lied #{237}a
tries
VOLUME 6 JULY 1950 NUMBER 1
ORIGINAL
ARTICLES
ENDOCRINE
HOMEOSTASIS
IN
CLINICAL
PEDIATRICS
By NATHAN B. TALBOT, M.D. Boston
S
x
MONTHS or a year ago it might have been appropriate to introduce these remarkswith comments on the fact that endocrinology encompasses much more than the
diagnosis and therapy of such primary endocrinopathies as pituitary gigantism,
thyro-toxicosis, sex precocity and the like. The remarkable current reports on the therapeutic
actions of adrenal cortical hormones and of pituitary adrenocorticotropic hormone
(ACTH) already have shown that there may be as much or more endocrinology in a
patient with rheumatoid arthritis, ruptured appendix, pneumonia, status asthmaticus or
thermal burn as in the pituitary dwarf or eunuch. In fact it appears safe to say that there
is hardly an organ or structure in the body that is not influenced directly or indirectly
by endocrine forces or a clinical condition that is not accompanied by functional or
homeostatic alterations on the activity of some endocrine gland.
These homeostatic reactions constitute to a major extent, as Walter Cannon once put it,
“the Wisdom of the Body.” Most of the time they work so efficiently that we forget
that they exist and are playing an important role in bodily defense and recovery reactions.
This thought may be worthy of illustration by a few arbitrarily selected situations. In
presenting these illustrations I wish to emphasize that they represent the cumulative
researches of many investigators working in many laboratories over a considerable period
of time.
Figure 1 presents observations on a child with psychogenic polydipsia who was
sub-jected to water restriction. This restriction was accomplished by omitting all fluids except those contained in solid foods. It is seen that such a physiologically normal individual is
able quite effectively to conserve body H20 (weight) and to prevent hemoconcentration
(elevation in blood hemoglobin) by increasing urine solute concentration (specific
gravity). This increase in concentration is brought about by an increase in posterior
E. Mead Johnson Award Address, read at the Annual Meeting, American Academy of Pediatrics,
San Francisco, Nov. 15, 1949.
From the Children’s Medical Service, Massachusetts General Hospital, and the Department of Pediatrics, Harvard Medical School, Boston.
‘75
BODY WEIGHT KILOGRAMS
70
2 HEMOGLOBIN GM./IOOCC.
URINE CONCENTRATION
SPECIFIC GRAVITY
TINE IN HOURS
AS. U.625239
S 12 lB 24 30 35
2 NATHAN B. TALBOT
pituitary antidiuretic hormone (ADH) production. ADH production is controlled by
hypothalamic osmo-receptors which Verney and others have shown to be acutely sensitive
to changes in blood osmotic pressure.
Figure 2, which presents data obtained on a patient with diabetes insipidus, shows
how seriously failure of this homeostatic mechanism handicaps an individual. Irrespective
of the needs of the organism for water conservation, urine water output is determined
by the load of solutes (osmoles) presenting to the kidneys for excretion. Consequently,
upon water restriction or deprivation, H20 is apt to be drained from the body with
I.03C
1.025
1.020
1.015
1.010
1.00
FIG. 1. Effect of restricting water intake to that contained in solid foods upon urine concentration, blood hemoglobin concentration and body weight of child with psychogenic polydipsia and polyuria.
(From unpublished data of Crawford, J. D., and Talbot, N. B.’)
resultant marked hemoconcentration and generalized dehydration (body weight loss).
(See Fig. 3.)
Figure 4 presents some information concerning the opposite phenomenon of
over-hydration due to overloading of the ADH-renal water excretory mechanism with
exces-sive amounts of H20. It is known that under conditions of zero ADH action and a
sizable urinary osmolar load, maximum urine volumes are produced. In the human this
urine volume is approximately equal to 15% of the glomerular filtration rate.* Stated
in other words it is about 15,000 ml./m2 (30 kg. child)/day. When the load of H20
presenting to the kidneys for excretion exceeds this ceiling value, excess H20 accumulates
* There is obligatory reabsorption of the other 85% of glomerular filtrate by renal tubules. In the
adult glomerular filtrate volume is about 100 l./m’/day. In the newborn period it is about half that
1200
lOO0
SOOt
URINE SOLUTES
24
THE RELATION OF URINE SOLU1’ES
TO URINE VOLUME IN
DIABETES INSIPIDUS
0
B 0 0
0
0
200
0
0 1000 2000 3000 4000 5000
URINE VOLUME
CC/U2/24_
ENDOCRINE HOMEOSTASIS IN CLINICAL PEDIATRICS 3
in the body and the blood becomes diluted. As this phenomenon becomes extended,
circulatory collapse, renal failure, hematuria and death occur.
