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Calcium regulation: Parathyroid physiology


Introduction

Calcium plays a fundamental role in the physiology of all living organisms.

  • At the macroscopic level, calcium is essential to maintaining the structural integrity of the skeleton.

  • At the molecular level, calcium is central to several physiologic processes, including neurotransmitter release, signal transduction, and blood coagulation.

Parathyroid hormone (PTH), the main product of the parathyroid glands, and vitamin D together regulate the serum calcium level.

System structure: The parathyroid glands and the distribution of calcium and phosphorus

The parathyroid gland synthesizes and secretes PTH. Typically, there are four parathyroid glands, with pairs located at the superior and inferior margins of the thyroid capsule ( Fig. 32.1 ).

  • Each parathyroid gland is small, averaging 6 × 4 × 2 mm in size and weighing 40 mg.

  • The parathyroid develops at 5 to 14 weeks of gestation from the third and fourth branchial pouches.

Fig. 32.1, Anatomy of the parathyroid glands. The four small parathyroid glands are found in the capsule of the posterior thyroid or embedded in the thyroid tissue. They share the thyroid’s blood supply.

There are two types of cells in the parathyroid:

  • 1.

    Chief cells

    • a.

      Critical for synthesis and secretion of PTH.

  • 2.

    Oxyphil cells

    • a.

      Unknown function, but have been shown to produce parathyroid-relevant genes, as well as certain autocrine and paracrine factors.

Extracellular and intracellular pools of calcium

The extracellular pool of calcium (the concentration of calcium in the plasma) is tightly regulated and remains remarkably constant, varying from 8.8 to 10.4 mg/dL (2.2–2.6 mM). This extracellular pool consists of three fractions:

  • 1.

    Free, ionized calcium (50%)

  • 2.

    Protein-bound calcium (40%)

  • 3.

    Calcium complexes with anions, such as citrate and phosphate (10%)

The free, ionized calcium fraction is physiologically active and under close regulation by PTH.

The equilibrium between free, protein-bound, and complexed fractions may change under certain conditions.

  • Acidosis increases the proportion of free calcium, while alkalosis decreases it.

  • Increases in citrate and phosphate concentration can also decrease ionized calcium levels.

    • Examples: Blood transfusion (contains citrate for preservation), crush injury (releases phosphate).

On an intracellular level, the concentration of free calcium is only 0.1 µM, or 1/10,000th of the extracellular concentration.

  • The magnitude of this gradient allows for rapid flow of calcium into the cell when calcium channels are opened, transiently increasing the intracellular concentration 10-fold to 100-fold.

  • Calcium pumps and exchangers actively restore and maintain this large gradient.

  • The endoplasmic reticulum, microsome, and mitochondria store calcium in bound form where it is available for rapid intracellular release when signaled.

Inputs and outputs of calcium

For calcium levels to remain stable, the daily amount of calcium absorption must equal the amount of excretion ( Fig. 32.2 ).

  • Dietary intake

    • The dietary intake of calcium of an American adult averages 0.4 to 1.5 g of calcium per day.

    • For reference, a quart of milk contains about 1.0 g of calcium.

  • Gastrointestinal absorption

    • Around 50% dietary intake is absorbed by the gastrointestinal tract, which is regulated by vitamin D (discussed later).

    • In addition, the body secretes calcium into the lumen of the gastrointestinal tract in digestive juices.

    • Incomplete absorption of dietary and secreted calcium results in an average of 0.35 to 1.0 g of calcium lost in the stool every day.

    • This balances out to a net gut absorption of 0.15 to 0.4 g of calcium per day (see Fast Fact Box 32.1 ).

Fast Fact Box 32.1

During periods of growth, pregnancy, and lactation, vitamin D increases the absorption of calcium.

  • Renal absorption

    • Net inputs from the gut are matched by losses from the urinary tract.

    • The kidney filters 10.0 g of calcium per day.

    • It reabsorbs 98% of the calcium, excreting only 0.15 to 0.3 g in the urine.

Fig. 32.2, The dietary intake of calcium of an American adult.

The skeleton serves as both a reservoir and a destination for calcium, depending on the hormonal milieu. There is a dynamic balance between the pool of calcium in the skeleton and in the extracellular fluid (ECF).

  • Skeleton versus ECF

    • About 98% of the body’s 1- to 2-kg total store of calcium is found in the skeleton as calcium hydroxyapatite [Ca 10 (PO 4 ) 4 (OH) 2 ].

