Page 133 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

Disorders of Calcium: Hypercalcemia and Hypocalcemia 123

Calcitriol also plays an important role in the regulation
1. DNA synthesis of PTH synthesis and secretion. 538 Calcitriol inhibits
PTH mRNA synthesis 537 and stimulates synthesis of
DNA 99
− 1,25 Vit D 3 the calcium receptor. These relationships explain the
2. Transcription + requirement for adequate blood concentrations of
Normocalcemia
calcitriol to maintain the ability of the parathyroid gland
Pre mRNA
to respond to changes in extracellular calcium
3. Post-transcriptional concentrations. 349,405 Increased intracellular iCa may
processing
mRNA also cooperate with calcitriol to reduce PTH synthesis
in chief cells by inhibiting the expression of calreticulin
(a blocker of VDR action). 526,600 Animals with uremia
4. Translation −
mRNA and reduced serum calcitriol concentrations have poorly
regulated chief cell function that results in renal second-
ary hyperparathyroidism, 217,401 but a significant part of
Secretion
the hyperparathyroid response in uremic patients is the
5 6 8
PreProPTH ProPTH PTH PTH result of a glandular hyperplasia caused by the changes
9
of both calcitriol and serum phosphorus. Serum phos-
Post-translational −
processing phorus concentrations are generally considered to regu-
7
late PTH secretion principally by indirect means. Renal
++
Ca
Amino acids calcitriol synthesis is reduced early in uremia by modest
hyperphosphatemia, and the plasma iCa concentration
Figure 6-4 Synthesis and secretion of parathyroid hormone. Note
sites of regulation of PTH biosynthesis by extracellular ionized may decrease because of reduced effects of calcitriol on
calcium or calcitriol (1,25-[OH] 2 -vitamin D 3 ) interaction. (Modified the intestine, bone, and kidneys. Markedly increased
from Habner JF, Rosenblatt M, Potts JT. Parathyroid hormone: serum phosphorus concentrations (as seen in advanced
biochemical aspects of biosynthesis, secretion, action, and renal failure) can lower the serum iCa concentration
metabolism. Physiol Rev 1984;64:1004.) (mass law effect), resulting in an increase in PTH secre-
tion because of the lowered calcium, but these effects
do not occur early in renal failure when serum phospho-
rus is only moderately increased. 401
Serum magnesium concentration has little role in the
In general, the parathyroid gland has evolved most of its control of PTH secretion under normal conditions, but
regulatory strategies to protect against hypocalcemia, PTH secretion can be inhibited by very high
with sensitive control of PTH synthesis and secretion concentrations of serum iMg. 478 Paradoxically, hypo-
being the dominant sites for regulation. 82,536 However, magnesemia or magnesium depletion also results in an
high serum iCa concentrations increase the rate of degra- inability to secrete PTH, but the cellular mechanism of
dation of PTH within the gland to protect against this effect is unclear. This effect may be partially caused
313
hypercalcemia. by reduced sensitivity of cell membrane receptors to iCa
Except for minor diurnal variation, PTH secretion is in the presence of low serum iMg concentrations. 231,382
relatively constant but may have a mild pulsatile pattern
in response to minor fluctuations in the concentration Set-Point for PTH Secretion
of serum iCa. 81 A relatively low rate of PTH secretion The set-point for PTH secretion is defined as the ECF iCa
is needed normally to maintain serum iCa concentration. concentration that occurs at the serum PTH concentra-
The basal secretory rate of PTH is approximately 25% of tion that is midway between maximal and minimal values
the maximal rate, and PTH is constantly secreted during of PTH obtained experimentally. 81 Normal serum iCa
normocalcemia. Complete inhibition of PTH secretion is concentration is maintained slightly higher than the
not achieved even in the presence of severe set-point; thus, PTH release normally is less than half-
hypercalcemia. 313 maximal (Fig. 6-5).
Hypocalcemia is the principal stimulus for PTH secre- The rate of PTH secretion is inversely proportional to
tion, but epinephrine, isoproterenol, dopamine, secretin, the concentration of extracellular calcium, but this pro-
prostaglandin E 2 , and stimulation of nerve endings portional secretion of PTH occurs only over a narrow
within the parathyroid gland may have minor effects. 231 range corresponding to a serum tCa concentration of
High concentrations of serum and intracellular iCa 7.5 to 11.0 mg/dL. 231 An inverse sigmoidal curve with
inhibit PTH secretion via increased arachidonic acid 62,101 a steep slope results when the relationship between
and possibly subsequent eicosanoid production. 101 The serum iCa concentration and PTH secretion is plotted
control at PTH mRNA synthesis is also critically over a larger range of calcium concentrations
important. 535 (see Fig. 6-5). 81 This ensures large changes in PTH