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Tufts OpenCourseware
Authors: George Tully, M.D., Anastassios G. Pittas, M.D.
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1. Goals

  • To review the hormonal regulation of calcium homeostasis
  • To learn the causes of hypercalcemia and hypocalcemia

2. Learning Objectives

  • Free (ionized) calcium is metabolically active and is tightly regulated. There are two hormones (PTH, vitamin D) and three organs (bone, kidney, small intestine) that are involved in calcium homeostasis. PTH mobilizes calcium from bone and promotes reabsorption of calcium and excretion of phosphorus from kidney. PTH is needed for vitamin D activation. The ionized calcium in the extracellular fluid is the principal regulator of PTH secretion. Vitamin D promotes calcium absorption of calcium from small intestine.
  • Hypercalcemia can affect the kidney (nephrolithiasis), bones (osteoporosis) and overall well-being (leading to malaise, fatigue, confusion).
  • In the outpatient setting, primary hyperparathyroidism (PHP) due to a parathyroid adenoma is the most common etiology. Most patients are asymptomatic. Kidney and bone evaluation is performed to determine need for treatment. Surgery to remove the adenoma (parathyroidectomy) is the treatment of choice. Indications for parathyroidectomy have been recently revised.
  • Familial hypocalciuric hypercalcemia (FHH) arises from a mutation in the calcium sensor. It is a benign disorder that does not require treatment. The clinical presentation of FHH mimics primary hyperparathyroidism, and it is therefore important to recognize to prevent unnecessary parathyroidectomy.
  • Among hospitalized patients with hypercalcemia, malignancy is the most common etiology. Humoral mechanisms account for the majority of malignancy-related hypercalcemia. Most patients are symptomatic and the presence of hypercalcemia generally suggests a poor prognosis.
  • Treatment of hypercalcemia is aimed at lowering the calcium level (if the patient is symptomatic) and managing the underlying cause. Treatment for acute hypercalcemia includes hydration followed by a loop diuretic and agents that inhibit bone resorption (such as bisphosphonates).
  • Symptoms and signs of acute hypocalcemia are neuromuscular and cardiac in origin. Trousseau's sign elicits carpo-pedal spasm. Chvostek's sign elicits ipsilateral contractions of the facial muscle.
  • The cause of hypocalcemia is due to PTH deficiency or resistance, vitamin D deficiency or resistance or complexation of calcium. The most common etiology of hypocalcemia is surgery in the neck (total thyroidectomy or parathyroidectomy).
  • Acute hypocalcemia is a medical emergency. Treatment of acute hypocalcemia requires appropriate amounts of IV calcium while treatment of chronic hypocalcemia requires oral calcium co-administered with the active form of vitamin D.

3. Review: Physiology of Calcium Homeostasis

3.1. Calcium Measurement

Calcium is essential for proper functioning of multiple tissues and organs in the body. Approximately 99% of the total body calcium is deposited in the skeleton, 0.9% is intracellular and 0.1% is extracellular. The latter two fractions play a significant role in cellular function and are tightly regulated. In the extracellular fluid, 50% of the calcium is bound (mostly to albumin with a smaller fraction to phosphorus and citrate) and 50% is free or ionized. Free (ionized) calcium is metabolically active and it is the fraction that is tightly regulated. In clinical situations, we are interested in free calcium. Ionized calcium can be measured directly (4.4 - 5.2 mg/dl) or it can be estimated by measuring total serum calcium (8.5 - 10.5 mg/dl) and correcting for the albumin level. When the albumin level is low (often the case in illness), less of the total calcium is bound to albumin and the proportion that is free is higher. The following formula is used to estimate free calcium in clinical practice: corrected free calcium = measured total calcium + 0.8 x (4.0 - serum albumin). Another factor affecting free calcium is blood pH. Alkalosis will increase calcium binding and will lower the free calcium. That explains why hyperventilation results in numbness (see below for symptoms of hypocalcemia).

3.2. Calcium Regulation

There are two hormones (PTH, vitamin D) and three organs (bone, kidney, small intestine) that are involved in calcium homeostasis. A third hormone, calcitonin, does not play a significant physiologic role. Table 1 summarizes the actions of each hormone and Figure 1 shows the interrelations between the hormones and organs that are involved in calcium homeostasis.

3.2.1. Parathyroid Hormone (PTH)

The actions of PTH are shown in Table 1.

