PHYSIOLOGY
OF THE
SWEAT
GLAND
IN
CYSTIC
FIBROSIS
OF THE
PANCREAS
By Sumner H. Gochberg, M.D., and Robert E. Cooke, M.D.
Departments of Pediatrics and Physiology, Yale University School of Medicine
(Submitted March 19, accepted April 19, 1956.)
Aided by a grant from the Playtex Park Research Institute.
Dr. Gochberg was a James hudson Brown Junior Fellow.
Dr. Cooke was a John and Mary R. Markie Scholar in Medical Science.
ADDRESS: (R.E.C.) Johns Hopkins Hospital, Baltimore 5, Maryland.
701
T
HE ORIGINAL demonstration by Darlinget al.’
of an elevated concentration ofsodium and chloride in the sweat of patients
with cystic fibrosis of the pancreas has been
confirmed
by
other workers.4 Thephysio-logic basis for the elevated concentration
of electrolyte in sweat has not been
estab-lished nor has an adequate relationship been
suggested between abnormal function of the
sweat gland and altered secretory function
of other glands.
It is the purpose of this paper to review
the physiology of the sweat gland with
special reference to the factors affecting the
concentration of sodium chloride in sweat.
In addition, experimental data are
pres-ented which suggest a possible basis for the
disturbance in glandular function.
REVIEW OF THE LITERATURE
Anatomy
and
Histochemistry
Human sweat glands are of two types:
eccrine and apocrine. In the eccrine glands,
which are present over most of the body
surface, the secretion is elaborated and
transported through the secretory cell itself.
In the apocrine glands, which are located
in the axibla and perianal region, the
secre-tion actually represents a portion of the
glandular protoplasm which is extruded.
The apocrine glands become functional only
at puberty and are of little importance in
relation to cystic fibrosis of the pancreas.
The eccrine sweat glands are coiled
tubu-lar glands. The secretory portion is a
simple tube formed of a single layer of
cuboidal cells folded into a tight coil. The
excretory duct is a narrow unbranched
tube lined by a double layer of epithelial
cells and a thick cuticular border.
Histochemical studies have shown the
presence of gbycogen and lipidvacuobes and
abundant glycerophosphatase in the eccrine
sweat gland.5 Other workers6 have noted
the presence of alkaline phosphatase and
the absence of acid phosphatase in the same
glands with the highest concentration of
phosphatase in the secretory cells.
By
con-trast, apocrine glands contain no glycogen
much less alkaline phosphatase and some
iron. Shelley7 has noted that the glycogen
in the secretory cells of the eccrine sweat
glands disappears with activity suggesting
that glycogen may be utilized for secretory
energy. The lactic acid of sweat is thought
by some to be derived from cell glycogen.5
Innervation
Thermal sweating is initiated by periodic
discharges from the sudomotor center in the
hypothalamus. .This center may be
stimu-lated directly by elevation of the
tem-perature of the blood perfusing the
hypo-thalamus or may be reflexly stimulated by
cutaneous and visceral impulses. The
im-mediate innervation of the sweat glands is
by means of the thoracolumbar outflow of
the sympathetic nervous system.
As demonstrated in the classic
experi-ments of Dale and Feldberg,9 the chemical
mediator of the postganglionic sympathetic
fibers to the sweat glands is acetylchobine.
In addition, it has been shown that
cho-linergic drugs such as pilocarpine and
methacholine chloride (Mecholyb#{174})
702
GOCHBERG
- SWEAT GLAND IN CYSTIC FIBROSISThis response is blocked by atropine. By
use of a special staining technique,
Hur-ley’#{176}has demonstrated the presence of
a specific cholinesterase in high
concentra-tion around the secretory cells of the
ec-crine glands. Such studies confirm the
theory that acetylchobine is the natural
chemical mediator of the nerve fibers to
the sweat glands. B’ contrast, no specific
cholinesterase could be demonstrated
around the apocrine sweat glands in which
adrenergic mediators probably produce
con-traction of the surrounding myoepithelial
elements and extrusion of duct contents.
