Introduction

Calcium is a prominent molecule involved in many biochemical processes throughout the body. It is an essential element for proper cardiac function, the structural integrity of bone, and muscular contraction and acts as an enzymatic signal in biochemical pathways.[1] Calcium is tightly regulated by the parathyroid hormone (PTH), calcitonin, and calcitriol, which regulate serum calcium levels. Calcium must be ingested endogenously, and absorption in the gastrointestinal system is influenced by hormones PTH and calcitriol (1,25-dihydroxy vitamin D).[2] 

Serum calcium can be measured by a venous sample, with physiologic levels ranging from 8.8 mg/dl to 10.4 mg/dL for total calcium and 4.7 mg/dL to 5.2 mg/dL for ionized calcium.[3] Total calcium values should be corrected for current albumin concentrations, which act as a carrier protein and can affect the reported results. Calcium can also be analyzed in the urine by calcium concentration, urine calcium to creatinine ratio (UCa:UCr), or fractional excretion of calcium (FeCa). Calcium derangements can result from many diseases or therapies that affect hormone secretion, receptor sensitivities, intestinal absorption, and renal effectiveness.[4] Laboratory error can cause inaccurately reported calcium levels, and preventive measures should be included in specimen collection and analysis. An interprofessional team is essential for proper patient management.[1]

Etiology and Epidemiology

Calcium is the fifth most common element in the body and the most prevalent cation. An average human body (70 kg) contains about 1 kg, or approximately 25 mol, of calcium.[5] The skeleton contains approximately 99% of the body’s calcium, predominantly as extracellular crystals of an unknown structure and a composition approaching that of hydroxyapatite.[4] Soft tissues and extracellular fluid contain about 1% of the body’s calcium. In blood, virtually all calcium is present in the plasma.[5]

About 50% of the calcium present in circulation is free (also known as ionized calcium); 40% of serum calcium is bound to proteins, especially albumin (80%) and, secondary, to globulins (20%); and about 10% exists as various small diffusible inorganic and organic anions (e.g., bicarbonate, lactate, citrate). The free calcium fraction is the biologically active form.[6] Because calcium binds to negatively charged sites on proteins, its binding is pH-dependent. Alkalosis leads to an increase in the negative charge of proteins, increasing binding, resulting in a decrease in free calcium; conversely, acidosis leads to a decrease in negative charge, decreasing binding and resulting in an increase in free calcium.[7] In vitro, for each 0.1-unit change in pH, approximately 0.2 mg/dL (0.05 mmol/L) of inverse change occurs in the serum-free calcium concentration.[8] Calcium can be redistributed among the three plasma pools, acutely or chronically, by alterations in the concentrations of protein and small anions, changes in pH, or changes in the quantities of free calcium and total calcium in the plasma.[9]

Physiologically, calcium may be classified as intracellular or extracellular. Intracellular calcium has key roles in many important physiologic functions, including muscle contraction, hormone secretion, glycogen metabolism, and cell division. The intracellular concentration of calcium in the cytosol of unstimulated cells is around 0.1 μmol/L, which is less than 1/20,000 of that in extracellular fluid.[10] Extracellular calcium provides calcium ions for maintaining intracellular calcium, bone mineralization, blood coagulation, and plasma membrane potential.[11] Calcium stabilizes the plasma membranes and influences permeability and excitability. A decrease in the plasma-free calcium concentration causes increased neuromuscular excitability and can lead to tetany; an increased concentration reduces neuromuscular excitability.[12]

Pathophysiology

Calcium is tightly regulated and rarely varies from physiologic levels within the body.[9] Homeostasis must be maintained as calcium plays a critical role in many principal cellular functions.