The ionized calcium in the extracellular fluid is the principal signal regulating PTH secretion. Parathyroid cells have a membrane receptor which acts as a calcium sensor. The calcium sensor is a member of the G protein - linked receptor family. Increased extracellular ionized calcium binds to the sensor and leads to activation of the G protein which, in turn, stimulates phospholipase C to generate inositol tri-phosphate (IP3). IP3 affects the intracellular distribution of calcium which results in inhibition of PTH secretion. The identification and characterization of the calcium sensor has opened the door to the development of drugs that bind to the sensor and mimic the action of calcium. These drugs, called calcimimetics, are currently tested in clinical trials and are very promising for treating hyperparathyroidism. Calcium also regulates PTH gene activity. A fall in ionized calcium leads to increased PTH gene expression.

1,25-OH Vitamin D (the active form of vitamin D) has a suppressive effect on PTH gene activity. High levels of l,25-OH Vitamin D decrease PTH mRNA. This observation is of interest clinically, as 1,25-OH Vitamin D or its analogs are useful in suppressing PTH hyperplasia in the secondary hyperparathyroidism of renal insufficiency.

Finally, low Calcium and low 1,25 OH vitamin D stimulate cell division and hyperplasia, while normal levels reduce cell division. In vivo, as blood calcium levels rise, PTH levels fall. However, PTH secretion does not drop to zero even at very high calcium levels. This basal rate of PTH secretion is referred to as the "non suppressible component."

3.2.2. Vitamin D

The actions of vitamin D are shown in Table 1.

Vitamin D is derived from 7-dehydrocholesterol, a precursor of cholesterol, which is found in large quantities in the skin. Under exposure of the skin to the sun (ultraviolet light) , 7-dehydrocholesterol is converted to vitamin D. This constitutes the major way humans derive vitamin D which is also found in foods such as fish oil, fish liver and eggs. A 5-10 minutes of daily exposure to the sun between 11 am - 2 pm provides adequate vitamin D synthesis. Because of the limited food sources of vitamin D and the lack of exposure to adequate sunlight in areas away from the equator (including areas such as New England), fortified food products (milk, orange juice) constitute a significant practical way of obtaining vitamin D. Once synthesized in the skin or absorbed from the gut, vitamin D has to be modified further to become biologically active. The liver converts vitamin D to 25-OH vitamin D which is the storage form of vitamin D. 25-OH vitamin D is converted in the kidney to the active form, 1,25-OH vitamin D.

3.2.3. Calcitonin

Although calcitonin has a pharmacologic role in calcium disorders, its physiologic role in calcium homeostasis is unclear.

Table 1. Actions of hormones regulating calcium
Hormone Organ Action
PTH Bone Activates osteoblasts/osteoclasts leading to bone resorption and release of calcium
Kidney Promotes conversion of 25-OH vitamin D to 1,25-OH vitamin D (active form of vitamin D)
Promotes reabsorption of calcium and excretion of phosphorus
1,25-OH Vitamin D Small Intestine Promotes absorption of calcium
Bone Activates osteoblasts/osteoclasts leading to bone resorption and release of calcium
Parathyroid Gland Decreases PTH gene expression
Figure 1. Calcium Homeostasis
Figure 1. Calcium Homeostasis

4. Hypercalcemia

4.1. Symptoms and Signs of Hypercalcemia

Hypercalcemia, defined as an elevation of the physiologically important free (ionized) calcium is a common clinical problem. Symptoms and signs may be due to the hypercalcemia itself as well as the underlying disease process responsible for the hypercalcemia. Symptoms and signs are also a function of the severity and duration of the hypercalcemia. Hypercalcemia itself can affect many organs and systems and the constellation of symptoms and signs which are often non-specific, have been summarized by the following mnemonic: "stones, bones, abdominal groans and psychic moans". These symptoms/signs, shown in table 2, are characteristic to the hypercalcemia caused by primary hyperparathyroidism. Hypercalcemia can be caused by many different conditions (see table 3) and these may contribute other symptoms/signs which may not be specific to hypercalcemia (for example, granulomatous disease may cause dyspnea). As most cases of hypercalcemia due to hyperparathyroidism (the most common cause) are currently identified at early stages through "routine" blood testing; only 20% of patients exhibit symptoms of hypercalcemia.

