Calcium: Role in Human Physiology and Clinical Chemistry Definition and Importance: Calcium is an essential mineral (an alkaline earth metal) in the body, acting as an electrolyte in blood and interstitial fluid. About 99% of the body’s calcium is stored in bone and teeth (as hydroxyapatite), providing structural strength and serving as a reservoir. The remaining calcium (~1%) circulates in the blood or is present in soft tissues, where it is critical for many biological processes. Key roles of calcium include the formation and maintenance of bones and teeth, enabling muscle contraction, activating many enzymes, supporting normal blood coagulation (clotting), and helping maintain normal cardiac (heart) function. Calcium ions also act as a universal second messenger inside cells, coupling signals (such as nerve impulses and hormone actions) to cellular responses. Thus, maintaining proper calcium levels is crucial for overall health and normal cellular function. Distribution in the Body: As noted above, about 99% of calcium is in the skeleton (bones and teeth). Only about 1% of total body calcium is found outside bone: roughly 0.1% is in the extracellular fluid (blood plasma and interstitial fluid) and the remainder is within cells or intracellular organelles. In blood serum, calcium exists in three forms: approximately 40–45% is bound to plasma proteins (mainly albumin), ~10% is complexed or chelated (to small anions like phosphate or citrate), and about 50% circulates as free (ionized) calcium. This ionized fraction is physiologically active. Intracellular free calcium concentration is normally very low (on the order of 10^–7 M) and is tightly regulated; calcium is sequestered in organelles like the endoplasmic reticulum and mitochondria, where it can be released rapidly in signaling processes. In summary, bone serves as the major calcium store, while blood plasma and cells have far lower levels to enable calcium’s signaling roles. Physiological Functions: Calcium’s functions span many systems: ● Bone and Teeth: Calcium phosphate (hydroxyapatite) gives strength to the skeleton and teeth. Continuous remodeling uses bone calcium to buffer blood levels if needed. ● Muscle Contraction: Ionized calcium is essential for muscle contraction in skeletal, smooth, and cardiac muscle. When a muscle cell is stimulated, calcium is released from internal stores and/or enters from the extracellular space, binding to regulatory proteins (e.g. troponin in skeletal muscle or calmodulin in smooth muscle) and allowing actin–myosin interactions that cause contraction. In cardiac muscle, calcium influx also triggers forceful heartbeats. ● Nerve Transmission: Calcium is critical for neurotransmission at nerve endings. When a nerve impulse reaches a synapse, calcium channels open and Ca^2+ enters the neuron, causing release of neurotransmitter into the synaptic gap (a calcium-triggered process), thus propagating the nerve signal. Calcium also contributes to the electrical depolarization of neuronal membranes. ● Blood Clotting: Calcium is a required cofactor in the coagulation cascade. It assists in multiple steps of clot formation, including activation of clotting factors (e.g. factor X) and the conversion of fibrinogen to fibrin. Without adequate calcium, blood fails to clot normally. ● Cell Signaling and Enzyme Function: As a second messenger, ionized calcium inside cells regulates many enzymes and cellular processes (e.g. secretion of hormones, enzyme activation, membrane stability). Calcium binding proteins (like calmodulin) modulate diverse pathways, and fluctuations in intracellular Ca^2+ trigger cell responses to hormones and other signals. In summary, calcium is indispensable for structural integrity and for the function of muscles, nerves, blood, and various cellular processes. Hormonal Regulation: The body maintains serum calcium in a narrow range via three main hormones: parathyroid hormone (PTH), active vitamin D (calcitriol), and calcitonin. ● Parathyroid Hormone (PTH): Secreted by the parathyroid glands when serum calcium falls, PTH raises blood calcium by multiple actions. PTH stimulates osteoclasts to resorb bone, releasing calcium (and phosphate) into the bloodstream. In the kidneys, PTH increases calcium reabsorption (so less is lost in urine) and simultaneously promotes phosphate excretion. PTH also stimulates the renal conversion of vitamin D to its active form (calcitriol). Calcitriol then enhances intestinal absorption of calcium (and phosphate). These coordinated effects restore serum calcium toward normal. When calcium is high, PTH secretion is suppressed. ● Vitamin D (Calcitriol): Vitamin D (obtained from diet or synthesized in skin) is converted in the liver and then the kidney (under PTH influence) into active 1,25-dihydroxy-vitamin D (calcitriol). Calcitriol acts on the small intestine to increase dietary calcium (and phosphate) absorption. It also promotes bone resorption in the presence of PTH. Adequate vitamin D is thus essential for calcium balance (hence recommended intakes of ~600–800 IU/day). ● Calcitonin: Produced by the thyroid gland’s parafollicular C cells when calcium is high, calcitonin has a minor hypocalcemic effect. It inhibits osteoclast activity (reducing bone resorption) and slightly increases renal calcium excretion[12]. Calcitonin provides a short-term check on hypercalcemia, but its role in humans is less critical than PTH and vitamin D. Together, these hormones ensure calcium homeostasis: PTH and vitamin D act to raise serum calcium when it drops, while calcitonin helps lower it when it rises. Hypocalcemia (Low Blood Calcium): Hypocalcemia occurs when serum calcium falls below the normal range. Causes include hypoparathyroidism (e.g. post-thyroidectomy damage to parathyroid glands), vitamin D deficiency (poor intake or low sunlight), chronic kidney disease (impaired activation of vitamin D and phosphorus