Calcium levels are managed by the parathyroid hormone (PTH), calcitonin, and calcitriol. The parathyroid hormone (PTH) is an essential regulator of calcium homeostasis, which acts on the renal, skeletal, and gastrointestinal systems to increase serum calcium levels. First, PTH promotes calcium absorption in the gut by stimulating the formation of renally derived calcitriol (1,25-dihydroxy vitamin D), which targets the intestines to increase calcium absorption.[11][13] Second, it stimulates calcium resorption from bone by increasing osteoclast number and activity.[14] Lastly, PTH promotes calcium absorption in the kidney by activating adenylyl cyclase in the distal nephron.[15] 

PTH is regulated by serum calcium via negative feedback, preventing excess PTH secretion when calcium is at the physiological level (10 mg/dL).[14] Calcium levels are continuously monitored by calcium-sensing receptors (CaSRs) of the parathyroid gland to control PTH secretion. Genetic mutations of CaSRs, such as those found in familial hypocalciuric hypercalcemia (FHH), can affect the sensitivity of the receptors to serum calcium levels resulting in hypo- or hypercalcemia.[9] Calcitonin is secreted by the parafollicular C-cells of the thyroid gland in response to elevated serum calcium levels and acts to inhibit osteoclast activity and decrease calcium absorption in the intestines and kidneys.[16] The overall result is lower serum calcium levels.

Calcium and the Renal System

The PTH acts on the renal system by activating adenylyl cyclase and 1 alpha-hydroxylase to increase calcium reabsorption and phosphate excretion. Adenylyl cyclase increases calcium reabsorption at the distal convoluted tubules. The enzyme 1alpha-hydroxylase increases the conversion of vitamin D to its active form, 1,25-dihydroxy vitamin D, which results in increased calcium absorption in the intestine.[17] In chronic kidney disease, the effect of PTH can become muted, leading to hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism.[5]

Calcium and the Gastrointestinal System

Humans do not endogenously create calcium, so it must be ingested and absorbed in the gastrointestinal tract. The amount of calcium absorbed in the small intestine is primarily influenced by current calcium levels and 1,25-dihydroxy vitamin D (calcitriol). Still, other factors such as age, gender, race, and comorbidities can affect calcium absorption. Calcitriol is increased in response to low serum calcium and triggers an active process in the duodenum to absorb more calcium.[13] If serum calcium levels are elevated, the active process is shut off, and calcium absorption happens passively at the jejunum and ileum, leading to lower calcium absorption rates.[5]

Since calcium is absorbed in ionic form, dietary intake of compounds that interact with calcium will reduce the amount of calcium available for absorption. These are primarily oxalate, phosphate, sulfate, citrate, fiber, and fats.[13]

Calcium and the Musculoskeletal System

Bone tissue stores calcium as hydroxyapatite, which is deposited when serum calcium levels are elevated and released when levels are low. This process is linked with the endocrine system via the thyroid and parathyroid glands. When serum calcium levels are elevated, the thyroid gland releases calcitonin, which inhibits bone resorption by halting osteoclast activity. The PTH effect on bone tissue is dependent on continuous versus intermittent exposure.[14] In a state of continuous exposure, PTH activates osteoclasts more readily by enhancing RANKL, which increases calcium resorption and bone loss, promoting an osteoporotic state.[17] Intermittent PTH exposure favors osteoblast activation, which promotes bone formation. However, chronically reduced PTH levels precipitate decreased bone remodeling and, subsequently, weak and brittle bones.[18]

Calcium is necessary for muscle contraction to occur. Contraction is initiated when actin and myosin subunits interact with each other and are inhibited by two regulatory subunits: troponin and tropomyosin. Tropomyosin obstructs the actin-myosin binding site, which prevents contraction by blocking actin and myosin interaction.[19] Muscle contraction occurs when calcium, released from the sarcoplasmic reticulum, binds troponin to force tropomyosin out of the binding site, thus allowing for actin and myosin interaction.[20]

Calcium and the Cardiovascular System

Calcium in the heart muscle cells is responsible for stabilizing the membrane potential.[9] Calcium influx during the plateau phase of myocardial contractility sets the speed of pacemaker potential. Dysregulation of either calcium or potassium can affect this delicate balance. For example, if a patient presents with severe hyperkalemia, it is important to order an electrocardiogram (EKG) to evaluate for abnormal changes, and administration of calcium gluconate is the initial step to stabilize the myocardium and prevent arrhythmias.[21]