Table 2. Symptoms, signs and complications of Hypercalcemia
"Stones" Renal stones (due to hypercalciuria)
Nephrocalcinosis (calcium deposition in kidneys)
Polyuria & Polydipsia (nephrogenic diabetes insipidus)
Renal insufficiency
"Bones" Osteitis Fibrosa
Osteoporosis (cortical (distal radius) > trabecular (spine)
Gout, Pseudogout, Chondrocalcinosis
"Abdominal groans" Constipation (decreased smooth muscle tone)
Indigestion/Abdominal discomfort
Gastritis/Peptic Ulcer (calcium stimulated gastric secretion)
Pancreatitis, acute (pancreatic duct obstruction from calcium)
"Psychic moans" Malaise
Memory loss
Confusion, coma (in severe hypercalcemia)
Other Hypertension (renal insufficiency, calcium induced vasoconstriction)
Proximal Neuromusclular weakness

4.2. Etiology of Hypercalcemia

There are multiple causes of hypercalcemia and there are various ways to classify the etiology of hypercalcemia. Table 3 shows one such classification that groups the causes of hypercalcemia according to pathophysiology. The most common causes are discussed in more detail in subsequent sections. Hypercalcemia is common in clinical practice both in the outpatient and inpatient setting. Hyperparathyroidism and malignancy account for over 90% of cases of hypercalcemia. Among hospitalized patients with hypercalcemia, malignancy is the most common etiology. Primary hyperparathyroidism (PHP) is the most common etiology in the outpatient setting. If the diagnostic work-up does not suggest these two common etiologies, then the other etiologies are entertained.

Table 3. Etiology of Hypercalcemia [mechanism]
Hyperparathyroidism-Primary [Adenoma, hyperplasia]
Hyperparathyroidism-Other Variant Forms
  • Familial benign Hypocalciuric Hypercalcemia [parathyroid calcium sensor defect]
  • Lithium therapy [Parathyroid calcium sensor set point shift. Lithium interferes with IP3 metabolism, an intracellular second messenger of the parathyroid calcium sensor. The result is incomplete inhibition of PTH release and mild hypercalcemia]
  • Tertiary hyperparathyroidism in renal failure [clonal expansion in the context of pre-existing non-clonal proliferation]
  • Solid tumor (e.g. lung, esophagus, head & neck, breast cancer), Leukemia [PTHrP secretion]
  • Lymphoma [1,25-OH vitamin D production due to 1-a hydroxylase activity in macrophages]
  • Multiple Myeloma [Local osteolytic factors: interleukin 1 and interleukin 6]
Granulomatous Disease
  • Sarcoidosis, Tuberculosis [1,25-OH vitamin D production due to 1-a hydroxylase in activated macrophages]
  • Thyrotoxicosis [bone resorption]
  • Adrenal insufficiency [hypocalciuria]
  • Pheochromocytoma [ectopic PTH secretion]
    This will have a high iPTH level making it difficult to differentiate from primary hyperparathyroidism
Drug Induced
  • Vitamin A intoxication
  • Vitamin D intoxication [increased calcium GI absorption and increased bone resorption]
  • Milk-Alkali syndrome
  • Thiazide diuretics [lowers urinary calcium excretion]
  • Immobilization
  • Acute renal failure
  • ICU hypercalcemia

4.2.1. Primary Hyperthyroidism Epidemiology

Primary hyperparathyroidism is the most common cause of hypercalcemia in the healthy ambulatory patient. The incidence of primary hyperparathyroidism has increased over the last few decades due to the introduction of "routine" biochemical profiles. It is seen in 1 in 500 patients. It is most commonly seen in the 6th decade and women are affected more often than men (3:1). Pathophysiology

Hypercalcemia results from inappropriate secretion of PTH by one or more of the four parathyroid glands. As reviewed above, calcium regulates PTH secretion and gene activity. In vivo, as blood calcium levels rise, PTH levels fall. In primary hyperparathyroidism, PTH levels are inappropriately high for any given level of free (ionized) calcium.

In 85% of cases, primary hyperparathyroidism is due to a single parathyroid adenoma. The adenoma results from clonal expansion of a single cell which has escaped the normal constraints of cell growth. Mutations that decrease the activity of tumor suppressor genes or increase the activity of proto-oncogenes have been described. In addition to increased cellular activity (higher PTH secretion), adenomas are also more cellular than normal parathyroid glands. Exposure to radiation increases the incidence of adenomas. However, most patients do not have exposure to a known mutagen. Parathyroid adenomas, once they become clinically apparent, maintain a relatively stable course which complicates management (see below). Parathyroid adenomas maintain some of the normal regulatory mechanisms of normal cells but at a blunted fashion. Namely, once a higher than normal calcium level is reached, they may stop growing.