retention), low magnesium, and acute severe pancreatitis (calcium binds free fatty acids in injured pancreas). Certain genetic conditions (e.g. DiGeorge syndrome) or medications (bisphosphonates, anticonvulsants, loop diuretics) can also lower calcium. In practice, any condition that impairs PTH production or action, reduces vitamin D, increases renal calcium loss, or significantly decreases intake/absorption can cause hypocalcemia. Symptoms and Complications: Mild hypocalcemia may be asymptomatic or cause vague symptoms. As calcium falls further, patients often develop neuromuscular irritability: muscle cramps or spasms (especially in back or legs), paresthesias (tingling or numbness) in the lips, tongue, hands, and feet, and even painful muscle stiffness. Acute severe hypocalcemia can lead to tetany – involuntary contractions of muscles in the limbs and face – as well as laryngospasm (which can impair breathing) and bronchospasm. Neurologically, hypocalcemia may cause irritability, confusion, seizures, and prolonged QT interval or other arrhythmias on ECG. Chronic hypocalcemia can produce skin and hair changes (dry skin, coarse hair, brittle nails), cataracts, and tooth decay. On exam, Chvostek’s sign (facial twitch when tapping the cheek) and Trousseau’s sign (carpopedal spasm with blood pressure cuff inflation) indicate neuromuscular excitability in hypocalcemia. If hypocalcemia is detected (often on routine labs), measurement of serum albumin is important, since low albumin falsely lowers “total” calcium (but ionized calcium may be normal). Treatment generally involves calcium supplementation (oral or IV if severe) and correcting underlying causes (e.g. giving vitamin D if deficient). Without treatment, severe hypocalcemia can be life-threatening due to tetany or cardiac complications. Hypercalcemia (High Blood Calcium): Hypercalcemia is usually defined as a serum calcium above the upper limit of normal. Causes include primary hyperparathyroidism (often a parathyroid adenoma secreting excess PTH) and malignancy. Many cancers (breast, lung, kidney, multiple myeloma) either produce PTH-related protein or metastasize to bone, releasing calcium. Excessive vitamin D intake (supplements or granulomatous diseases like sarcoidosis producing calcitriol) and certain drugs (thiazide diuretics) can also raise calcium. Milk-alkali syndrome (too much calcium/antacid) is another cause. Prolonged immobility or bone diseases (e.g. Paget’s disease) can mobilize bone calcium. In summary, hypercalcemia usually results from either increased bone resorption (PTH or bone destruction) or increased intestinal absorption (vitamin D or supplements). Symptoms and Complications: Mild hypercalcemia is often asymptomatic or causes vague symptoms. When more pronounced, patients may experience the mnemonic "bones, stones, groans, thrones, and psychiatric overtones." Early symptoms include gastrointestinal distress (nausea, vomiting, constipation, abdominal pain) and polyuria (leading to dehydration and thirst). Chronic high calcium commonly causes kidney stones (nephrolithiasis) and can lead to nephrocalcinosis or renal insufficiency. Neuropsychiatric symptoms become prominent with higher calcium levels: confusion, lethargy, depression, or even psychosis can occur. Muscle weakness is common (calcium interferes with neuromuscular activity). Cardiac effects include shortened QT interval and arrhythmias (bradycardia or heart block). In extreme cases, hypercalcemia can cause coma and be life-threatening. Physical exam may reveal hypertension or altered reflexes. Treatment focuses on the cause (e.g. parathyroid surgery, treating cancer) and may include hydration and diuretics to promote calcium excretion[31]. Laboratory Measurement: Serum calcium is usually measured as total calcium in a blood sample (mg/dL or mmol/L). Normal adult total calcium is roughly 8.5–10.2 mg/dL (2.15–2.55 mmol/L), though reference ranges vary slightly by lab. About 40–45% of total calcium is albumin-bound, ~10% complexed, and ~50% free (ionized). Since only ionized calcium is physiologically active, low albumin levels can make total calcium appear low even if ionized calcium is normal. In such cases, a corrected calcium is calculated: for every 1 g/dL drop in serum albumin below 4.0 g/dL, about 0.8 mg/dL is added to the measured total calcium. Equivalently, clinicians may order a direct ionized calcium test. Normal serum ionized calcium is roughly 4.5–5.3 mg/dL (1.1–1.3 mmol/L) in adults. Laboratory evaluation of calcium disorders also includes albumin, phosphate, magnesium, PTH, and vitamin D levels. An EKG may be checked (hypocalcemia prolongs QT; hypercalcemia shortens it). Interpretation: Low total calcium with normal albumin suggests true hypocalcemia only if ionized calcium is also low. Conversely, hyperalbuminemia can falsely raise total calcium. Always assess albumin when interpreting calcium results. Dietary Sources and Requirements: Because the body cannot produce calcium, it must be obtained from the diet. Dairy products (milk, yogurt, cheese) are the richest sources. Other good sources include canned fish with bones (e.g. sardines, salmon), green leafy vegetables (kale, broccoli, bok choy), nuts, and fortified foods (certain juices, cereals, plant milks). For example, an 8‑oz glass of milk or cup of yogurt provides about 250–300 mg of calcium. The U.S. Recommended Dietary Allowance (RDA) for most adults (19–50 years) is 1,000 mg/day. Women over 50 and both genders over 70 are advised about 1,200 mg/day to maintain bone health. Adolescents (9–18 years) need even more (about 1,300 mg) for growth. Vitamin D intake (e.g. 600–800 IU/day) should accompany calcium to ensure adequate absorption. If dietary intake is insufficient, supplements (such as calcium carbonate or citrate) are often recommended, especially for at-risk groups (postmenopausal women, elderly) to prevent osteoporosis.