Prospective cohort studies have shown no relationship between dietary calcium intake and the risk of heart disease, death, or myocardial infarction.[22] Results conclude unclear interpretation of whether absorption of dietary calcium versus calcium supplements has any indications regarding cardiovascular risks. Therefore, further investigations are recommended to discover the role of these supplements in cardiovascular prevention.[23]

Calcium is a key cofactor in the coagulation cascade and is necessary for appropriate coagulability. During primary hemostasis, von Willebrand Factor (vWF) is released from injured tissue to act as a bridge for the endothelium and platelet GpIb receptors for proper platelet adhesion. After a platelet adhesion to the endothelium, calcium is released to assist with other coagulation factors of the clotting cascade.[24] Tissue factor, which is released from subendothelial tissue, binds to both calcium and factor VII to promote thrombin formation. Calcium is also involved with the formation of the prothrombinase complex, which converts prothrombin to thrombin and further creates insoluble fibrin.[25] A study of intracerebral hemorrhage among 2103 patients showed that hypocalcemia was associated with subtle coagulopathy and correlated with increased bleeding in patients with intracerebral hemorrhage.[26]

Specimen Requirements and Procedure

Fasting is not a requirement to evaluate serum calcium levels. Calcium is included in the comprehensive metabolic panel (CMP), facilitating routine evaluation. Fist-clenching or forearm exercise can lead to falsely elevated ionized (free) calcium levels. The sample should be drawn with the patient in a sitting position. Standing increases the total calcium concentration.[27] Hemolysis and delayed plasma/serum separation lead to a decreased calcium concentration. Samples collected in tubes containing citrate, oxalate, or ethylenediaminetetraacetic acid (EDTA) are unsuitable for calcium testing.[28]

A venous blood sample is required to evaluate serum levels. For children, a lancet needle can be used on a finger, and the sample can be collected in a pipette, slide, or test strip. Whole blood specimens should be analyzed within 15 to 30 minutes of collection. If this is not possible, the specimen should be kept on ice. On the ice, the specimen is stable for at least 2 hours; however, if concurrent potassium testing is requested on the same specimen, the low temperature leads to a spurious increase in potassium within 1 hour of collection.[29] If the specimen cannot be analyzed within 1 hour, the preferred specimen is serum. The specimen should be centrifuged, and the serum or plasma should be removed from the cells within 2 hours of collection.[30]

Samples can be stored at room temperature for 8 hours or refrigerated at 2 to 8 C for up to 48 hours. If assays are not completed within 48 hours or the separated sample is to be stored beyond 48 hours, samples should be frozen at -15 C to -20 C. Frozen samples should be thawed only once. Analyte deterioration may occur in samples that are repeatedly frozen and thawed.[29]

Urine calcium can be kept dissolved by adding 10 mL of 6 M HCl to the collection container before a 24-hour specimen is collected. Urine should be well-mixed during the collection period. A 24-hour urine sample, timed collection, or random urine sample can be useful to diagnose metabolic abnormalities and a patient’s disposition to form stones.[31] Urine calcium can be measured in three ways: urine calcium concentration, urine calcium to creatinine ratio (UCa:UCr), and fractional excretion of calcium (FeCa). Normal levels of UCa:UCr is less than 0.14, and elevated levels higher than 0.20 indicates hypercalciuria.[32] FeCa can also be used to identify abnormal calcium metabolism, but it also requires urine and serum labwork for determination.[33]

FeCa = (Urine Calcium x Serum creatinine) / (Serum calcium × Urine creatinine)

Testing Procedures

Total calcium can be measured using the ISE potentiometric method, but the sample must be pre-acidified to release all bound and complexed calcium to a free form. However, total calcium is commonly measured with spectrophotometric methods, such as the o-Cresolphthalein Complexone method, Arsenazo III method, atomic absorption spectrometry, or, rarely, isotope dilution mass spectrometry (ID-MS).[34] Ionized calcium can be measured in whole blood using the ion-specific electrode (ISE) potentiometric method.[35]