About 15% of cases are due to parathyroid hyperplasia which frequently occurs in family clusters and may be seen as part of multiple endocrine neoplasia syndromes (MEN). The gene responsible for MEN 1 has been linked to markers on the long arm of chromosome 11(11 q 13). MEN 1 patients are missing the band on 11 q 13 that is inherited from the normal parent; thus the abnormal allele expression (or lack of expression) results in the development of neoplasia/hyperplasia. Perhaps this allele encodes for a "tumor suppressor" protein. This 11 q 13 site may also be important in some cases of sporadic parathyroid adenomas. MEN syndromes will be covered during pathology.

Parathyroid cancer is very rare and may run an indolent course mimicking an adenoma. Clinical Presentation and Laboratory Evaluation

The classical manifestations of primary hyperparathyroidism which include nephrolithiasis (kidney stones), nephrocalcinosis (deposition of calcium-phosphate complexes in the renal parenchyma) or Osteitis Fibrosa Cystica (resorption of distal phalanges, "salt and pepper" appearance of skull, bone cysts) are rare. The majority of patients are asymptomatic and the hypercalcemia is discovered at the time of "routine" laboratory tests. A few patients may have vague symptoms such as fatigue, weakness, depression or diminished intellectual function. Subtle defects in renal function (decreased renal concentrating ability or proximal renal tubular acidosis) or reduced bone density (as determined by bone densitometry) may be present.

Laboratory tests are crucial in establishing the diagnosis of primary hyperparathyroidism as most patients will have no symptoms or signs.

  • Blood calcium will be higher than normal - ionized calcium may be used or total calcium may be measured and corrected for serum albumin as described above.
  • In the presence of high ionized calcium, an elevated intact blood PTH level makes the diagnosis of primary hyperparathyroidism. However, occasionally, PTH may be "within normal limits" but it will be clearly "inappropriate" for the level of hypercalcemia.
  • Serum phosphorus tends to be low but it may be normal.
  • Serum alkaline phosphatase may be elevated, indicating a high rate of bone turnover. These patients are at risk for developing hypocalcemia following parathyroidectomy due to "hungry bone syndrome".
  • Assessment of end organ damage will dictate treatment plan.
    • Kidney function evaluation begins with a 24-hour urine collection for calcium and creatinine. Hypercalciuria predisposes patients to developing nephrolithiasis. Measurement of urinary calcium is also very important to rule out familial hypocalciuric hypercalcemia. (urine calcium will be low - see below). Plain x-ray films of the kidney may reveal nephrocalcinosis or kidney stones.
    • Bone evaluation is done with bone densitometry, cortical bone (wrist, hip) is affected primarily. Elevation in alkaline phosphatase is a late finding of bone involvement.
  • Localization of abnormal parathyroid gland(s) . Technetium 99-sestamibi scan of the parathyroid glands is most helpful in localization of adenomas. Arteriogram may be helpful in identifying intrathoracic lesions. Selective venous sampling may help in patients who have had prior neck surgery. Please note that, as in other endocrine diseases, imaging is not done for diagnosis but to confirm the clinical/biochemical diagnosis and to assist the surgeon in localizing the tumor prior to surgical removal. Treatment

Life threatening hypercalcemia associated with hyperparathyroidism is rare. When it does occur it must be addressed as described below in the treatment of malignancy associated hypercalcemia. Surgical removal of the affected parathyroid gland is the definitive therapy for patients with primary hyperparathyroidism. Because all 4 parathyroid glands are involved in hyperplasia, successful therapy requires the removal of 3-1/2 glands. An experienced surgeon is essential for optimal results. Please note that the presence of asymptomatic hypercalcemia secondary to primary hyperparathyroidism is not an indication for surgery. In 1991, the NIH developed a consensus statement outlining the indications for surgical treatment of hyperparathyroidism. These guidelines were updated in 2002 and a summary of the latest guidelines is shown in Table 4.

Table 4. Indications for parathyroidectomy in patient with primary hyperparathyroidism
Measurement Guidelines (2002)
Serum Calcium 1 mg/dl above upper limit of normal
Symptoms/Signs Life threatening episode of hypercalcemia
Presence of of other symptoms/signs of hypercalcemia
Kidney Nephrolithiasis
Hypercalciuria > 400 mg/24 hour
Reduced creatinine clearance by more than 30%
Bone Osteoporosis as defined by a T score less than 2.5 in any site
Age Under age 50 years
Other Patient who requests surgery
Non compliant patient
Patient with comorbidities complicating acute and chronic medical management

Older patients who have a high surgical risk may be followed without surgery. Younger patients should be considered for surgery as the risk of progressive osteopenia is real and frequent medical follow-up is expensive and often incomplete.

