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
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.]