Disorders of Calcium and Phosphorus Balance

Miraie Wardi

Daniel Coyne

General Principles

The average daily intake of calcium is widely variable, ranging from 400 to 1500 mg/day, much of which is supplemented with oral calcium.
- From that, 20% to 40% is absorbed in the small intestine; the remaining calcium is excreted in the stool along with a small amount of calcium from colonic secretions.
- Maintenance of calcium balance involves buffering in the skeletal system and tightly controlled excretion in the kidneys.
  - In the kidney, 80% to 85% of the calcium load is reabsorbed along the proximal nephron. In the ascending loop of Henle, calcium is reabsorbed passively through the tight junction protein, paracellin-1.
  - Although a smaller percentage is reabsorbed in the distal tubule, distal calcium reabsorption is actively regulated by the actions of parathyroid hormone (PTH).
Over 99% of total calcium in the adult body is stored in the bone complexed as hydroxyapatite crystals. The remaining total body calcium remains in the extracellular fluid (ECF).
The normal total calcium range in the ECF is 8.6 to 10.3 mg/dL. In the ECF:
- 50% of calcium is in the ionized state.
- 40% is bound to albumin; this form is not filterable in the kidney.
- 10% is bound to anions like citrate, sulfate, and phosphate as a filterable complex.
The ionized fraction is physiologically active and plays an important role in neuromuscular activity, secretion, and signal transduction; therefore it is tightly regulated in a narrow range (4.5 to 5.1 mg/dL) by the following mechanisms:
- PTH
  - PTH is released in response to hypocalcemia. The parathyroid gland senses the drop in the ECF ionized calcium concentration via a calcium-sensing receptor, which stimulates the release of PTH.
  - PTH maintains calcium homeostasis via three mechanisms.
    - Increases 1- hydroxylase activity in the proximal tubule, which stimulates the production of calcitriol. Calcitriol increases intestinal calcium and phosphorus absorption.
    - Enhances proximal tubular reabsorption of calcium and decreases proximal tubular reabsorption of phosphorus.
    - Simulates bone turnover and a release of calcium and phosphorus into the ECF.
- Vitamin D is a fat-soluble vitamin present in diet and produced in the skin in the presence of ultraviolet light. 25-Hydroxylase in the liver forms calcidiol.
- Calcitriol is formed in the proximal tubule from 1-α hydroxylation of calcidiol. It can also be formed in activated macrophages.
  - Calcitriol has multiple actions that are crucial in calcium homeostasis:
    - It stimulates calcium absorption in the intestines.
    - It inhibits PTH synthesis and secretion at the parathyroid gland.
    - It promotes osteoclastic bone resorption leading to a release of calcium and phosphorus from the bone.
  - In the bone, calcitriol also increases the production of fibroblast growth factor 23 (FGF23), a key regulator of serum phosphorus levels.
  - Calcitriol is inactivated by 24-hydroxylase. Activity of this enzyme is increased by calcitriol and decreased by PTH.
FGF23 plays a central role in the control of serum phosphorus, but it also contributes significantly to calcium homeostasis as a key regulator of calcitriol and inhibitor of PTH secretion.

Hypercalcemia

General Principles

Clinically significant hypercalcemia can be due to increased bone resorption, increased intestinal absorption, and decreased renal clearance. Primary hyperparathyroidism and malignancy account for the majority (>90%) of cases (please see Table 5-1).

Increased bone resorption

Primary hyperparathyroidism (sporadic, familial, MEN1, MEN2, lithium therapy) is the most common cause of hypercalcemia in ambulatory patients.

An adenoma of a single gland is found in 85% of cases and 15% of cases are due to hyperplasia of all four glands.
Parathyroid carcinoma is responsible for <1% of the cases.
Most patients are asymptomatic with modest hypercalcemia (<11 mg/dL) found incidentally.

These patients remain at risk for long-term consequences of hyperparathyroidism such as nephrolithiasis and osteopenia.

TABLE 5-1 CAUSES OF HYPERCALCEMIA

Increased Bone Resorption
Primary hyperparathyroidism
MEN1 and MEN2A
Malignancy
Postrenal transplant
Immobilization
Familial hypocalciuric hypercalcemia
Thyrotoxicosis
Paget disease
Vitamin A intoxication
Lithium
Adrenal insufficienc

Increased Intestinal Absorption
Milk-alkali syndrome
Granulomatous disease
Vitamin D intoxication

Decreased Renal Excretion
Thiazide diuretics
Acute renal failure
Volume depletion
Vasoactive intestinal polypeptide tumors (VIPoma)
Pheochromocytoma

TABLE 5-2 MALIGNANCY-RELATED HYPERCALCEMIA

Cause	Mechanism	Implicated Malignancies
Osteolytic hypercalcemia	Cytokines produced by the tumor act locally to stimulate bone resorption.	Breast cancer, non–small-cell lung cancer, myeloma, lymphoma
Humoral hypercalcemia	Tumor products act systemically to stimulate bone resorption (PTHrP).	Squamous cell carcinomas and renal, bladder, ovarian cancers
Tumoral calcitriol production	Tumor promotes activation of calcitriol.	Lymphomas