Non-surgical approaches are of limited value. Estrogen therapy limits the rise in calcium and protects bones in the selected group of postmenopausal women. However, use of estrogen therapy has risks. Raloxifene, an selective estrogen receptor modulator is a potential alternative. Dietary calcium recommendations are individualized but, in general, calcium intake should not be restricted. Low calcium intake may limit the rise in serum calcium and may reduce the amount of calcium filtered by the kidney, but may accelerate bone loss. Low level of vitamin D supplementation is also recommended. Finally, adequate fluid intake is important to prevent dehydration.

Oral phosphate therapy has limited long term usefulness and may increase soft tissue damage caused by dystrophic calcification. Calcimimetics are new agents that bind to the parathyroid calcium sensor and increase its affinity for extracellular calcium thereby decreasing the release of PTH and reducing the adverse effects of hyperparathyroidism.

4.2.2. Familial Hypocalciuric Hypercalcemia (FHH) Pathophysiology

This is a genetic syndrome with autosomal dominant inheritance. Its clinical presentation mimics primary hyperparathyroidism. Indeed, FHH was first recognized by examining families with hypercalcemia that were not cured by surgery for primary hyperparathyroidism. The pathophysiology of this syndrome has recently been elucidated. In some families the problem is caused by a mutation in the parathyroid calcium sensor. Several point mutations in the extracellular and transmembrane portion of the sensor have been found. Mutations reduce the "sensitivity" of the sensor to ionized calcium such that a higher calcium level is required to suppress PTH release. The parathyroid glands are normal to slightly cellular. A similar calcium sensor exists in the kidney which explains the low urinary calcium excretion (calcium is reabsorbed in the kidney inappropriately). Clinical Presentation & Laboratory Evaluation

Patients are asymptomatic or have non-specific complaints. There is no evidence for end organ damage .The cardinal features of FHH are:

  1. Hypercalcemia which may be identified at any age is mild and persists unchanged until old age.
  2. Hypocalciuria - 24 hour measurement of urinary calcium is needed to distinguish from primary hyperparathyroidism. Urinary calcium/creatinine ratio of less than 0.01 is characteristic of FHH.
  3. PTH level tends to be slightly high or within normal limits but clearly inappropriate for the level of calcium. Treatment

FHH is a benign condition that does not require treatment. It is therefore important to recognize to prevent unnecessary parathyroidectomy.

4.2.3. Malignancy Associated Hypercalcemia Epidemiology

Hypercalcemia of malignancy is the most common etiology of hypercalcemia in the hospitalized patient. Pathophysiology

Hypercalcemia of malignancy is due to excessive efflux of calcium from bone. Two major mechanisms have been described that explain malignancy associated hypercalcemia.

Humoral hypercalcemia is the most common mechanism. It occurs in numerous common tumors such as squamous carcinomas (lung, head and neck, cervix), renal carcinomas, bladder carcinomas and ovarian carcinomas. Affected patients have little or no evidence for bony metastases when hypercalcemia is noted. Bone biopsy shows increased osteoclastic activity. The humoral factors produced by these tumors may be normal products of the tumor derived cells (i.e. eutopic not ectopic). The list of candidates for the humoral factor of malignancy has been selectively shortened recently:

  • Parathyroid hormone related peptides (PTHrP) seen in lung, esophagus, breast cancer and leukemia. PTHrP is a 141 amino acid protein which resembles PTH in the first 13 amino terminal amino acids. This peptide appears to activate osteoclasts via binding to PTH receptors. The gene for PTHrP has been located on human chromosome 12 and may be part of a gene family, which includes the PTH gene (located on the short arm of chromosome 11). The normal function of PTHrP includes lactation and local regulation of calcium pump activity.
  • 1,25-OH vitamin D seen in lymphoma. Certain lymphomas can activate 25-OH vitamin D due to excess 1-hydroxylase enzyme activity.
  • Tumor derived growth factor seen in multiple myeloma. Epidermal growth factor, platelet derived growth factor and transforming growth factors have been isolated in several different settings. These can promote bone resorption. They also cause cells to lose contact inhibition and grow in culture. These factors may not act alone but in concert or with PTHrP.

