Hypocalcemia in the Older Adult: Pathophysiology, Diagnosis, and Treatment
Key words: Hypocalcemia, hypoparathyroidism, vitamin D deficiency, hungry bone syndrome, primary hypoparathyroidism.
Calcium is the third most abundant ion in the body and plays a significant role in maintaining normal cellular function, neural transmission, cell membrane stability, blood coagulation, intracellular signaling, and integrity of bone structure. In plasma, calcium takes three forms: (1) ionized (the biologically active form), accounting for 50% of total serum calcium, (2) bound to plasma proteins, typically albumin, accounting for 40% to 45% of total serum calcium, and (3) complexed to anions, including bicarbonate, lactate, phosphate, and citrate, accounting for the remaining 5% to 10% of total serum calcium.1 When calcium levels drop below normal levels, hypocalcemia results. Hypocalcemia is defined as a total serum calcium level lower than 8.5 mg/dL or an ionized serum calcium level lower than 4.7 mg/dL.2 It is a relatively common electrolyte disturbance, and it is not uncommonly observed in a broad spectrum of older adults, from asymptomatic persons to those who are critically ill. Although values of total calcium in the serum may be below what is considered normal based on reference ranges, it is important to remember that it is the ionized calcium and not the total (bound and unbound) that is associated with symptoms of deficiency, such as fragile bones, bone and joint pain, kidney stones, excessive urination, fatigue, nausea, vomiting, and loss of appetite.
Approximately 80% of the protein-bound fraction of calcium is bound to albumin; thus, persons with abnormally high or low levels of albumin will have either a falsely high or low value of total serum calcium, respectively. In hyperalbuminemic or hypoalbuminemic states, a formula is commonly used to “correct” for high or low levels of serum albumin: subtracting or adding 0.8 mg/dL (0.2 mmol/L) for every 1 g change in serum albumin above or below the mean reference value for these laboratory assessments, respectively.3 Since the accuracy of this method of estimating the true value of serum calcium is poor, an ionized calcium concentration should be obtained whenever there is concern. Normal levels of serum ionized calcium are 4.65 mg/dL to 5.25 mg/dL (1.16-1.31 mmol/L). When abnormal serum ionized calcium levels are found, corrective measures should be taken. This article discusses the clinical manifestations of hypocalcemia, the underlying pathophysiological mechanisms that lead to abnormally low calcium levels, and how patients should be assessed and treated when hypocalcemia is observed.
Clinical Manifestations of Hypocalcemia
Hypocalcemia results whenever there is a net efflux of calcium from the extracellular fluid in greater quantities than the intestines or bones can replace. Symptoms are primarily neurological, with the inadequate calcium levels causing hyperexcitability of neuronal membranes. Neurological symptoms may include an altered mental status, confusion, depression, psychosis, gait disturbances, muscle twitching, paresthesias, tremors, seizures, muscle rigidity, or tetany. Clinical signs of latent tetany may include the Trousseau sign, in which a carpopedal spasm occurs when an inflated blood pressure cuff is left on the arm for several minutes, thereby creating ischemia of the nerves in the upper arm.3 The Trousseau sign is usually achieved by inflating a sphygmomanometer cuff to 20 mm Hg above the systolic blood pressure for 3 to 5 minutes. The result is thumb adduction, metacarpophalangeal joint flexion and interphalangeal joint extension, and the Chvostek sign, which occurs when one taps on the facial nerve in front of the ear causing a contraction of the muscles of the eye, mouth, and nose.4 Tetany may be associated with numbness, cramps, carpopedal spasm, laryngeal stridor, and generalized convulsions.
Hypocalcemia may also cause cardiac effects, including prolongation of the QT interval, which is typically one of the condition’s earliest manifestations. Other signs and symptoms may include subcapsular cataracts in those with prolonged hypocalcemia, and calcifications in areas of the brain, such as the basal ganglia, cerebral cortex, and cerebellum, as noted on computed tomography scans. In rare cases, Parkinsonism, choreoathetosis, and even dysphonic spasms may be noted.
Numerous conditions can cause hypocalcemia (Table). What follows is a review of some of the most common causes of hypocalcemia.
The four parathyroid glands, lying on the outer corners of the thyroid gland, produce and secrete parathyroid hormone (PTH). Along with the hormone vitamin D, PTH regulates the body’s calcium and phosphate levels and activates the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the active form of vitamin D that stimulates calcium and phosphate absorption from the gastrointestinal tract. When the parathyroid glands fail to secrete sufficient quantities of PTH, hypoparathyroidism develops, which is a low calcium level paired with a high phosphorus level. In patients with hypoparathyroidism, PTH is either undetectable or inappropriately normal in the setting of low serum calcium levels. This helps distinguish this entity from pseudohypoparathyroidism, a rare familial disorder with target tissue resistance to PTH, in which hypocalcemia is associated with hyperphosphatemia and elevated PTH levels.
Hypoparathyroidism can occur sporadically or from a primary disorder caused by a genetic mutation that is either autosomal dominant (eg, Barakat syndrome), autosomal recessive (eg, Wilson’s disease), or X-linked with or without other polyglandular failure.3 Activating mutations of the parathyroid and renal calcium-sensing receptor leads to inhibition of parathyroid hormone secretion and, hence, hypocalcemia and hypercalciuria. The hypocalcemia is usually mild and asymptomatic and may escape detection until late in life.3 Autoimmune hypoparathyroidism may occur in isolation or in patients with one or more other autoimmune disorders, such as autoimmune polyendocrine syndrome type 1. Idiopathic hypoparathyroidism is an uncommon condition characterized by the absence of, fatty replacement of, or atrophy of the parathyroid glands. It may be familial or sporadic. To diagnosis idiopathic hypoparathyroidism, the following criteria are necessary: low serum calcium levels; high serum phosphorous levels; and the absence of renal insufficiency, steatorrhea, chronic diarrhea, and alkalosis. Rickets and osteomalacia must also be excluded and patients must not have recently received transfusions or chelating agents. While idiopathic or autoimmune hypoparathyroidism is usually diagnosed earlier in life, it may not be diagnosed until maturity is reached and should always be considered if other causes of hypocalcemia have not been found. With proper treatment, individuals may attain normal levels of serum calcium and be able to lead normal lives.
Hypoparathyroidism may also have a variety of other etiologies. Injury to or removal of the parathyroid glands during neck surgery is the most common cause of hypoparathyroidism. With advancement in surgical techniques and improved medical care, more elderly patients are undergoing neck surgeries, resulting in a rising incidence and prevalence of acquired hypoparathyroidism in this population. Postsurgical hypoparathyroidism is usually transient, but it can be permanent due to irreversible damage to the parathyroid glands. Other possible etiologies of hypoparathyroidism include immune-mediated destruction of parathyroid glands; defective regulation of parathyroid hormone secretion, activating mutations of calcium-sensing receptors; infiltration of the parathyroid glands by iron, copper, amyloid protein, or metastasis; defects in the parathyroid hormone molecule; reduced parathyroid function due to chemical or drug toxicity; sarcoidosis; radiation or mechanical injury; or infection.3,5 Hypoparathyroidism may exist for many years without any clinical signs or symptoms and may only be diagnosed after another condition further lowers the patient’s calcium level.