1 demonstrated that
dibena-mine, a sympatholytic agent, given
intra-venously almost completely blocks
spon-taneous sweating or sweating induced by
local injection of epinephrine. He concluded
that endogenous epinephrine or
epineph-rine-bike compounds stimulated the sweat
glands, especially of the palms and soles,
and were responsible for the production of
the thick and sticky sweat noted in anxiety.
Sonnenscheinl2 showed that local atropine
completely blocks the sweating on the
palms associated with anxiety and
con-eluded that there was no evidence that
adrenergic mediators played any role in
the transmission of nervous impulses to the
eccrine sweat glands. Likewise, Chalmers
demonstrated that local application of
sym-patholytic agents did not block nervous or
thermal sweating. Since local atropine
blocked both types of sweating, he
con-cluded that acetylchobine is the sole
chemi-cal mediator to the sweat glands. It is possi
ble that intradermal epinephrine stimulates
the myoepitheliab elements of the glands
and leads to evacuation of the ducts as in
apocrine sweating rather than to true
secre-tion. Recent studieslt indicate that each
eccrine sweat gland is responsive to heat,
epinephrine and acetylchobine and that three
different types of eccrine sweat glands
which respond to separate mediators do not
exist. In summary, the data unequivocally
establish that the natural chemical
medi-cator of sudomotor nerves is acetylcholine.
In this respect the sweat gland must be
con-sidered analogous to the mucous glands of
the bronchi, the cholinergic secretory phase
of the salivary glands and the pancreas.
Secretory Mechanics
The manner in which sweat is discharged
from the secreting unit has recently been
described. Kuno’5 states that the secretory
pressures of an individual sweat gland may
be as high as
250
mm Hg. Sweat is secretedin pulsatile bursts rather than
continu-ously.16 At low rates of sweating droplets
appear in infrequent bursts; at moderate
rates of sweating pulsatile flow occurs
regu-larly with an average frequency of 6 to
7/mm. The initial response to mild exercise
is an increase in the number of functioning
glands; with greater stimulation there is an
increase in the output of each gland.17 The
mean output of a single sweat gland has
been calculated to be 0.03 mg/mm. A gland
on the dorsum of the hands secrets at about
one-half the rate of a gland on the arms or
legs. However, the number of sweat pores
varies considerably from one region of the
body to another, ranging from 350 on the
dorsum of the hand to
150
on the anteriorchest.18
Rates of sweating differ markedly in
vari-ous areas of the skin.’9’20 Thermal sweating
is greatest on the trunk, less on the head
and least on the extremities. Weiner2’
calcu-lated the relative intensity of sweating for
various regions of the body utilizing the
relationship of percentage of total sweat
contributed by a region of the body to the
percentage of total surface contributed by
the same region. The relative intensity was
as high as 1.4 on the head and as low as
0.2 on the palms during thermal sweating.
As noted above, the glands of the palms
of the hands, soles of the feet and axiblae
are primarily activated in response to
emo-tion.
Chemical Composition
Sodium, potassium, chloride, lactate and
urea comprise 90% of the osmotically active
substances in sweat.4#{176} Relative to cystic
703
TABLE I
FAcTOIIS 1’RODUCING A DECIIEASE IN CONCENTRATION
OF’ SODIUM AND/OR CHIORIDE IN SWEAT
A.Systemic
1. Relative hyperadrenalism
a. l)OCA, ACTH
b. Adrenal tumor
c. Hyperthyroidism
d. Increased K intake
e. Na deficit
f. Acclimatization
g. Repeated muscular work
B. Local
1. Low skin temperature
a. Acclimatization (?)
. Flushing gland
of sodium chloride in sweat is of greatest
importance. In Table I are listed factors
which decrease the sodium chloride
con-centration of sweat. These factors have
been divided somewhat arbitrarily into
systemic and local influences.
An increased output of salt and water
hormone of the adrenal or injection of
desoxycorticosteroid (DOCA)-like steroids
markedly reduces the concentration of
so-dium chloride in the sweat.22’ 23
Adreno-corticotropin (ACTH) produces a similar
effect but cortisone administration does not
alter sweat electrolyte concentration.24 It is
of interest that the effect of injected adrenal
steroids on renal reabsorption of sodium
chloride is transitory, whereas the decreased
sodium chloride concentration of sweat is
present as long as the drug is administered.