Local osteolytic hypercalcemia due to metastatic solid tumor. This was formerly thought to be the principal mechanism for hypercalcemia. It probably only accounts for 20% of cases. Metastatic tumors can release factors that directly resorb bone. Metastases can also release factors, which activate local osteoclasts. Breasts and renal carcinomas can release PGE2, a potent stimulator of osteoclasts. Other cytokines may also be important.

Hematologic malignancies. Myeloma and lymphomas can activate osteoclasts through the release of several cytokines (interleukin 1, lymphotoxin and tumor necrosis factor, etc.). The term OAF, Osteoclast Activating factor, encompasses all of these cytokines. Clinical Presentation & Laboratory Evaluation

Severe, acute hypercalcemia from malignancy is common. Volume depletion, vomiting and change in mental status are often seen. Evidence for malignancy is generally present. Hypercalcemia as the first and only presenting feature of cancer is uncommon. The hypercalcemia generally suggests a poor prognosis. Because hypercalcemia is a primary phenomenon, intact PTH is appropriately low. Treatment

Treatment is directed towards lowering the calcium level (see below) and treating the underlying malignancy.

4.3. Laboratory Evaluation of Hypercalcemia

The initial laboratory evaluation of hypercalcemia of unclear etiology includes

  • Free (ionized) calcium or total calcium corrected for albumin
  • Phosphorus
  • Intact PTH

If calcium and iPTH are high, then primary hyperparathyroidism (or its variants) is the cause. A 24-hour urine measurement of calcium is needed to separate among these causes.

If calcium is high and iPTH is low, then further biochemical work-up (e.g. measurement of PTHrP, 1,25-OH vitamin D etc.) is needed . Laboratory evaluation will be further discussed during the small group sessions.

4.4. Treatment of Hypercalcemia

Treatment of hypercalcemia is aimed at lowering the calcium level as well as treating the underlying cause. The following approaches are used for lowering calcium:

  1. Increase urinary calcium excretion - this is accomplished by:
    • Hydration which serves 2 purposes: (1) improves volume contraction which may be profound and (2) increases delivery of sodium, water and calcium to the proximal tubule and loop of Henle.
    • Diuretics (furosemide) - this should be used only after full volume restoration.
  2. Inhibit bone resorption - this is accomplished by agents that inhibit osteoclast function:
    • (Salmon) Calcitonin, given IM/SC works rapidly but loses its efficacy within 2-3 days.
    • Bisphosphonates (Pamidronate IV, Etidronate, Alendronate). These are very effective agents. However, their full effect is not seen until a few days after administration but the effect persists for weeks.
      Other less commonly used agents that inhibit bone resorption include:
    • Mithramycin - efficacious but toxic, so it is rarely used.
    • Gallium Nitrate - efficacious but can be nephrotoxic, so it is rarely used.
  3. Decrease intestinal absorption of calcium
    • Glucocorticoids - decrease conversion of 25-OH vitamin D to 1,25-OH vitamin D. Glucocorticoids are used in lymphoma and granulomatous disease.
    • Phosphate - form insoluble calcium phosphate complex in the gut and will therefore decrease calcium absorption.
  4. Dialysis - may be of benefit to patients who can not tolerate large volumes of fluid.
  5. Chelation of ionized calcium - using sodium EDTA or IV phosphate. May be toxic so this method is rarely used.

5. Hypocalcemia

5.1. Symptoms and Signs of Hypocalcemia

Hypocalcemia, defined as a decline of the physiologically important ionized or free calcium is seen infrequently in clinical practice. Symptoms and signs may be due to the hypocalcemia itself as well as the underlying disease. Symptoms/signs are also a function of the severity and duration of the hypocalcemia. The main symptoms and signs of acute hypocalcemia are neuromuscular and cardiac in origin. Severe acute hypocalcemia is life threatening. Chronic hypocalcemia affects the eye, skin and brain. See Table 5 for symptoms and signs of hypocalcemia.