The free calcium analyzer consists of a system of pumps under microprocessor control that transport calibration solutions, samples, and wash solutions through a measuring cell containing calcium ion-selective, reference, and pH electrodes. Sensitive potentiometers measure the voltage difference between the calcium or pH and reference electrodes for calibrating solutions or samples. A microprocessor calibrates the system and calculates calcium concentration and pH.[36] Most instruments simultaneously measure the actual free calcium and pH at 37 C.[37]

Calcium ISEs contain a calcium-selective membrane that encloses an inner reference solution of calcium chloride, often containing saturated silver chloride (AgCl) and physiologic concentrations of sodium chloride and potassium chloride, and an internal reference electrode. The reference electrode, usually Ag/AgCl, is immersed in this inner reference solution. Modern calcium ISEs use liquid membranes containing the ion-selective calcium sensor dissolved in an organic liquid trapped in a polymeric matrix.[38] Because ISEs measure ion activity, they are affected by the ionic strength of a specimen. Free calcium analyzers (and the associated calibrators) are optimized for specimens of serum, plasma, or whole blood. Because the ionic strength of these fluids is primarily a result of the concentrations of Na+ and Cl− ions, calibrators usually are prepared in buffer and sodium chloride with a final ionic strength of 160 mmol/kg.[36]

Although the range of Na+ and Cl+ concentrations usually observed in serum or plasma does not cause a clinically significant error in the measurement of free calcium, significant errors can occur with other specimens unless the matrices and the ionic strength of the calibrators and samples are matched closely. Modern electrodes have high selectivity for calcium over Na+, K+, Mg2+, H+, and Li+ ions.[39]

Interfering Factors

Reported calcium levels can be influenced by many factors, such as the patient's age, comorbidities, lifestyle, gender, medical therapies, and conditions during specimen retrieval. For example, if the sample was poor quality due to it being lipemic or hemolyzed, then calcium levels can be inaccurate.[40] Exercise immediately prior to specimen retrieval has also been shown to increase calcium levels.[41]

Certain medications may precipitate inaccurate measurements of calcium levels. Perchlorate has been reported to cause discrepancies in ionized calcium measurements, leading to false diagnoses of hypo or hypercalcemia.[42] Medications known to increase serum calcium levels are thiazide diuretics, lithium, antacids, and vitamin D supplements.[43]

Urine calcium excretion is highly related to sodium excretion; as such dietary sodium can influence reported levels. Diets high in sodium yield higher calcium excretion; similarly, low-sodium diets equal lower calcium excretion.[44] Among children, the provider should keep in mind that children have an increased calcium-to-creatinine ratio and might be falsely determined to be hypercalciuric if following adult guidelines.[45]

Albumin is a carrier protein for calcium and can result in an inaccurately reported serum calcium level. Evaluating albumin levels to correct for total calcium and differentiate true versus factitious calcium dysregulation is important.[46] The equation is as follows:

Albumin Correction

• True Calcium (mg/dL) = reported total calcium (mg/dL) + 0.8 (4.0 – serum albumin (g/dL))

If the corrected serum total calcium levels are between the normal levels of 8.8 mg/dL to 10.4 mg/dL, then the laboratory-reported calcium is fictitious due to impaired serum albumin levels.[47]

Results, Reporting, and Critical Findings

Hypercalcemia

Hypercalcemia is defined as calcium levels elevated above 10.4 mg/dL or ionized serum calcium above 5.2 mg/dL.[47] Patients with hypercalcemia may experience an array of symptoms, some of which include increased calcium stones, bone fragility/fractures, abdominal pain, constipation, thirst, frequent urination, and altered mentation in severe cases. Clinical findings may show tongue fasciculations, bradycardia, or hyperreflexia.[48] The first step after identifying hypercalcemia is to confirm by albumin correction. After confirming hypercalcemia, the next step is to measure the PTH level. If PTH is elevated, the patient’s hypercalcemia is PTH-dependent and can be caused by primary hyperparathyroidism, familial hypocalciuric hypercalcemia, or medication side-effect. If PTH is suppressed, it is PTH-independent with a much broader differential, and lab values for parathyroid-related protein (PTHrP), 25-hydroxyvitamin D, and 1,25-dihydroxy vitamin D levels should be evaluated. The differential diagnosis for PTH-independent hypercalcemia includes immobilization, malignancy, medication-induced thyrotoxicosis, and vitamin D toxicity.[49]