It is likely that the significantly lower
con-centration of sodium in sweat in cases of
severe hyperthyroidism as contrasted with
mild cases is due to the relative
hyper-adrenocorticism that accompanies this
dis-order. Sodium depletion, potassium excess,
acclimatization and repeated muscular work
probably express their effects through
in-creased output of adrenal steroids. Relative
hyperadrenalisni must be only one factor in
acclimatization since increased sweating at
lower rectal temperature and lower skin
temperature and improved cardiovascular
tolerance to heat have all been observed
after 10 to 14 days’ exposure to high
en-vironmental temperatures.2528
Local factors such as preliminary
flush-ing of the sweat gland reduce the
concentra-tion of nitrogen and potassium in sweat and
bead to more stable values for the
concentra-tions of sodium and chloride. This
phe-nomenon has been described as a washing
out of retained sweat concentrated by the
ducts.29
The factors which are known to increase
the concentration of sodium chloride are of
even more importance in regard to cystic
fibrosis of the pancreas (Table II).
Hor-monal influences such as hypoadrenalism
produce an effect opposite to that
pro-duced by hyperadrenalism. In addition,
certain nonendocrine factors influence the
electrolyte composition of sweat. An
in-creased rate of sweating, elevated skin
temperature, elevated rectal temperature
and elevated deep skin temperature lead
to an increase in concentration of sodium
and chloride in sweat.28’3032 Locke et al.24
devised a chloride rate index as an
expres-sion of electrolyte concentration to correct
in part at least for these nonhormonal
fac-tors. This index will be discussed in detail
later. It has also been demonstrated that
sweat collected from different skin areas of
the same individual varies in salt
con-TABLE II
FACrOR8 PRODUCING AN LxcasE IN CONCENTRATION
OF SODIUM AND/OR ChLORIDE IN SWEAT
A. Systemic
1. Relative hypoadrenalism
a. Addison’s disease
b.Panhypopituitarism
c. High NaCl intake 2. Elevation of rectal temperature 3. Elevation of deep skin temperature
B. Local
I. Region-espeeially palmar
2. apor barrier
3. Skin temperature
4. Increased rate
5. Prolonged sweating (fatigue)
6. Arterial occlusion
704
GOCHBERG
-SWEAT
GLAND
IN
CYSTIC
FIBROSIS
533 Palmar and axiflary sweat have
very high concentrations of sodium
chlor-ide especially with intermittent sweating.
Numerous studies have shown that sweat
collected under an impermeable vapor
barrier has higher solute concentration
than sweat collected from the whole
29336 Whether this increased
con-centration is due to back diffusion of
water, increased skin temperature or
in-creased rate of sweating, or a combination
of these factors has not yet been fully
de-termined.
Prolonged diaphoresis brings about a
lowering of the rate of sweating and a rise
in concentration of the electrolytes in
sweat.37 The recent study of Schwartz59
indicates that this effect is due to a local
“fatigue” of the sweat gland and is not due
to an effect on innervation. The same effect
has been noted with intermittent arterial
occlusion.#{176} Randall concluded that
ische-mia affected the nervous regulation of
secre-tion and that the site of this action was not
primarily in the glands.39 Yet in view of the
marked alteration in composition of sweat,
the ischemia may well involve the activity
of the glands themselves.
The factors which have been shown to
produce little or no change in
concen-trations of electrolytes in sweat are listed in
Table III. No detailed discussion need be
given.
EXPERIMENTAL STUDIES
The following experimental studies were
undertaken to determine the possible role
of some of these factors in causing the high
concentrations of electrolytes in sweat
TABLE III
FAc’roRs PRODUCING No CHANGE IN CONCENTRATION
OF SODIUM OR CHLORIDE IN SWEAT
A. Systemic
1. Prehydration
2. Plasma [Na] or [Cl]
3. Pitressin 4. Physical condition
B. Local
1. Relative humidity
which characterize patients with cystic
fibrosis of the pancreas. Only a relatively
small number of cases have been studied
since this was not an attempt to confirm
or deny the finding of abnormal sweat in
all patients with cystic fibrosis of the
pancreas. The purpose of these studies was
to ascertain the physiologic basis for the
high concentrations of sodium chloride by
the use of techniques not previously
re-ported in the study of these patients.
