Disorders of Calcium and Phosphate Metabolism

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An overview of the interaction between calcium, phosphate, PTH, calcitriol, and calcitonin:

 

  Physiology:

Calcium and phosphate metabolism is based on a balance between intestinal absorption, bone mineralization and demineralization, and urinary filtration and reabsorption.  The major direct regulators of this balance (besides dietary intake) are parathyroid hormone (PTH) and 1,25 (OH)₂-cholecalciferol (aka calcitriol), with a minor contribution from calcitonin. 

PTH is a peptide hormone secreted by the chief cells of the parathyroid glands.  PTH levels change very rapidly with alterations in serum calcium, as the half-life of PTH is only 10 minutes.

Calcitriol is the active form of vitamin D₃, a hormone produced from cholesterol, through enzymatic steps in the liver and kidneys, and a non-enzymatic UV-dependent step in the skin (which can be bypassed by adequate dietary intake of cholecalciferol).

Calcitonin is a peptide hormone secreted by the C cells of the thyroid.  Calcitonin levels are generally very low (sometimes non-detectable) in most people, only rising in the setting of severe hypercalcemia or medullary carcinoma of the thyroid.

In general, changes in serum calcium affect PTH levels more, while changes in serum phosphate affect calcitriol levels more.  Although both electrolytes are interrelated, an isolated derangement of one generally leads to only a mild derangement of the other.

Production of calcitriol:

           

Regulation of PTH Secretion:		Effect of pH on Calcium/Phosphate Metabolism: Low pH ? Increased secretion of PTH ? Increased urinary excretion of phosphate ? Increased net acid excretion by increased buffering of excreting H+ ions

                                   

At any one time, most of the calcium in the body exists as the mineral hydroxyapatite, Ca₁₀(PO₄)₆(OH)₂.

Calcium in the plasma:               45% in free, ionized form (the physiologically active form)

45% bound to proteins (predominantly albumin)

10% complexed with anions (citrate, sulfate, phosphate)

To estimate the physiologic levels of ionized calcium in states of hypoalbuminemia:

 [Ca⁺²]_Corrected = [Ca⁺²]_Measured  +  [ 0.8 (4 ? Albumin) ]

The binding of calcium to albumin is also pH dependent, increasing with alkalosis, and decreasing with acidosis.

Overview of the Differential Diagnosis of Calcium Disorders

Hypercalcemia

Symptoms: Polyuria, dehydration, confusion, depression, fatigue, nausea/vomiting, anorexia, abdominal pain, and renal stones.  (Aside from nephrolithiasis, most symptoms are not seen until serum [Ca⁺²] > 12mg/dL.)

Signs: Diminished reflexes, short QT interval on ECG.

Etiologies:

Increased GI Absorption of Calcium

Milk-alkali syndrome (The combination of hypercalcemia, alkalosis, and renal insufficiency seen in the setting of high intake of milk or CaCO₃.  Predominantly occurs in renal failure, osteoporosis, or GERD)

                Elevated Calcitriol

Vitamin D excess

Chronic granulomatous diseases ? This is most common in sarcoidosis, but also is seen in TB & histoplasmosis.  It occurs because calcitriol can be produced by activated macrophages within granulomas.

                                                Excessive vitamin D intake

Acromegaly (although the combination of acromegaly and hypercalcemia should suggest MEN I)

                                                Lymphoma

                                Elevated PTH (see below)

                                Hypophosphatemia (see section on hypophosphatemia)

Increased Calcium Loss From Bone

Increased Bone Resorption

                                Elevated PTH

                                                Primary hyperparathyroidism

                                                                Adenoma (80% of 1? hyperparathyroidism)

                                                                Hyperplasia (15%)

                                                                Carcinoma (<5%)

Tertiary hyperparathyroidism ? This occurs when an autonomous parathyroid nodule develops in the setting of long standing secondary hyperparathyroidism.

                                                Chronic lithium therapy (probable mechanism)

                                                Acidemia (from any cause)

                                Malignancy (Hypercalcemia in malignancy is a grave prognostic factor: Median survival = 1-6 months)

                                                Osteolytic disease

                                                PTHrP secreting tumor (most commonly squamous cell carcinoma of the lung)

Pheochromocytoma (although the combination of of pheochromocytoma & hypercalcemia should suggest MEN II)

Increased bone turnover

                                Immobilization

                                Hyperthyroidism

                                Hypervitaminosis A / retinoic acid

                                Paget?s disease of bone

                Elevated calcitriol (see above)

Decreased Bone Mineralization

                Aluminum intoxication ? This is most commonly seen in end-stage renal disease.

                Elevated PTH (see above)

Decreased Urinary Calcium Excretion

                Thiazide diuretics

                Familial hypocalciuric hypercalcemia

                Elevated calcitriol (see above)

Pseudohypercalcemia (due to increased protein binding of calcium in hyperprotiein states)

                Severe dehydration (due to concentration of albumin)

                Multiple Myeloma

In ambulatory patients, 90% of cases will be due to hyperparathyroidism.

In hospitalized patients, 65% of cases will be due to malignancy.

Diagnosis:		Phosphate	PTH	Calcitriol	Urinary Calcium
	Primary Hyperparathyroidism	?	??	Variable	? / Normal
	Malignancy	Variable	? / Normal	?	?
	Vitamin D Excess	?	? / Normal	??	? / Normal
	Granulomatous Disease	?	? / Normal	?	?
	Milk-Alkali Syndrome	? / Normal	? / Normal	Normal	Normal
	Thiazide Diuretics	? / Normal	? / Normal	Normal	?