Patients who are asymptomatic with albumin-corrected calcium levels less than 12 mg/dL are advised to avoid precipitating factors such as dehydration, inactivity, a calcium diet greater than 1000 mg/day, and certain medications (lithium carbonate, thiazides).[50] Patients with albumin-corrected calcium levels greater than 12 mg/dL may present with mild, moderate, or severe symptoms.[51] Patients with chronic and mild symptoms of hypercalcemia may not require immediate treatment. However, patients with albumin-corrected calcium greater than 14 mg/dL require more urgent attention.[52] 

Treatment with normal saline is the most beneficial early management of these patients. The addition of calcitonin should result in a significant reduction of serum calcium within 48 hours. Furthermore, administering bisphosphonates will provide a more sustained effect that will reduce calcium levels in two to four days.[52] Patients with renal failure or refractory to treatment with bisphosphonates can be managed with Denosumab. Denosumab suppresses bone remodeling and may cause hypocalcemia; therefore, patients should be monitored for serum calcium and serum 25-hydroxyvitamin D.[53] As a last resort to treating severe hypercalcemia, hemodialysis is indicated for patients with malignancy-associated hypercalcemia and renal insufficiency.[54] Careful monitoring is required to avoid fluid overload, especially among patients with a compromised cardiac reserve and renal insufficiency.[55]

Hypocalcemia

Hypocalcemia is defined as total serum calcium levels below 8.8 mg/dL or ionized serum calcium below 4.7 mg/dL.[56] Due to multiple causal factors, patients with hypocalcemia must be carefully assessed based on laboratory values, clinical presentation, symptoms, medications, and comorbidities. The first step in diagnosing hypocalcemia is to confirm by albumin correction. One of the first signs of hypocalcemia is neuromuscular irritability, which presents with symptoms such as tingling and numbness around the mouth and at the fingertips, paresthesia of the extremities, and painful muscle cramps.[57] 

The physical exam could likely demonstrate contraction of facial muscles ipsilaterally by tapping on the skin overlying the facial nerve (Chvostek sign) and painful carpal spasms with wrist flexion and interphalangeal joint extension while the blood pressure cuff is set 20 mmHg above the patient’s systolic pressure (Trousseau’s signs).[58] Acute versus chronic hypocalcemia can present differently. Acute hypocalcemia is more likely to present with cardiac dysfunctions such as QT-prolongation and T-wave abnormalities. Chronic hypocalcemia can present with skin manifestations, such as dry skin, coarse hair, and brittle nails, and neurologic problems, such as calcification of brain parenchyma.[59]

Hypocalcemia can occur due to diseases, treatments, medications, and electrolyte abnormalities. Metabolic alkalosis can cause decreased serum ionized calcium due to calcium-binding albumin more readily during alkalotic states. Chronic diseases of note are hypoparathyroidism, chronic kidney disease, liver disease, and vitamin D deficiency.[60] Acute illnesses such as sepsis, pancreatitis (due to fat saponification), and acute kidney injury can also result in hypocalcemia. Severe hypomagnesemia can secondarily cause hypocalcemia, as is sometimes seen in proton-pump inhibitor (PPI) therapy. PPI therapy also decreases stomach acidity, decreasing calcium absorption via the intestinal tract. A case report in 2017 discussed two children on dialysis for chronic kidney disease (CKD) who experienced acute hypocalcemia and alkalotic episodes a week after starting sodium polystyrene sulfonate (SPS) for the treatment of hyperkalemia.[61]

Other medications of note that can result in hypocalcemia are the long-term use of corticosteroids, antiepileptics, aminoglycosides, cisplatin, and bisphosphonates.[56] Acute hypocalcemia is common among patients receiving large transfusions, such as during treatment of traumatic hemorrhage, due to citrate and chelation products. As calcium is vital for proper coagulation, trauma patients receiving blood transfusions should be monitored closely to avoid severe hypocalcemic events.[62]