    • The ECF described earlier contains a small fraction—only 0.9 g.

  • Remodeling

    • During the course of normal day-to-day bone remodeling, 0.25 to 0.5 g of calcium enters and leaves the ECF from the skeleton, for a net skeletal balance of 0.

    • In times of duress, the skeleton can rapidly mobilize its pool of calcium and replenish the calcium in the critical ECF pool in a matter of hours.

    • This skeletal reservoir is sufficient to prevent hypocalcemia for months to years.

    • However, mobilization of these skeletal reservoirs, as might be expected, can lead to fractures as the bone is depleted of calcium (see Clinical Correlation Box 32.1 ).

Clinical Correlation Box 32.1

The size of the skeletal reservoir of calcium changes with age. Strictly speaking, the net skeletal balance of zero described earlier exists only between the ages of 20 and 30 years. During the period of growth and development of childhood, a gradual positive skeletal balance occurs, and more calcium enters than leaves the skeleton. After about age 30 years, there is a progressive negative skeletal balance. In its more extreme forms, the deficit may lead to osteoporosis.

In light of the effects of aging on bone mass, it is recommended to increase dietary intake of calcium with age.

  • By increasing dietary calcium levels, the body relies less on the skeletal calcium reservoir for maintaining appropriate levels of calcium in the body.

  • The skeletal reservoir is thus protected and the integrity of the skeletal system preserved.

Phosphorus

The hormones that regulate calcium homeostasis are also responsible for regulating phosphorus homeostasis. Phosphorus has numerous roles throughout the body, including:

  • Component of calcium hydroxyapatite that forms bone, phosphorus.

  • Covalently modifies enzymes and substrates during signal transduction (in the form of phosphate).

  • Participates in energy transactions (e.g., adenosine triphosphate [ATP], creatine phosphate).

The distribution of phosphorus is roughly similar to calcium. The adult human body contains roughly 600 g of phosphorus, distributed as follows:

  • Some 85% is stored in crystalline form in the skeleton.

  • Around 100 g is found in the soft tissues as phosphate esters.

  • Around 550 mg is found in the extracellular pool, which is in equilibrium with soft tissues and bone.

    • Phosphorus, generally in the form of inorganic phosphate (HPO 4 2– and H 2 PO 4 – ), circulates at concentrations of 2.8 to 4 mg/dL (0.9–1.3 mM) (see Fast Fact Box 32.2 ).

Fast Fact Box 32.2

Calcium and phosphate circulate at concentrations close to their saturation point. This fact underscores the importance of coordinating the regulation of calcium and phosphate, so that it does not precipitate out into organs or the vasculature.

The gastrointestinal tract absorbs phosphorus considerably more efficiently than calcium, which is more than sufficient for daily requirements.

The regulation of phosphate levels takes place primarily at the level of the kidney by PTH, but vitamin D also plays a role.

  • Increased PTH levels lead to lower plasma phosphate levels by enhancing urinary phosphate excretion.

  • Vitamin D defends against hypophosphatemia by inhibiting the production of PTH.

Overall, the regulation of calcium balance is much tighter than the regulation of phosphate.

System function: Parathyroid hormone and vitamin D

Two principal hormones regulate plasma levels of calcium in response to rapid, daily fluxes of calcium inputs and outputs:

  • PTH

  • Vitamin D

    • 1,25-dihydroxyvitamin D (1,25(OH) 2 D) is the active metabolite of vitamin D.

Specifically, PTH and vitamin D work in concert to raise calcium levels.

  • PTH regulates calcium minute to minute.

  • Vitamin D, on the other hand, acts on a longer time frame and facilitates the effects of PTH.

PTH increases calcium levels by three mechanisms:

  • 1.

    Increasing bone resorption.

  • 2.

    Increasing the renal reabsorption of calcium at the proximal tubule.

  • 3.

    Increasing the synthesis of active vitamin D by the kidney.

Vitamin D increases calcium levels by two mechanisms:

  • 1.

    Increasing the intestinal absorption of calcium.

  • 2.

    Increasing bone resorption.

Fig. 32.3 summarizes the actions of and interactions between PTH and vitamin D in response to a hypocalcemic challenge.