Table 5. Symptoms and signs of hypocalcemia
Onset of Hypocalcemia Affected Organ Symptoms/Signs
Acute Neuromuscular Acroparesthesias (perioral, fingers and toes)
Tetany, Latent (Trousseau's and Chvostek's signs)
Tetany, Spontaneous (carpopedal, laryngeal spasm)
Cardiac QT interval prolongation
Chronic Eye Papilledema
Skin Dermatitis
Brain Basal ganglia calcification
Mental retardation (children)
Dementia (adults)

Neuromuscular irritability is the hallmark of acute hypocalcemia. Initially, latent tetany may be the only sign elicited by the Trousseau and Chvostek maneuvers. Trousseau's sign is elicited by inflating a blood pressure cuff above systolic pressure for up to 3 minutes. A positive sign is carpo-pedal spasm. Chvostek's sign is elicited by tapping the facial nerve about 1-2 inches anterior to the ear (below the zygoma). A positive sign is ipsilateral contractions of the facial muscle (i.e. twitching of the angle of the mouth). Chvostek's sign is sensitive but not specific for hypocalcemia (up to 25% of people may have it - try it on yourself!). Neuromuscular and cardiac symptoms and signs progress as the degree of hypocalcemia worsens. Tetany is seen when the serum ionized calcium is less than 4 mg/dl which corresponds to 7.5 mg/dl of serum total calcium. Eventually, death may occur from asphyxiation if tetany involves the laryngeal muscle or from cardiac arrhythmias. Alkalosis may enhance the symptoms of hypocalcemia.

Certain symptoms are related not to the hypocalcemia per se but are associated to the underlying etiology (e.g. dysmorphic changes in Albright's osteodystrophy).

5.2. Etiology of Hypocalcemia

There are multiple causes of hypocalcemia and there are various way to classify the etiology. Table 6 shows one such classification that groups the causes based on whether PTH or Vitamin D are involved in the pathogenesis or whether there is complexation of calcium.

Table 6. Etiology of Hypocalcemia [mechanism]

PTH Deficiency

  • Acquired
    • Post surgical, after parathyroidectomy or total thyroidectomy
    • Autoimmune, often as part of autoimmune polyglandular syndromes
    • Hypomagnesemia [causes defective regulation of PTH secretion]
    • Irradiation
    • Infiltrative
  • Congenital
    • Developmental defects of parathyroid glands (DiGeorge's syndrome - aplasia of third and fourth pouch)
    • Autosomal Dominant Hypocalcemia [activating mutation of calcium receptor gene]
PTH Resistance
  • Renal insufficiency [inability to convert 25-OH vitamin D to its active form 1,25-OH vitamin

  • Hypomagnesemia

  • Pseudohypoparathyroidism [congenital defect leading to target organ unresponsiveness to PTH]

Vitamin D Deficiency
  • Nutritional deficiency & lack of skin exposure [decreased synthesis]
  • Rickets type 1 [Hereditary vitamin D deficiency due to lack of 1-alpha hydroxylase]
  • Renal insufficiency [inability to convert 25-OH vitamin D to its active form 1,25-OH vitamin D]
Vitamin D Resistance
  • Rickets type 2 [target organ unresponsiveness to vitamin D due to a defect in the vitamin D receptor]
Complexation of Calcium
  • Extravascular deposition leading to decreased total and ionized calcium
    • Hyperphospatemia due to tumor lysis, rhabdomyolysis or renal failure
    • Pancreatitis [precipitation of calcium soaps in abdomen]
    • "Hungry Bone Syndrome" after parathyroidectomy
  • Intravascular deposition leading to decreased ionized calcium
    • Citrate in blood transfusion [calcium binds to citrate in blood products]
    • Lactate, [calcium binds to lactate]
Intensive Care Unit [multiple mechanisms operating simultaneously]

5.2.1. PTH Deficiency

The most common etiology is hypocalcemia following surgery in the neck (total thyroidectomy or parathyroidectomy). Most patients will develop some degree of hypocalcemia following total thyroidectomy or parathyroidectomy but the majority of them will recover and will not require treatment. Hypocalcemia may also occur as an autosomal dominant condition characterized by an activating mutation of the calcium receptor, which results in hypocalcemia and hypercalciuria. This is the phenotypic opposite of FHH, described above.

5.2.2. PTH Resistance

Pseudohyoparathyroidism presents with hypocalcemia and hyperphosphatemia but increased levels of PTH which suggests resistance to the action of PTH. There are two types.

  • Type 1. There is a defect in the Gs protein of the adenyl cyclase complex which results in decreased cAMP response after PTH binds to the receptor.
    • Type 1a (Albright's hereditary osteodystrophy), in addition to hypocalcemia, is also characterized by an abnormal phenotype (round face, short stature).
      However, if the gene is transmitted from the father, then the affected individual has the phenotype but no hypocalcemia. This disease is an interesting example of imprinting, that is the phenotype varies depending on where the gene came from.
    • Type 1b. There is hypocalcemia only. The defect is still in the Gs protein but the mutation has not been characterized yet.
  • Type 2. There is a blunted phosphaturic response to PTH. The mutation is unclear.