Treatment for hypocalcemia depends on the severity of the symptoms. Patients experiencing mild symptoms should be treated with calcitriol 0.5 mcg orally twice daily and calcium in the combined form of calcium carbonate taken with the dose of 500 mg orally four times daily to achieve optimal absorption. There are several options in which calcium can be administered. Calcium carbonate can be taken orally via pill, or it can be crushed and mixed with liquid. The absorption of calcium carbonate is dependent on stomach acidity. For better absorption, it may be taken with food or substituted with calcium citrate to stimulate an acidic environment.[63] If serum calcium levels are persistently low, possible hypomagnesemia must be evaluated and corrected to normalize serum calcium levels.[56]

On the other hand, calcium gluconate is available in liquid form. In severely symptomatic patients with hypocalcemia, it is essential to maintain a calcium level above 8 mg/dL (2 mmol/L). Hence calcium gluconate can be administered by continuous intravenous drip infused over 10-20 minutes to avoid cardiac complications such as arrhythmias.[64] Serum calcium should be evaluated every 3-6 months, and 24-hour urine calcium should be evaluated annually. If the patient has comorbid hyperphosphatemia, phosphate binders should be provided to avoid calcium phosphate precipitation and soft-tissue calcification.[60]

Hypocalciuria

Hypocalciuria can occur due to medications, diseases, and genetic disorders. Common medications that result in reduced urine calcium are thiazides and estrogen. Genetic conditions such as familial hypocalciuric hypercalcemia (FHH), an autosomal dominant disease that decreases the sensitivity of calcium-sensing receptors (CaSRs) of the parathyroid gland, maintain serum calcium levels at an elevated baseline with resulting hypocalciuria.[65] Another possible genetic cause is Gitelman syndrome, a salt-wasting tubulopathy that presents with spasms, muscle weakness, and salt cravings with multiple electrolyte derangements, including hypocalciuria.[66] Differential diagnosis also includes hypoparathyroidism, pseudohypoparathyroidism, intestinal malabsorption, rickets, and hypothyroidism are other diseases implicated in hypocalciuria.[67]

Hypercalciuria

Hypercalciuria can occur as an effect of medications, diseases, and genetic disorders. Common medications involved are spironolactone, corticosteroids, and acetazolamide.[68] Supplements containing extra calcium should also be considered. Differential diagnosis includes hyperparathyroidism, malignancy, multiple myeloma, sarcoidosis, Paget disease, increased intestinal absorption, and osteoporosis.[69]

Clinical Significance

Calcium dysregulation can be a sign of many diseases, just as much as dysregulation can cause many adverse effects. This section will highlight various areas throughout the body in which calcium is related to pathologies.

Bone Health and Osteoporosis

Osteoporosis is a disorder that influences bone composition, affecting both density and mineralization. The consequences can be dire as gradual bone loss can result in bone fragility and, ultimately, bone fracture. There are an estimated 1.5 million fractures each year due to osteoporosis, as this disorder affects more than 10 million U.S. adults, the vast majority of whom are women.[70] However, men affected with osteoporosis are often unidentified and undertreated, with higher mortality rates due to hip fractures. Consumption of both dietary calcium and vitamin D from childhood to early adulthood helps patients reach peak bone mass and delay severe bone loss during aging. For osteoporosis prevention, The American College of Obstetricians and Gynecologists have released recommendations for calcium and vitamin D supplementation for women starting as early as nine-years-old, with dosage varying according to age.[71]  Furthermore, calcium supplements reduce the risk of fractures and falls in adults aged 65 and higher.[72] 

The United States Food and Drug Administration (FDA) association has approved a health claim suggesting that sufficient calcium and vitamin D intake, with consistent physical activity, might reduce the risk of osteoporosis later in life.[73] However, in contrast to this view, in 2018, the U.S. Preventive Services Task Force (USPSTF) maintained there is insufficient evidence to suggest that supplementation with calcium and vitamin D has greater benefits than potential harm. Thus, the 2018 USPSTF guidelines recommend against supplementation of vitamin D and calcium for the prevention of fractures among "community-dwelling, asymptomatic adults." This recommendation does not apply to symptomatic patients with a history of osteoporosis or vitamin D deficiency.