The combination of a thorough history and physical exam, CXR, calcium, albumin, phosphate, alkaline phosphatase, vitamin D level (or calcitriol), and SPEP will correctly identify the etiology of hypercalcemia 95% of the time.  Adding the relatively expensive intact PTH assay to this increases the diagnostic yield to 99%.  The presence of PTHrP can also be checked if its presence is suggested by the preceding tests.

Treatment:

Primary Treatment		Secondary Treatment
Normal Saline (4-6L/day) Furosemide (IV q2 ? q6 hrs; start only after fluid replete)		Bisphosphanates (most useful in hypercalcemia due to malignancy) Calcitonin (develops tachyphylaxis) Glucocorticoids

           

Long-term medical treatment is largely ineffective.

                       

Indications for surgical parathyroidectomy:           1. Serum calcium > 11.5 mg/dL

                                                                        2. Decreased creatinine clearance

                                                                        3. Urine calcium > 400 mg/day

                                                                        4. Decreased bone mass

                                                                        5. Nephrolithiasis

Hypocalcemia

Symptoms: Irritability, muscle cramps, depression, psychosis, bronchospasm, and seizures.

Signs: Increased reflexes, prolonged QT interval on ECG (the only cause of a prolonged QT with a normal duration of the T wave itself)

            Chvostek?s sign ? Tapping of the facial nerve induces contractions of the facial muscles

            Trousseau?s sign ? Inflation of a blood pressure cuff induces carpal spasm

Etiologies:

Decreased GI Absorption of Calcium

            Poor dietary intake of calcium

            Decreased GI absorption with normal dietary intake

                        Decreased calcitriol

                                    Vitamin D deficiency

                                                Poor dietary intake of vitamin D

                                                Inadequate sunlight exposure

Malabsorption syndromes

Drugs ? Any drug which increased activity of the P-450 system, increases inactivation of vitamin D.  These include isoniazid, theophylline, rifampin, and most anticonvulsants.

Nephrotic syndrome ? Due to loss of vitamin D binding protein in the urine

                                    Decreased conversion of vitamin D to calcitriol

                                                Liver failure ? The conversion of vitamin D to calcidiol occurs in the liver

Renal failure - In chronic renal failure there is impaired production of calcitriol from calcidiol, predisposing the patient to osteomalacia, osteitis fibrosa cystica, and osteoporosis.  The hyperphosphatemia often seen in renal failure also blocks conversion to calcitriol.  This condition is often referred to as secondary hyperparathyroidism.

Low PTH (see below)

Hyperphosphatemia ? This is due to the direct inhibition of 1? hydroxylase, which leads to decreased conversion of calcidiol to calcitriol.

Vitamin D dependent rickets, type 1 (aka psuedovitamin D deficient rickets) ? An autosomal recessive disorder caused by a deficiency of 1? hydroxylase.

            Vitamin D resistance

Hereditary vitamin D resistant rickets (formerly called vitamin D dependent rickets, type    2) ? A disorder which manifests as end-organ resistance to calcitriol, most commonly due to mutations in the calcitriol receptor.

Increased Bone Mineralization

            Low PTH (see below)

            PTH resistance (see below)

            Hungry bones syndrome ? The rapid mineralization of bones following parathyroidectomy

            Osteoblastic metastases ? Occurs predominantly in patients with metastatic prostate or breast cancer.

Decreased Bone Resorption

            Low PTH (see below)

            PTH resistance (see below)

            Decreased calcitriol (see above)

Increased Urinary Excretion of Calcium

Low PTH (aka hypoparathyroidism)

                        s/p thyroidectomy (most common cause of hypoparathyroidism)

                        Post I¹³¹ therapy for Graves disease or thyroid cancer

                        Autoimmune hypoparathyroidism

                                    Isolated

Polyglandular Autoimmune Failure, type I ? This is the combination of hypoparathyroidism, Addison?s disease, and chronic mucocutaneous candidiasis.

                        Hereditary hypothyroidism

                        Infiltration of the parathyroid

                                    Hemochromatosis

Wilson?s disease

Metastatic cancer

Congenital hypoparathyroidism

Autosomal dominant hypocalcemia ? The most common form of congenital hypoparathyroidism, characterized by mild to moderate hypocalcemia, relatively high urinary calcium excretion, and relatively low serum PTH concentrations.  The disorder is caused by various activating mutations in the calcium-receptor gene.

DiGeorge Syndrome ? This condition is associated with defective development of the third and fourth pharyngeal pouches, resulting in an absent/hypoplastic thymus, cardiac defects, and parathyroid hypoplasia.  DiGeorge syndrome is usually due to a deletion on chromosome 22.

Hypomagnesemia ? This is seen primarily in alcoholism, malabsorption syndromes, diarrhea, and aminoglycoside use.

PTH Resistance (aka pseudohypoparathyroidism) ? A heterogeneous group of disorders characterized by end-organ resistance to PTH, classified as types 1a, 1b, 1c, 2, and pseudopseudohypoparathyroidism.

            Deficiency of calcitriol (see above)

Internal Redistribution

Pancreatitis (due to formation of calcium salts in retroperitoneal fat)

Intravascular Binding

Citrate excess from multiple transfusions ? Citrate chelate calcium in the serum, dropping levels of the active ionized form, without affecting total calcium levels.

Acute respiratory alkalosis ? Elevated pH causes more calcium to become bound to albumin, also dropping levels of ionized calcium.

Diagnosis:		Phosphate	PTH	Calcitriol
	Hypoparathyroidism	?	?	?
	Psuedohypoparathyroidism	?	??	?
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