5.2.3. Vitamin D Deficiency & Resistance

Hypocalcemia due to vitamin D problems are more common that due to PTH problems. Patients with vitamin D problems tend to have low Phosphorus in addition to hypocalcemia (see below).

Vitamin D deficiency in adults is most commonly seen due to inadequate nutrition or sun exposure. It is very common in older individuals especially in the northern part of the globe where the intensity of sunlight is diminished in the winter months. In adults, symptoms and signs of vitamin D deficiency are non-specific (fatigue, lethargy, pains and aches) and may be ignored. The diverse role of vitamin D in health and disease is increasingly being appreciated.

Supplementation of food products (dairy, orange juice) with vitamin D has lessened the frequency of vitamin D deficiency.

In renal insufficiency, there is inability to convert 25-OH vitamin D to its active form 1,25-OH vitamin D. These patients need to be supplemented with the active form 1,25-OH vitamin D.

5.2.4. Complexation of Calcium

Calcium may be complexed with other substances resulting in decreased amount of ionized calcium. Complexation may occur either extravascularly or intravascularly, as described in table 6. An example of complexation is "Hungry Bone Syndrome": which may occur, occasionally, after parathyroidectomy for a long-standing parathyroid adenoma. This occurs because there is rapid accumulation of calcium in the bone in the absence of PTH.

5.3. Laboratory Evaluation of Hypocalcemia

Often the etiology of hypocalcemia is obvious (surgical parathyroidectomy). If it is not, then a careful laboratory evaluation will almost always determine the cause. The initial laboratory evaluation of hypocalcemia of unclear etiology includes a measurement of the following in the same sample:

  • Free (ionized) calcium or total calcium corrected for albumin. To confirm hypocalcemia
  • Phosphorus. Low levels suggests an abnormality with vitamin D, high levels suggest hypoparathyroidism (PTH deficiency or resistance)
  • Magnesium. If low, it needs to be repleted
  • 25-OH vitamin D. To assess body stores of vitamin D. A low level reflects inadequate nutritional intake and/or sun exposure
  • 1,25-OH vitamin D. To assess conversion to the active form. It is low in renal insufficiency, Rickets-type 1 or hypoparathyroidism. A high level suggests vitamin D resistance (most often due to Rickets-type 2)
  • Intact PTH. Low levels suggests PTH deficiency, high levels suggest PTH resistance or appropriate response to low vitamin D

Further work-up is dictated by the results of the above testing. Laboratory evaluation will be further discussed during the small group sessions.

5.4. Treatment of Hypocalcemia

The treatment of hypocalcemia varies based on symptoms/signs and the acuity and severity of hypocalcemia. Symptomatic hypocalcemia, especially of acute onset, is a medical emergency and should be approached as such. The treatment of acute hypocalcemia is relatively straightforward. However, a mistake that is often done is that patients do not receive enough calcium. Patients should receive IV calcium, 1-2 ampules of calcium gluconate (180 mg of elemental calcium) over 20 minutes. This should be followed by a slow infusion of calcium over several hours. Intravenous calcium needs to be continued until the patient is on a stable regimen of calcium and 1,25-OH vitamin D (see below). Hypomagnesemia needs to be treated with magnesium supplementation.

Treatment of chronic hypocalcemia depends on the underlying etiology. Patient will generally require a combination of oral calcium and vitamin D (in the form of the precursor vitamin D [ergocalciferol], or the active form [1,25-OH vitamin D] depending on the etiology. It is important to remember that calcium can not be absorbed in the absence of active vitamin D. Similar to the acute situation, one needs to be clear as to the dose and type of the various calcium formulations that are available in the market.

6. References

  • Bushinsky DA, Monk RD. Calcium. Lancet 1998 Jul 25;352(9124):306-11.
  • Riccardi D, Gamba G. The many roles of the calcium-sensing receptor in health and disease. Arch Med Res. 1999 Nov-Dec;30(6):436-48.
  • Strewler GJ. Mechanisms of Disease: The physiology of parathyroid hormone-related protein. N Engl J Med 2000 Jan 20;342(3):177-85
  • Bilezikian JP. Summary Statement from a Workshop on Asymptomatic Primary Hyperparathyroidism: A Perspective for the 21st Century. J Clin Endocrinol Metab 2002 December 87 (12): 5353-5361.
  • Marx, SJ. Hyperparathyroid and Hypoparathyroid Disorders. N Engl J Med 2000 343 (25): 1863-75.