Gastrointestinal Malignancy

Calcium binds to bile acids and fatty acids to form insoluble complexes that protect the cell lining of the gastrointestinal tract from acids and their metabolites. Also, calcium is involved in improving signaling within the cells, which may reduce cell proliferation by promoting cells to undergo differentiation and or apoptosis.[74] Although studies are inconsistent, conclusions from data collection suggest that calcium may play a role in the prevention of colorectal cancer. The association between daily calcium intake and prevention of colorectal cancer showed an inverse association most strongly among older women and the distal colon.[75] However, more trials are needed to conclude different studies on this topic further. Currently, there is no FDA indication for calcium and cancer of the colon and rectum, as further studies are under current investigation.

Hypoparathyroidism

Low levels of PTH occur due to autoimmune or surgical destruction, abnormal congenital development, impaired PTH regulation, or muted PTH effect. The systemic effect is hypocalcemia, which can range from mild to severe symptoms.

Surgical destruction most often occurs during thyroid, parathyroid, or neck surgery. For example, it is the most common complication following a thyroidectomy, in which patients experience acute symptoms of seizures, laryngospasm, prolonged QT, or tetany.[76] Postsurgical symptoms can be transient due to glandular stress or partial parathyroid excision or permanent due to accidental excision.[77][78] Thus, patients should start taking calcium and vitamin D supplements after thyroid surgery and then taper slowly for three to six weeks to avoid symptoms of hypocalcemia.[76]

Autoimmune destruction is another acquired cause and typically begins during childhood or adolescence. The destruction that happens in permanent hypoparathyroidism is a part of autoimmune polyglandular syndrome type 1(APS 1) due to mutations of the autoimmune regulator (AIRE) gene.[79] Further, activating CaSR antibodies can develop, causing fictitious negative feedback and decreased PTH secretion.[80]

Abnormal parathyroid development in utero can be a cause of hypoparathyroidism identified in infants and children. An example of this is DiGeorge Syndrome which happens due to a 22q11 deletion resulting in defective development of the pharyngeal pouch and its derivatives. The effects are cardiac anomalies, hypocalcemia, hypoplastic thymus, and immunodeficiency.[81]

Peripartum Effects

Professional organizations such as the American College of Obstetrics and Gynecology (ACOG) recommend 1,500 mg to 2,000 mg of calcium to prevent the risk of preeclampsia in pregnant women with a baseline calcium intake of 600 mg or less. Similarly, the World Health Organization (WHO) also recommends the same dosage of 1,500 mg to 2,000 mg for pregnant women with low dietary calcium intake and a high risk of gestational hypertension.[82] In a 2020 study, mouse models revealed that placental efficiency was improved among mice receiving adequate amounts of vitamin D and further showed that deficiencies resulted in altered placental morphogenesis and microstructure.[83] Calcitonin has also been shown to increase during pregnancy and among lactating mothers and is thought to be a protective measure to suppress maternal bone loss.[16]

Neonatal hypocalcemia can occur within the first few days of life. Prematurity is the most common factor predisposing a neonate to develop neonatal hypocalcemia. Other conditions that increase the risk include maternal diabetes, maternal hyperparathyroidism, and being small for gestational age.[84] Early-onset neonatal hypocalcemia is often asymptomatic and occurs within the first few days of life. Neonates at high risk for hypocalcemia should be monitored for the first 72 hours for possible hypocalcemia. Late-onset, which occurs after 72 hours, is generally symptomatic, and the neonate may show tachycardia, tachypnea, episodes of apnea, and seizures.[85]

