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chapter 37

Minerai Metabolism

and bilateral renal failure or nephrectom y causes severe

h ypocalcem ia in hum ans.

A n exception seem s to be the hypercalcem ia that occurs

in som e patients w ith chronic granulom atous diseases,

such as tuberculosis, sarcoidosis, and silicosis. The ob-

served increase in circulating l,2 5 -(O H )2D is presum ably

due to the increased 25-(O H )D -la-h yd roxylase activity

found in the inflam m atory cells in the granulom as. The

hydroxylase activity does not appear to be under the usual

tight feedback control by serum calcium levels.

Renal osteodystrophy [due to decreased synthesis o f

l,2 5 -(O H )2D secondary to kidney failure] is treatable

with synthetic l,2 5 -(O H )2D or la-(O H )D . T hese com -

pounds are also useful in other renal disorders such as

hypoparathyroidism and vitam in D -dependent rickets.

D eficien cy o f renal la-h yd roxylase has been found

in patients with hereditary vitam in D -dependent rickets

type I, in w hich the serum concentration o f l,2 5 -(O H )2D

is low. Patients respond to treatment with 1,25-(O H )2D.

Synthesis o f 1,25-(O H )2D is the principal control point

in vitam in D m etabolism . A lthough the serum concentra-

tions o f vitam in D and 25-(O H )D 3 show seasonal and other

types o f variation, serum concentration o f 1,25-(O H )2D re-

m ains constant ow ing to feedback control o f its synthesis.

A ctivity o f renal la -h y d ro x y la se is increased by PTH,

h ypocalcem ia (both through PTH and directly), and hy-

pophosphatem ia. C alcitonin has no effect on the activity o f

the la-h yd roxylase. The interaction o f these factors in cal-

cium and phosphate hom eostasis is show n in Figure 37-3.

Growth horm one, estrogens, androgens, prolactin, and in-

sulin m ay also influence the activity o f la-h yd roxylase

indirectly (Table 37-1). T hyroxine and glucocorticoids

are necessary for bone m ineralization and indirectly influ-

en ce calcium hom eostasis and synthesis o f l,2 5 -(O H )2D

(Table 37-1). G lucocorticoids appear to act as antagonists

o f l,2 5 -(O H )2D , reducing intestinal calcium absorption

independently o f any effect on vitam in D m etabolism . B e-

cause o f the high plasm a concentration o f 25-(O H )D and

the short h alf-life o f circulating l,2 5 -(O H )2D (1 -5 hours),

sm all changes in activity o f the la-hyd roxylase rapidly

change the plasm a concentration o f l,2 5 -(O H )2D. D ev i-

ations from normal serum concentrations o f calcium and

phosphate are rapidly corrected by this m echanism .

The major target tissues for l,2 5 -(O H )2D are bone,

intestine, and kidney (Figure 37-3). In the intestine, ab-

sorption o f dietary calcium and phosphorus is increased.

In bone, resorption is accelerated. In the kidney, 1,25-

(O H )2D is localized in the nuclei o f the distal convoluted

D IE T

S K IN

Cholecalciferol

(DO

l

FIGURE 37-3

Interaction of PTH, calcitonin, and serum concentrations of calcium and phosphate in calcium and phosphate

homeostasis. [Modified and reproduced, with permission, from A. W. Norman,

V itam in D : The C a lciu m H o m eo sta tic

H o rm o n e.

Academic Press, New York, 1979.]