Such data remind us of the fact that we are constantly being served, in fact one might
say saved, by this remarkable hypothalamic-posterior pituitary-renal mechanism. Provided
this mechanism and the cardiovascular system are intact, one need not worry about
ad-ministering any volume of isotonic, electrolyte-free H20 which does not too closely
approach the ceiling rate of 15 l./m’/day, or 10 ml.,/m’/minute. Recognition of this fact
has aided us in the management of patients requiring parenteral fluid therapy. For
ex-.imple, Dr. James L. Gamble once pointed out that the factor which may determine more
FIG. 2. Observations on relation between urine volume and urine solute (osmole) output of patient with diabetes insipidus. Note that relation between these 2 variables remains constant. (From
un-published data of Crawford, J. D., and Talbot, N. B.’)
than any other the survival of infants suffering from severe chronic diarrhea is exhaustion
of body caloric stores.#{176}Simple calculations reveal that an adequate caloric intake can be
provided by the intravenous administration of 5 or 10% dextrose in H20 in amounts
(for example, 6000 ml. of 5% dextrose/m2) which are comfortably within the limits just
mentioned. The same thesis holds with respect to other substances which one may wish to
administer but may hesitate to infuse in high concentration.
As a second illustration, one may turn to phosphorus homeostasis and the parathyroid
glands. Figure 5 sets forth observations obtained in intact and parathyroidectomized rats.
The abscissa indicates that groups of animals were fed rations varying in phosphate
content* from nearly zero to the maximum quantity which can normally be eliminated
* Note that only a portion of phosphate intake is eliminated by way of urine; the remainder either
FIG. 3. Effect of water deprivation upon urine concentration, blood hemoglobin concentration and body weight of patient with diabetes insipidus. Patient of this experiment is same as that of Fig. 2.
(From unpublished data of Crawford, J. D., and Talbot, N. B.’)
FIG. 4. Illustration of effect of increasing rate of water administration above physiologic limits upon
rate of urine production, body weight and blood hemoglobin concentration of normal rats. Note that
as rate of water administration is increased, there is cbmpensatory increase in urine flow up to ceiling
value equal to approximately 15% of assumed glomerular filtration rate of 50 l./m2/day. Incidentally,
note also that increase in water intake initially resulted in overadjustment of urine water outgo. This
re-sulted in transient period of body weight (water) loss which was unaccompanied by detectable changes
ENDOCRINE HOMEOSTASIS IN CLINICAL PEDIATRICS . 5
with the aid of the parathyroid-renal mechanism without prompting significant pathologic
disturbances in body fluid composition (i.e., serum phosphorus concentration) . It is seen
that the intact animals were able to take and excrete the various amounts of phosphate
indicated without showing more than minor changes in serum phosphorus concentration.
By contrast, it is evident that the parathyroidectomized animals developed marked
hyperphosphatemia which culminated in tetany and death if their phosphorus intake was
raised even slightly.
z 0 I-4 I-z 0 O’ 00 OG In 0 I 0. Id U) 0 4. 0 -Jc,,J Il) U) 0 I 0.
FIG. 5. Illustration of effects of varying phosphate intake upon urine phosphorus output and serum
inorganic phosphorus concentration of normal, intact and of parathyroidectomized rats. Note that
lower left-hand ordinate scale is expressed as mg./m’/24 hr. Because renal glomerular filtration rate
in rats is approximately same as in newborn human infants (circa 50 l./m’/day), data shown for rats
may be considered comparable to data obtained for young infants. Hence parenthetic indications of
breast milk and cow’s milk phosphorus intake equivalent. (From unpublished data of Crawford, J. D.,
Osborne, M. M., and Talbot, N. B.6)
These phenomena find a counterpart in infant feeding. Note first that the infant fed
human milk is receiving a phosphate intake comparable to the lowest recorded in figure
5. As recently shown by Drs. L. I. Gardner and A. M. Butler, such infants rarely show
a pathologic elevation in serum phosphorus concentration.7 By contrast, the infant fed a
cow’s milk formula is receiving a much higher phosphate intake. Infants over 3 to 4 weeks
of age can assimilate and eliminate this higher phosphate intake without developing
hyperphosphatemia. However, younger babies are apt, like the parathyroidectomized ani-mals, to develop hyperphosphatemic, hypocalcemic tetany.
Studies have shown that this neonatal lack of ability to eliminate phosphate in
ac-cordance with need can be corrected experimentally by the administration of parathyroid
tern-6 NATHAN B. TALBOT
porary failure of the parathyroid homeostatic mechanism and (b) transgression of the
natural intent that human babies be breast fed.
As a third and final illustration, one aspect of the adrenal cortical “alarm reaction”
to stress may be considered. Figure 6 shows how stress of any sort activates a chain of
reactions which start in the hypothalamus, are mediated by the anterior pituitary and are
culminated by an increase in adrenal cortical hormone production.8 Figure 7 describes
STRESS
I
HYPOTHALAMUiJ
‘I!