Chronic Kidney Disease

During chronic kidney disease, the effect of PTH can be decreased due to poor renal response. As such, hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism can occur.[17] Due to elevated serum phosphate levels, the parathyroid glands will be activated to secrete more PTH, and the diseased kidney will remain unresponsive. Calcium-containing phosphate binders may be used to lower phosphate levels. Calciphylaxis is a rare complication from calcium-phosphate complexes due to rapid calcification of subcutaneous tissues causing necrotic skin ulcers, and most commonly occurs during advanced renal failure.[86] The use of calcium citrate should be avoided in such patients due to increased intestinal aluminum absorption leading to neurotoxicity and the onset of osteomalacia.[87]

Clinicians should consider the potential consequences of oral calcium intake among patients with chronic kidney disease. Increased oral calcium intake is associated with an increased risk of vascular calcification, especially among patients on dialysis receiving calcium-containing phosphate binders versus non-calcium-containing phosphate binders. According to research analysis, treatment with calcium phosphate binders increased the progression of coronary and aortic calcification in patients with chronic kidney disease concomitantly undergoing hemodialysis.[88]

Conversely, the Dallas Heart Study examined the association between coronary artery calcification (CAC) in adults with end-stage kidney disease in the presence of diabetes. The study concluded that adults with comorbid diabetes and chronic kidney disease had an increased risk of coronary artery calcification as opposed to patients with chronic kidney disease alone.[89]

Calcium Nephrolithiasis

Increased calcium excretion contributes to the development of renal stones, comprised of either calcium oxalate or calcium phosphate.[13] In the past, patients were counseled to decrease their calcium intake to prevent hypercalciuria. However, according to research studies, dietary calcium intake appears to decrease the risk of kidney stone formation.[13] It is believed to be related to oxalate absorption through the intestinal tract. When calcium is ingested, a complex with oxalate can be formed, which limits the intestinal absorption of both molecules. However, with dietary calcium restriction, oxalate is more freely absorbed through the intestinal tract and subsequently excreted in greater quantity by the kidneys. As more oxalate is present in the renal system, there is increased calcium-oxalate complex formation leading to kidney stones. A 2012 study evaluated this effect among 5400 women, and it was observed that women with a history of kidney stones had higher levels of calcium absorption and similarly found that increasing calcium intake resulted in lower levels of absorption.[13] Thiazide diuretics increase renal calcium reabsorption, remove calcium from the renal system, and can be prescribed for calcium stone prevention in the absence of primary hyperthyroidism.[90]

Quality Control and Lab Safety

Laboratory errors during retrieval and analysis can provide inaccurate information to the medical team. Errors in calcium measurements have been reported when anticoagulant-containing collecting tubes are inadequately filled.[91] The method and quality of the sample can also affect calcium levels, especially among lipemic or hemolyzed samples, due to hemoglobin interference. Lipemia should be removed from the specimen before testing, as it is a source of many laboratory errors. A 2018 study analyzed methods used to recover lipemic samples and promote removal by ultracentrifugation as the best method to maintain specimen integrity without exceeding the limit for clinically significant interference.[92] It has also been reported that venous occlusion during retrieval can mildly elevate calcium levels at the site due to hemodynamic changes. Suspicion of a lab error requires that a new sample be retrieved and evaluated.[5]

Enhancing Healthcare Team Outcomes

Patients should be managed appropriately to receive the best care to improve outcomes and reduce morbidity. Given that calcium is implicated in various biochemical pathways, it is important to understand how it can be affected by various diseases and medical therapies. An interprofessional approach is recommended to tailor each patient’s needs and treatment accordingly. For example, patients taking bisphosphonates should receive continuous follow-ups for the adverse effects of long-term use, such as osteonecrosis of the jaw, particularly in patients with multiple myeloma or metastatic bone disease.[93] Many medical therapies and interventions can affect calcium homeostasis, which necessitates that medical teams coordinate and communicate to discuss recommendations and assure patient safety.[94]

Interprofessional patient care involving clinicians (MD, DO, NP, and PA), nursing staff, pharmacists, and possibly dieticians can address calcium levels and coordinate activity to provide corrective actions when necessary, leading to optimal patient outcomes. [Level 5]