Fig. 32.3, Response to hypocalcemia. Low serum calcium levels lead to an increased release of parathyroid hormone ( PTH ) and increased synthesis of 1,25(OH) 2 D, the active metabolite of vitamin D. The increase in PTH stimulates bone resorption (thereby increasing the flux of calcium from the skeleton to the extracellular fluid), the renal reabsorption of calcium, and the synthesis of vitamin D by the kidney. The increase in vitamin D in turn increases the intestinal absorption of calcium and increases bone resorption. PTH promotes the wasting of phosphate ( PI ) in the kidney, while vitamin D increases its absorption in the intestine.

Calcitonin, a peptide hormone secreted by C cells in the thyroid, also plays a role in calcium homeostasis by lowering plasma calcium levels. However, the participation of calcitonin in calcium regulation is much smaller than PTH and vitamin D and will be discussed later.

Parathyroid hormone

As the most significant mediator of calcium homeostasis, PTH warrants a detailed discussion.

Parathyroid hormone synthesis

The regulation of PTH synthesis occurs via negative feedback loops.

  • Vitamin D and high levels of calcium suppress transcription of the PTH gene.

  • Conversely, hypocalcemia stimulates the synthesis of PTH.

Parathyroid hormone secretion and calcium levels

The secretion of PTH is exquisitely sensitive to circulating free, ionized calcium levels (recall that this is the physiologically active pool).

  • Decreases in calcium levels increase PTH secretion.

  • Fig. 32.4 illustrates the steep, inverse sigmoidal relationship between calcium and PTH secretion.

    • The steep portion of the curve corresponds to the normal range of calcium, reflecting the sensitivity of the parathyroid to minor changes in calcium levels.

    • Small decreases in calcium concentrations dramatically increase PTH secretion.

    Fig. 32.4, The inverse sigmoidal relationship between serum ionized calcium levels and parathyroid hormone ( PTH ). Parathyroid sensitivity is maximal within the normal range, indicated by the shaded area .

The parathyroid detects calcium levels through the calcium-sensing receptor, an extracellular, 120-kDa G protein-linked receptor.

  • Calcium ions serve as the ligand for this receptor.

  • Stimulation of this receptor depresses PTH secretion through the activation of Gq, which is coupled to phospholipase C.

    • This initiates the inositol trisphosphate and diacylglycerol signaling pathway common to many other cell types.

  • The same calcium-sensing receptor is also present in renal tubule cells and in the thyroid C cells, which secrete calcitonin (see Clinical Correlation Box 32.2 ).

Clinical Correlation Box 32.2

Mutations that inactivate the calcium-sensing receptor affect calcium homeostasis. One example is familial hypocalciuric hypercalcemia (FHH), an autosomal dominant, benign condition.

  • Key finding : hypocalciuria in the presence of parathyroid hormone (PTH)-mediated hypercalcemia.

  • In FHH, the mutation alters the set point for calcium in the parathyroid, leading to inappropriate PTH release and thus hypercalcemia.

  • Simultaneously, the same abnormal receptor in the kidney inhibits the renal excretion of calcium, exacerbating the hypercalcemia.

Other modulators of the parathyroid hormone level

Other factors that influence PTH secretion include magnesium, lithium, and aluminum.

  • Magnesium

    • As with calcium, low serum levels of magnesium stimulate PTH secretion, and high levels suppress it.

    • However, paradoxically, chronic, severe hypomagnesemia (1.0 mg/dL, 0.4 mM) suppresses PTH secretion because of depletion of intracellular magnesium levels.

  • Lithium

    • Lithium stimulates PTH secretion by changing the set point for PTH secretion (see Fast Fact Box 32.3 ).

Fast Fact Box 32.3

Hypercalcemia may be seen in patients who receive lithium for manic depression.

  • Aluminum

    • High levels of aluminum inhibit PTH secretion.

    • May be seen in patients with renal failure who are dialyzed against solutions containing aluminum, or who are being treated with aluminum-containing phosphate binders for the hyperphosphatemia observed in renal failure.

Table 32.1 summarizes the regulation of PTH synthesis and secretion.

TABLE 32.1
The Regulation of Parathyroid Hormone Secretion
↑ Secretion ↓ Secretion
↓ [Ca 2+ ] ↑ [Ca 2+ ] negative feedback
↓ [Mg 2+ ] ↑ [Mg 2+ ]
Vitamin D (negative feedback via synthesis inhibition)
PTH , Parathyroid hormone.

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