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Endocrinology - Calcium-Based Disorders - Fast Facts | NEJM Resident 360

More than 99% of calcium in the human body is found in the skeleton. The remaining calcium is in blood and maintained between 8.5–10.5 mg/dL. Nearly half the calcium in blood is bound to either negatively charged proteins or anions, and the remainder is free (ionized) calcium. Control of serum calcium concentration involves the interplay of bone resorption, urinary excretion, and intestinal absorption, which is mediated in part by parathyroid hormone (PTH) and vitamin D.

In this section, we review the presentation, diagnosis, and management of the following calcium-based disorders:

• Hypercalcemia

• Hypocalcemia

Hypercalcemia

Hypercalcemia is defined as a serum calcium level of two standard deviations above the mean of values found in people with normal calcium levels. Hypercalcemia is a common presentation in primary care and the emergency department. Malignancy is the most common cause of hypercalcemia presenting acutely and symptomatically, while primary hyperparathyroidism is the most common cause of chronic or incidentally noted hypercalcemia. Together, they account for >90% of cases. Other causes of hypercalcemia are noted in the following figure:

Calcium Homeostasis and Selected Causes of Hypercalcemia

The serum calcium level is determined mainly by the interplay of three dynamic processes: absorption from the gut, reabsorption by the kidneys, and bone remodeling. Two main calciotropic hormones orchestrate these processes through feedback-loop mechanisms: calcitriol (1,25-dihydroxyvitamin D3) enhances absorption from the small intestine, and parathyroid hormone (PTH) promotes calcium mobilization from the bones and reabsorption in the kidneys, causing an increase in serum calcium levels. Selected causes of hypercalcemia in children are shown at their main sites of pathology. The encircled plus signs indicate the major processes that are enhanced by PTH and calcitriol to increase serum calcium levels. The main mechanisms of action of each hormone are indicated by solid arrows. The main mechanisms involved in disease states are indicated by dashed arrows.
(Source: Case 4-2011 — A 4-Year-Old Boy with Back Pain and Hypercalcemia. N Engl J Med 2011.)

Hypercalcemia of malignancy: Malignancy can cause hypercalcemia through several mechanisms:

• humoral hypercalcemia of malignancy (HHM): caused by systemic secretion of parathyroid hormone (PTH)–related protein (PTHrP)

• activation of vitamin D into its active form (1,25-dihydroxyvitamin D [1,25(OH)2D]) by some lymphomas

• receptor activator of nuclear factor-κB ligand (RANKL)–associated secretion in acute lymphoblastic leukemia (ALL) and some T-cell lymphomas

• ectopic secretion of authentic PTH (rare)

(Source: Hypercalcemia Associated with Cancer, N Engl J Med 2005.)

Hypercalcemia due to primary hyperparathyroidism: In patients with primary hyperparathyroidism, serum calcium levels are elevated due to elevated parathyroid hormone levels. In 80% of cases, this is due to a single parathyroid adenoma. The remainder of cases are due to more than one adenoma or hyperplasia of all four glands. Patients with hyperparathyroidism, including mild cases, are at increased risk for renal stones, bone loss, and fractures.

Surgery is indicated in symptomatic individuals and in asymptomatic individuals who meet one of the following criteria:

• age <50 years of age

• osteoporosis on DXA scan or based on the presence of a fragility fracture

• renal calculi

• impaired renal function

• hypercalciuria

• blood calcium level ≥1 mg/dL above the upper limit of normal

In patients who meet surgical indications but who decline surgery or cannot undergo surgery due to medical comorbidities, medical management with cinacalcet can be used to correct serum calcium levels but may not be as effective in preventing the adverse effects of primary hyperparathyroidism.

Clinical Features

The following table summarizes signs and symptoms of elevated calcium levels:

Signs and Symptoms of Hypercalcemia

Nervous system	Fatigue, depression, irritability Short-term memory and concentration problems
Muscle	Muscle weakness Muscle pain
Bone and joint	Weakening bones Bone and joint pain
Kidney	Kidney stones Frequent urination Kidney disease
Digestive problems	Abdominal pain Nausea, vomiting Constipation Ulcers Pancreatitis

Diagnosis

• Most laboratories measure total serum calcium level.

• Serum level of ionized calcium is important to measure in situations (including malignancy) where changes in albumin level can affect total serum calcium level.

• PTH should be measured to help differentiate between PTH-related causes of hypercalcemia (including malignancy, primary hyperparathyroidism) and non-PTH related causes (including sarcoidosis and milk alkali syndrome).

• Phosphorous and vitamin D (at least 25-hydroxyvitamin D); plasma 1,25(OH)2D can also be considered and should be measured if granulomatous disorders or the 1,25(OH)2D lymphoma syndrome are included in the differential diagnosis.

Management

Treatment for hypercalcemia is aimed at lowering serum calcium by inhibiting bone resorption, increasing urinary calcium excretion, or decreasing intestinal calcium absorption. Use of the following treatment options will depend on the cause and severity of hypercalcemia:

• aggressive intravenous (IV) volume repletion: usually at a rate of 200–500 mL/hr but depends on the patient’s volume state; target urine output of approximately 2 mL/kg/hr

• loop diuretics (furosemide): only after the patient is adequately volume repleted to allow continued volume expansion without causing volume overload

• IV bisphosphonates (zoledronic acid or pamidronate, adjusted for presence of renal dysfunction): should be administered immediately because they can take as long as 2 days to start working

• denosumab: a human monoclonal antibody against RANKL that inhibits the maturation, function, and survival of osteoclasts

• other medications:

• • glucocorticoids: reserved for hypercalcemia due to granulomatous disease/elevated 1,25(OH)2D levels

  • calcitonin: can be used as a bridge treatment until bisphosphonates start working but can be associated with development of tachyphylaxis after several days of use

• following serum phosphorus levels closely and keeping in range

• discontinuing oral calcium supplements and calcium in enteral feeding

• reviewing medications for drugs (including lithium) that may independently increase calcium levels

• treating underlying condition, including malignancy and granulomatous disease following treatment of acute symptomatic hypercalcemia

• dialysis as last resort

The Society for Endocrinology Endocrine Emergency Guidance provides a guideline for nonspecialists for the initial phase of assessment and management of acute hypercalcemia.

Hypocalcemia

Hypocalcemia is less common than hypercalcemia and can be classified as acute or chronic. Patients with acute hypocalcemia can have symptoms ranging from perioral numbness and muscle cramps to carpopedal spasm, laryngospasm, and focal or generalized seizures. On physical examination, patients may have signs of neuromuscular irritability, which can be elicited with Trousseau sign or Chvostek sign. Severe hypocalcemia can be associated with ECG changes.

Causes of Hypocalcemia Associated with Low or High PTH

Low PTH	High PTH

• Acquired hypoparathyroidism (surgery or autoimmune)

• Hereditary hypoparathyroidism

• Hypomagnesemia

• Abnormal parathyroid gland development (DiGeorge syndrome)

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• Vitamin D deficiency (decreased intake or malabsorption)

• Vitamin D–dependent rickets

• Chronic kidney disease

• Sepsis

• Hyperphosphatemia (tumor lysis syndrome or acute kidney injury)

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Treatment

• For patients with serum calcium levels between 7.5–8.0 mg/dL:

• • oral calcium and vitamin D supplementation

• For patients with serum calcium levels <7.5 mg/dL:

• • IV calcium

  • frequent monitoring of serum calcium

  • repletion of magnesium

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