Malignancy is responsible for the majority of cases of hypercalcemia among hospitalized patients. Malignancy induces hypercalcemia in three ways (please see Table 5-2).
Tertiary hyperparathyroidism: Long-term dialysis patients may develop parathyroid hyperplasia and an autonomous secretion of PTH.
Immobilization: Prolonged bed rest leads to an increase in bone resorption and may lead to hypercalcemia.
- This is typically seen in critically ill patients, patients with spinal cord injuries, and those in full body casts.
- Mobilization corrects hypercalcemia.
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder in which mutations in the calcium-sensing receptor lead to decreased receptor activity.
- Patients have a mild hypercalcemia, hypophosphatemia, and normal or mildly elevated PTH levels.
- FHH can be differentiated from primary hyperparathyroidism by a low urinary calcium level.
- Parathyroidectomy is not indicated.
Thyrotoxicosis may stimulate osteoclastic bone resorption, causing a mild hypercalcemia. Concurrent hyperparathyroidism can also occur.
Vitamin A intoxication (doses >50,000 IU/day) can be associated with hypercalcemia secondary to increased osteoclast bone resorption.

Increased intestinal absorption
- Milk-alkali syndrome due to ingestion of large quantities of calcium carbonate–based antacids. It is characterized by hypercalcemia, alkalemia, nephrocalcinosis, and renal failure.
- Granulomatous disease: Granulomatous diseases such as sarcoidosis, tuberculosis, and leprosy cause hypercalcemia due to exogenous production of 1-α hydroxylase which converts calcidiol to calcitriol. Treatment of the underlying disease corrects the hypercalcemia.
- Vitamin D intoxication: May be observed in dialysis patients overtreated with vitamin D analogs. Hypercalcemia is usually mild and improves with dose adjustment or discontinuation of the drug.
Decreased renal excretion
- Acute renal failure
- Volume depletion
- Thiazide diuretics can be associated with a mild hypercalcemia likely due to increased proximal reabsorption from volume contraction.

Diagnosis

Clinical Presentation

Mild hypercalcemia is often asymptomatic and incidentally discovered on routine blood tests. Long-term manifestations include osteoporosis, nephrolithiasis, and chronic kidney disease (CKD).
Severe hypercalcemia is often associated with neurologic and gastrointestinal (GI) symptoms.
- GI symptoms include anorexia, nausea, vomiting, and constipation.
- Neurologic symptoms include weakness, fatigue, confusion, stupor, and coma.
- Renal manifestations include polyuria and nephrolithiasis. Polyuria combined with nausea and vomiting can cause volume depletion, resulting in impaired calcium excretion and worsening of hypercalcemia.

Diagnostic Testing

The first step in the evaluation of presumed symptomatic hypercalcemia is measurement of calcium level. This should be interpreted in the context of the plasma albumin concentration (corrected calcium) or an ionized calcium should be measured.
Confirmed hypercalcemia can then be divided into PTH and non–PTH-related mechanisms with the measurement of intact PTH.
Intact PTH levels are either elevated or inappropriately normal such as seen in primary hyperparathyroidism, FHH, tertiary hyperparathyroidism, and lithium-induced hypercalcemia.
Urinary calcium should be ordered to distinguish FHH from primary hyperparathyroidism. Low urinary calcium concentrations (<200 mg calcium per 24 hours or fractional excretion of calcium <1%) are suggestive of FHH.
Non–PTH-related hypercalcemia can be due to PTH-related peptide or vitamin D metabolite–related mechanisms.
- 1,25(OH)₂D₃ (calcitriol) levels are elevated in granulomatous disorders and calcitriol overdose.
- 25(OH)D levels are elevated with noncalcitriol vitamin D intoxication (rare).
Phosphorus may be low in settings of elevated PTH (primary hyperparathyroidism) or PTHrP (e.g., humoral hypercalcemia of malignancy). Phosphorus may be high in vitamin D toxicity or increased bone resorption without hyperparathyroidism (Paget disease).

Treatment

Volume repletion
- Correction of hypovolemia is the initial goal and often requires at least 3 to 4 L of 0.9% saline in the first 24 hours.
- Continuing maintenance IV fluids after restoring ECF volume promotes further calcium excretion.
- Electrolyte concentrations should be monitored every 8 to 12 hours during induction and maintenance of diuresis.
While repleting intravascular volume is the mainstay of hypercalcemia management, drug therapy is indicated in certain situations.
Dialysis: Both hemodialysis and peritoneal dialysis using dialysate with low calcium are very effective means of treating hypercalcemia. Very low calcium dialysis baths should be used with caution as rapid development of hypocalcemia can occur.
Parathyroidectomy in cases of hyperparathyroidism is indicated if the following criteria are met:
- Corrected plasma calcium >1 mg/dL above upper limit of normal
- Hypercalciuria >400 mg/day
- Renal insufficiency
- Reduced bone mass (T-score <−2.5 by DEXA)
- Age <50 years
- Nephrolithiasis
- Lack of feasibility of long-term follow-up