatient therapy.
Hypocalcemia is found in over half the patients admitted to intensive care units (ICUs).[45, 33] Studies in critically ill patients have yielded conflicting results, with some suggesting that hypocalcemia is likely a marker of disease severity, and that calcium values usually normalize spontaneously with resolution of the primary disease process.[46, 33] Indeed it has been posited that low levels in critical illness may be protective and attempted correction may be harmful.[46]
In contrast, other studies have concluded that both moderate and mild hypocalcemia are associated with increased mortality, whereas mild hypercalcemia is associated with lower mortality.[45] One large retrospective study found that calcium supplementation during the ICU stay improved 28-day survival in critically ill adult patients.[47]
In patients whose symptoms are not life-threatening, confirm ionized hypocalcemia and check other pertinent laboratory tests. If the cause is not obvious, send a blood sample for a PTH level. Depending on the PTH level, the endocrinologist may do further laboratory workup, particularly an evaluation of vitamin D levels.
Oral repletion may be indicated for outpatient treatment; patients requiring intravenous (IV) repletion should be admitted. The recommended dose of elemental calcium in healthy adults is 1-3 g/d.)
Supportive treatment (ie, IV fluid replacement, oxygen, monitoring) often is required prior to directed treatment of hypocalcemia. Be aware that severe hypocalcemia often is associated with other life-threatening conditions. Check ionized calcium and other pertinent screening laboratory tests.
IV replacement is recommended in symptomatic or severe hypocalcemia with cardiac arrhythmias or tetany. Doses of 100-300 mg of elemental calcium (10 mL of calcium gluconate contains 90 mg elemental calcium; 10 mL of calcium chloride contains 272 mg elemental calcium) in 50-100 mL of 5% dextrose in water (D5W) should be given over 5-10 minutes. This dosage raises the ionized level to 0.5-1.5 mmol and should last 1-2 hours. Caution should be used when giving calcium chloride intravenously.
Calcium chloride 10% solution delivers higher amounts of calcium and is advantageous when rapid correction is needed, but it should be administered via central venous access. Calcium infusion drips should be started at 0.5 mg/kg/hr and increased to 2 mg/kg/hr as needed, with an arterial line placed for frequent measurement of ionized calcium.
Measure serum calcium every 4-6 hours to maintain serum calcium levels at 8-9 mg/dL. If low albumin is also present, ionized calcium should be monitored. Admit the patient for further evaluation and observation.
Patients with cardiac arrhythmias or patients on digoxin therapy need continuous electrocardiographic (ECG) monitoring during calcium replacement because calcium potentiates digitalis toxicity. Identify and treat the cause of hypocalcemia and taper the infusion.
Start oral calcium and vitamin D treatment early. Patients with postparathyroidectomy hungry bone disease, especially those with osteitis fibrosa cystica, can present with a dramatic picture of hypocalcemia. Treatment with calcium and vitamin D for 1-2 days prior to parathyroid surgery may help prevent the development of severe hypocalcemia.
Treatment of chronic hypocalcemia depends on the cause of the disorder. Patients with hypoparathyroidism and pseudohypoparathyroidism can be managed initially with oral calcium supplements. The hypercalcemic effects of thiazide diuretics may offer some additional benefits.
In patients with severe hypoparathyroidism, vitamin D treatment may be required; however, remember that PTH deficiency impairs the conversion of vitamin D to calcitriol. Therefore, the most efficient treatment is the addition of 0.5-2 mcg of calcitriol or 1-alpha-hydroxyvitamin D3. Parathyroidectomy (subtotal or total) may be indicated in certain patients with severe secondary hyperparathyroidism and renal osteodystrophy.
Recombinant human parathyroid hormone (rhPTH, Natpara) is commercially available in the United States and is indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism. Its approval was based on the REPLACE trial, in which 48 of 90 patients (53%) receiving rhPTH, but only one of 44 patients in the placebo group (2%), achieved >50% reduction of daily PO calcium and vitamin D from baseline while maintaining serum calcium above baseline concentrations and less than upper limits of normal at week 24 (P< 0.0001).[48]
Although most patients on hemodialysis will be hypercalcemic, those who have undergone parathyroidectomy may have considerable difficulty in maintaining appropriate calcium levels. These levels can be managed several ways. First, oral calcium supplements should be provided. They must be given between meals; otherwise, they will primarily act as phosphate binders. Active vitamin D (calcitriol) enhances the absorption of calcium. Finally, the calcium in the dialysate bath can be increased.