Sweat was collected from the whole body
to avoid the effects produced by an
im-permeable vapor barrier and regional
van-ations in composition of sweat. This
tech-nique also permitted a more accurate
measurement of rates of thermal sweating
under controlled conditions of temperature
and humidity.
Subjects
Nine children#{176} with cystic fibrosis of the
pancreas and six normal controls were studied
in these experiments. Ages ranged from 6 to 13
‘ears. The diagnosis in these children had been
established by clinical course, duodenab
intuba-tion and roentgenograms of the chest. Previous
studies of sweat had been performed in some
cases. Siblings were used as controls. Two of
the six had previously been shown to have
normal concentrations of electrolytes in sweat.
None had ever manifested any of the clinical
stigmata of cystic fibrosis of the pancreas. It is
realized that any differences in composition of
sweat between these patients and their
sib-lings might be bess than similar
compari-sons with nonrelatives since incomplete
ex-pression of the disease might be present in
the siblings. All subjects were on normal diets
except for some limitation of fat intake in
pa-tients with cystic fibrosis of the pancreas. The
study was conducted in the midsummer of
1955. Patients and controls were studied
simul-taneously in order to eliminate differences in
acclimatization.
Procedure
All subjects were initially washed with tap
water and then rinsed several times with a
* We are indebted to Dr. Harry Shwachman,
Boston, Massachusetts, for permission to study two
of his patients and to the Children’s Cystic Fibrosis
Association of Connecticut for their co-operation
total of 3 to 6 liters of distilled water. After
being dried with towels previously freed of
electrolyte by repeated washing in distilled
water, the subjects were weighed on a beam
balance sensitive to thlO gm. They were then
seated in a large chemically clean metal tub.
Room temperature was maintained at 36.6
0.6#{176}C.Relative humidity remained between 50
and 60% throughout the experiments.
After 1 hour of exposure the subjects
breathed through a Collins two-way flutter
valve for 6 minutes. The inlet valve led from
a Douglas bag inflated with air which had been
freed of carbon dioxide and water by previous
passage through sodium hydrate asbestos and
anhydrous calcium sulphate absorbents. The
expired air was collected in another Douglas
bag and subsequently was forced through
columns of the same two absorbing agents.
Output of water and of carbon dioxide was
calculated from the change in weight of
ab-sorbents.
At the termination of the 2-hour period of
heat exposure, the entire body surface was
washed with distilled water. The subjects were
dried with an electrolyte-free towel which was
left in the tub to equilibrate with the 3 to 6
liters of body washings. The subjects were
then reveighed and samples of venous blood
were drawn.
Methods
Skin washings were drained through a
stop-cock in the base of the tub and measured in a
graduated cylinder. They were filtered through
electrolyte-free filter paper to remove body
detritus and stored in a refrigerator. Aliquots
of washings and serum for determination f
urea were frozen to minimize the activity of
urea splitting organisms. Sodium and potassium
were determined by internal standard flame
photometry. Chloride was determined on a
Patwin polarograph by the author’s
modifica-tion of the method of Zimmerman and Layton41
using a mercurous sulfate electrode and
sul-furic acid as the supporting electrolyte. This
method agreed within 2% of the open Carius
method and had a reproducibility of ±1.5%.
The concentration of urea in serum and
wash-ings was determined by a modification of the
coborimetric method of Archibald2 or by the
Conway microdiffusion method. Analyses for
lactate in sweat collected beneath a vapor
barrier in other subjects were performed by the
coborimetric method of Barker and
Summer-son.44
Calculations
I. Sweat Vol. (gm) = AWt. of body - Resp.
H2O
- Insensible cutaneous H20 -(CO2
02)
a. Insensible cutaneous H20 = 0 since
diffusion theoretically stops when skin
is covered with moisture.45
b. CO2 - 02 0 since this correction
is bess than 3% even in the al)sence of
sweating and less than 0.5% at these
sweat rates.54
II. Solute Concentration in Sweat (mEq/l) =
Vol. wash X Cone, in wash
Sweat Vol.