ANTERIOR
PITUITARY
“A CjTH”
ADRENAL
CORT
ICES
1
ADRENAL
CORTICAL
HORMONES
FIG. 6. Schematic presentation of mechanism by which stress may act to prompt increase in adrenal
cortical hormone production.
diagrammatically one effect of these adrenal cortical hormones upon body metabolism.
It is seen in the left-hand diagram that they act to limit Na and to facilitate potassium
excretion by the kidneys.#{176} These actions greatly increase the body’s ability to support the
vitally important extracellular fluid volume, if need be at the expense of some
intra-cellular water depletion. As has been shown by Darrow and Yannet,1#{176}osmotic pressure
relationships determine the distribution of water between extra- and intracellular
com-partments. Conservation of extracellular Na and elimination of intracellular K favor a
shift of H20 from the intracellular to the extracellular space.
BODY WATER
ENDOCRINE HOMEOSTASIS IN CLINICAL PEDIATRICS 7
such conditions of increased adrenal cortical activity. It is seen that the administered
sodium salt is apt to exaggerate the homeostatic tendency to potassium excretion to a
serious extent. The Na tends to enter the cells and to displace more K. There results
a state of severe intracellular potassium deficiency. This is characterized clinically by
somatic and cardiac muscle weakness, circulatory failure and death. As is being demon-strated with increasing frequency, these unfortunate phenomena can largely be prevented
by administering solutions containing more physiologic mixtures of electrolytes, namely,
solutions of nearly neutral ash and of approximately equal potassium and sodium content.
STRESS STRESS + No CI THERAPY
Extra-cellular Intracellular
,- -‘
Na K
I
Urine Urine
Na K
ADRENAL CORTICAL HORMONES ACT TO IN.
HIBIT RENAL Na AND TO FACiLITATE RENAL
K EXCRETION.
FIG. 7. Schematic diagrams showing how adrenal cortical hormones tend under conditions of stress to inhibit renal Na and to facilitate renal K excretion. As shown in left-hand diagram, this permits body to sustain extracellular fluid volume for time at expense of intracellular water if necessary. In
right-hand diagram it is indicated that isotonic sodium chloride therapy may exaggerate tendency to intracellular potassium loss to pathologic degree.
In conclusion it may be said that the material just presented has illustrated only in
part possible relations between endocrine phenomena and ordinary clinical problems.
For example, no mention has been made of situations where homeostatic endocrine
reac-tions appear, paradoxically, to be working against rather than for the best interests of
the organism. Nor has much been said about natural and artificial factors which may
modify the behavior of the glands of internal secretion and the concentrations of their
respective hormones in the circulation. On the other hand, it is hoped that the material
set forth adequately supports the thought that endocrinology can no longer be relegated
to a small group of enthusiastic specialists. It must gradually become an intrinsic part
of our regular medical practice.
ACKNOWLEDGM ENT
In accepting this award I wish to express my appreciation to you who give it. I should
also like to state my debt to my several associates in the Children’s Medical Service at
Mc-8 NATHAN B. TALBOT
Arthur, Dr. Edna Sobel, Dr. Concepcion Uribe R., Miss Aniela Zygmuntowicz, Dr.
Maurice Osborne, Dr. William Locke and Miss Elsie MacLachlan who have contributed
in a very major way to any accomplishments which this award may recognize. Finally,
it is a pleasure to acknowledge the generous support provided our research endeavors by
Dr. Allan M. Butler.
REFERENCES
1. Crawford, J. D., Nicosia, A. R., and Talbot, N. B., Water homeostasis neurohypophyseal
anti-diuretic mechanism, to be published.
2. McCance, R. A., and Young, W. F., Secretion of urine by newborn infants, J. Physiol. 99:265, 1941.
3. Young, W. F., and McCance, R. A., Secretion of urine by dehydrated and normal infants, Arch.
Dis. Childhood 17:65, 1942.
4. Rubin, M. 1., Bruck, F., and Rapoport, M., Maturation of renal function in childhood: Clearance
studies, J. Clin. Investigation 28: 1144, 1949.
5. Gamble, J. L., Deficits in diarrhea, J. Pediat. 30:488, 1947.
6. Crawford, J. D., and others, Use of ratio of renal tubular phosphorus reabsorption to glomerular filtrate phosphorus as index of parathyroid hormone activity with comments on phosphorus homeostasis, to be published.
7. Gardner, L. I., and others, Etiologic factors in tetany of newly born infants, PEDIATRICS 5:228, 1950.
8. Hume, D. M., Role of hypothalamus in pituitary-adrenal cortical response to stress, J. Clin.
Investigation 28:790. 1949.
9. Forsham, P. H., Thorn, G. W., Prunty, F. T. G., and Hills, A. G., Clinical studies with pituitary
adrenocorticotropin, J. Clin. Endocrinol. 8:15, 1948.
10. Darrow, D. C., and Yannet, H., Changes in distribution of body water accompanying increase and
decrease in extracellular electrolyte, J. Clin. Investigation 14:266, 1935.