Nutritional vitamin D deficiency from lack of sunlight exposure or poor oral intake of vitamin D responds to treatment with ultraviolet light or sunlight exposure.[49] Treat nutritional rickets with vitamin D2. Oral calcium preparations containing 1-2 g of elemental calcium per day can treat patients with a calcium deficiency. For infants who are breastfed, adjust the dose to 30 mg/kg/day. Calcitriol may be used, but it has the disadvantages of a higher price and the possibility of producing hypervitaminosis D with hypercalcemia.
An increase in dietary calcium to greater than 1 g/day is an important part of the treatment of chronic hypocalcemia, particularly in cases of vitamin D deficiency. In patients with hypocalcemia and chronic renal failure, the dietary intake of phosphate should be lowered to 400-800 mg/day to prevent hyperphosphatemia.
Patients with chronic hypocalcemia should be educated about the early symptoms of hypocalcemia, such as paresthesias and muscle weakness, so that they can obtain care before more severe symptoms develop.
Given the variety of causes that hypocalcemia may have, multiple consultations may be necessary. Depending on the clinical situation, consultations may include one or more of the following:
After determining the cause of hypocalcemia, direct the treatment at preventing further episodes of hypocalcemia and avoiding the complications of chronic hypocalcemia. Although uncommon, outpatient evaluation by an endocrinologist or an internist is appropriate in some patients who present to the ED with hypocalcemia. Patients with diseases that predispose them to the development of hypocalcemia should have scheduled appointments with an outpatient provider.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Patients with hypocalcemia due to resistance to parathyroid hormone (PTH) generally will require long-term therapy with vitamin D and calcium supplementation. Patients with hypocalcemia associated with chronic renal failure often require phosphate binders and vitamin D supplementation.
Clinical Context: Calcium chloride moderates nerve and muscle performance by regulating the action potential excitation threshold. This form of calcium is preferred for patients in cardiac arrest and in other serious cases.. The 10% IV solution provides 100 mg/mL of calcium chloride equaling 27.2 mg/mL (1.4 mEq/mL) of elemental calcium (ie, 10 mL of calcium chloride 10% solution contains 272 mg of elemental calcium).
Clinical Context: Calcium gluconate moderates nerve and muscle performance and facilitates normal cardiac function. It is the preferred form of calcium for patients not in cardiac arrest. One ampule contains 93 mg of elemental calcium. After IV treatment, calcium levels can usually be maintained with a high-calcium diet, although some patients also require oral calcium supplementation.
The oral formulation is usually used as supplementation to IV calcium therapy. Amounts of elemental calcium in calcium gluconate are as follows:
• 500-mg tablet: 45 mg
• 650-mg tablet: 58.5 mg
• 975-mg tablet: 87.75 mg
• 1-g tablet: 90 mg
Clinical Context: Calcium carbonate is indicated to restore and maintain normocalcemia when hypocalcemia is not severe enough to warrant rapid replacement. It is used orally as supplementation to IV calcium therapy. Calcium carbonate moderates nerve and muscle performance by regulating the action potential excitation threshold. Amounts of elemental calcium in calcium carbonate tablets are as follows: Tums, 200 mg; Rolaids, 220 mg; Os-Cal, 500 mg
Clinical Context: Calcium citrate is an oral formulation usually used as supplementation to IV calcium therapy. Calcium moderates nerve and muscle performance by regulating the action potential excitation threshold and facilitating normal cardiac function. Give the amount needed to supplement dietary intake, so as to reach recommended daily amounts. The amount of elemental calcium in 1000 mg of calcium citrate is 210 mg.
Intravenous calcium chloride or gluconate infusions restore serum calcium levels. Calcium chloride delivers 3 times more elemental calcium than calcium gluconate.
Clinical Context: Calcitriol increases calcium levels by promoting calcium absorption in the intestines and calcium retention in the kidneys. To prevent hyperparathyroidism, patients on dialysis may require higher doses, such as 1-2 mcg/day IV administered 2-3 times per week (approximately every other day).
Vitamin D restores calcium levels in conditions associated with vitamin D deficiency. Vitamin D helps control hyperparathyroidism in patients with chronic renal failure and end-stage renal disease.
Clinical Context: Parathyroid hormone raises serum calcium by increasing renal tubular calcium reabsorption, increasing intestinal calcium absorption, and increasing bone turnover. rhPTH is indicated as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism.
Recombinant human parathyroid hormone may be required in addition to calcium and vitamin D supplementation for hypocalcemia.
Electrocardiogram (ECG) findings in severe hypocalcemia.
Electrocardiogram (ECG) findings in severe hypocalcemia.
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