Table of Contents
Calcium is required for efficient cellular function and signaling, as well as neuromuscular transmission, cardiac contractility, hormone secretion, and blood coagulation. Extracellular calcium concentrations are controlled within an extremely narrow range thanks to a number of feedback processes including parathyroid hormone (PTH) and the active vitamin D metabolite 1,25-dihydroxyvitmin D [1,25(OH)2D].
By activating the calcium sensor receptor on parathyroid cells, a reduction in extracellular calcium (Ca2+) causes an increase in parathyroid hormone (PTH) release (1 in figure below). PTH enhances renal 1,25(OH)2D synthesis and increases tubular calcium reabsorption by the kidney (2 and 3 in figure below). To improve calcium absorption, 1,25(OH)2D operates primarily on the gut (4 in figure below). These homeostatic systems all work together to maintain normal serum calcium levels.
If serum PTH levels are low (hypoparathyroidism) or high (hyperparathyroidism), the causes of hypocalcemia can be distinguished (secondary hyperparathyroidism). Hypocalcemia can be caused by a variety of factors, but the most prevalent are a lack of PTH or vitamin D production. Because PTH is the body’s primary defense against hypocalcemia, problems involving PTH deficiency or secretion can result in severe, life-threatening hypocalcemia.Hypocalcemia can be caused by vitamin D deficiency, decreased 1,25(OH)2D production (most commonly due to renal insufficiency), or vitamin D resistance. However, because the parathyroids are capable of establishing a compensatory rise in PTH production, the degree of hypocalcemia in these illnesses is usually not as severe as in hypoparathyroidism. Hypocalcemia can also develop in disorders like burns, rhabdomyolysis, tumor lysis, or pancreatitis, which are all linked to significant tissue damage. Hypocalcemia in these circumstances can be caused by a combination of low albumin, hyperphosphatemia, calcium accumulation in tissues, and reduced PTH production.
Clinical Signs and Symptoms
Hypocalcemia can be asymptomatic if the reduction in serum calcium are minor and long-term, or it can cause life-threatening consequences. Increased neuromuscular irritability causes moderate to severe hypocalcemia, which is characterized by paresthesias in the fingers, toes, and circumoral areas. A Chvostek’s sign (twitching of the circumoral muscles in response to light tapping of the facial nerve slightly anterior to the ear) can be evoked during a physical examination, but it is also present in around 10% of healthy people. A blood pressure cuff inflated to 20 mmHg over the patient’s systolic blood pressure for 3 minutes might cause carpal spasm (Trousseau’s sign). Seizures, carpopedal spasm, bronchospasm, laryngospasm, and a prolonged QT interval can all be symptoms of severe hypocalcemia.
The amounts of albumin, phosphorus, and magnesium can all be measured in addition to serum calcium. The absence or diminished PTH secretion (hypoparathyroidism) is established as the cause of hypocalcemia when the PTH level is suppressed (or “inappropriately low”). The vitamin D axis should be considered as the cause of hypocalcemia if the PTH level is increased (secondary hyperparathyroidism). Serum 25-hydroxyvitamin D levels, which indicate vitamin D reserves, are the best way to determine vitamin D insufficiency nutritionally. Serum 1,25(OH)2D levels are useful in the diagnosis of renal insufficiency or vitamin D resistance.
Derangements in the normal feedback mechanisms that regulate serum calcium can be used to understand and classify the causes of hypercalcemia. Primary neoplastic disorders of the parathyroid glands (parathyroid adenomas, hyperplasia, or, rarely, carcinoma) are associated with increased parathyroid cell mass and impaired calcium feedback inhibition, resulting in excessive PTH production that is not appropriately suppressed by increased serum calcium concentrations. Heterozygous inactivating calcium sensor receptor (CaSR) mutations impede extracellular calcium detection by the parathyroid glands and kidneys, leading in familial hypocalciuric hypercalcemia (FHH).
Although cancers seldom secrete PTH, many solid tumors generate PTH-related peptide (PTHrP), which has a 13-amino-acid similarity with PTH and interacts to the PTH receptor, simulating PTH’s effects on bone and kidney. PTH levels are inhibited by elevated blood calcium levels in PTHrP-mediated malignancy-induced hypercalcemia.
Exogenous calcium overload, such as in milk-alkali syndrome, or total parenteral nutrition with excessive calcium supplementation, as well as disorders that directly increase calcium mobilization from bone, such as hyperthyroidism or osteolytic metastases, cause hypercalcemia with suppressed PTH secretion.
Clinical Signs and Symptoms
Mild hypercalcemia (up to 11–11.5 mg/dL) is frequently asymptomatic and only detectable by routine calcium testing. Some individuals may have a variety of neuropsychiatric symptoms, such as difficulty focusing, personality changes, or depression. Other signs and symptoms include peptic ulcer illness or nephrolithiasis, as well as an increased risk of fracture. Hypercalcemia that is more severe (>12–13 mg/dL), especially if it occurs suddenly, can cause lethargy, stupor, or coma, as well as gastrointestinal problems (nausea, anorexia, constipation, or pancreatitis).
Hypercalcemia reduces the capacity of the kidneys to concentrate, resulting in polyuria and polydipsia. Patients with long-term hyperparathyroidism may experience bone discomfort or pathologic fractures. Finally, hypercalcemia can cause severe electrocardiographic alterations such as bradycardia, AV block, and a short QT interval; the QT interval may be used to track changes in blood calcium.
The first step in diagnosing hyper- or hypocalcemia is to rule out the possibility of aberrant albumin concentrations causing the change in blood calcium levels. Only about half of total calcium is ionized, with the remainder bound to albumin mostly. Although direct measurements of ionized calcium are feasible, they are easily impacted by collection procedures and other artifacts; hence, it is often preferred to measure total calcium and albumin to “correct” the serum calcium. For every 1.0 g/dL decrease in serum albumin below the reference value of 4.1 g/dL for albumin, a corrected calcium concentration is calculated by adding 0.2 mM (0.8 mg/dL) to the total calcium level, and vice versa, for every 1.0 g/dL increase in serum albumin above the reference value of 4.1 g/dL for albumin.
Individuals with familial hypocalciuric hypercalcemia (FHH) may also have modestly raised PTH levels and hypercalcemia; nevertheless, parathyroid surgery is unsuccessful in this situation. A calcium/creatinine clearance ratio of less than 0.01, which is computed as urine calcium/serum calcium divided by urine creatinine/serum creatinine, is indicative of FHH, especially if there is a family history of moderate, asymptomatic hypercalcemia.
Non-parathyroid-mediated hypercalcemia, most typically owing to underlying malignancy, is associated with a decreased PTH level in the context of hypercalcemia. Despite the fact that a tumor that produces hypercalcemia is usually visible, a PTHrP level may be required to confirm the diagnosis of malignant hypercalcemia.
Harrison Endocrinology 3rd Edition.