III. Resp. 1120 (gm/kg/hr) =
zWt. of absorbent(H20)
x
60Time X Body Wt.
IV. Sweat Rate (gm/rn2) =
Sweat Vol. in 2 hours
Surface area jn rn2
V. Caloric Expenditure =
Wt. of absorbent(c02
x
22.4 X 4.8120Results
RQ X Time X 44
The rate of sweating in the patients with
cystic fibrosis of the pancreas ranged from
267 to
406
gm/m2/2 hr with a mean of 299;the values in the controls ranged from 224
to 368 gm/m2/2 hr with a mean of 257.
These differences were not considered
sig-nificant especially since estimation of
sur-face area from the nomogram of Dubois
may be in error in malnourished patients.
The respiratory water loss in four subjects
with cyctis fibrosis of the pancreas varied
from 0.59 to 0.83 gm/kg/hr with a mean
of 0.65. In controls values ranged from 0.57
to 0.67 with a mean of 0.64. Levine
et al.’#{176}
found that under basal conditions children
had a total insensible water loss of 1.0
gm/kg/hr. Burch and Winsor47 state that
52% of the total insensible weight loss is
derived from respiratory water loss. The
increased environmental temperature
pro-* At the assumed respiratory quotient of 0.82
each liter of 02 consumed is equivalent to 4.812
706 COCHBERC - SWEAT GLAND IN CYSTIC FIBROSIS
N
u’nerIii,’
CONTROLS
C.F.
a
50 30 50 10 10 ISO 530
of
Na
tsjum ter
4
n
#{234}6.O&
[j
8087(1TPDLS C.F
2
10 30 50 79 90 ISo 130
mEM/L
of
CI.
Fa;. 1 (Upper). Distribution of values for the concentration of sodium in whole body sweat in nine patients and six controls. The mean values are given aiove the graphs.
a
I
H
FIG. 3. Distribution of values for the concentration of potassium in whole body sweat.
(lucmg some hyperventilation probably
accounted for the higher values obtained in
this study.
The calculation of caloric expenditure
for the 2-hour period revealed a mean
ex-penditure of 107 calories in the patients
with a range from
85
to 120 calories and amean of 151 calories in the controls with
a range from 110 to 184 calories. In four
patients the mean rate of sweating per 100
calories was 274 grn while in the
corre-sponding controls the mean value was 211
gm per 100 calories. The unavoidable
hy-perventilation of untrained subjects,
espe-cially controls who had never received
aerosol therapy, probably accounted for the
elevated carbon dioxide output and thus
the high calculated caloric expenditure.
The concentration of sodium in whole
body sweat of nine patients with cystic
fibrosis of the pancreas ranged from 42 to
87 mEq/l with a mean of 79. The range for
the controls was from 11 to 35 mEq/l with
a mean of 18. The concentrations of chloride
N
correlated closely with the concentrations
of sodium, ranging from 51 to 137 mEq/l
in the patients, with a mean of 80, while
the concentrations in the controls ranged
from 10 to 35 mEq/l with a mean of 16.
The concentration of potassium in the
sweat of the patients with cystic fibrosis
of the pancreas ranged from 5 to 29 mEq/l
with a mean of 10, while the
concentra-tions in sweat of the controls ranged from
4 to 8 mEq/l with a mean of 6. As shown
1w Figures 1 and 2, there was no
over-lapping of values for sodium and chloride
concentration between patients and
con-trols. Figure 3 demonstrates the frequent
overlap of values for potassium.
The concentration of urea in the sweat
averaged 55 mg/100 ml in the patients and
58 mg/100 ml in the controls with a
nar-row range of values in both groups (Fig.
4). Urea concentrations in the plasma were
within normal limits in all subjects (two
samples lost in laboratory accident). The
mean ratio of urea concentration in sweat
6.47 10.66
4
3
H
CONTROLS C.. F.
___
--3
ill
5 10 15 20 25 302
3
2
3o So
o
90iso
UREA
M/ioo
cc.
of
Sat
FIG. 4. I)istribution of values for the concentration of urea in whole body sweat.
70S GOCHBERG - S\VEAT GLAND IN CYSTIC FIBROSIS
Number
3
158.5
U
CONTROLS C.F.
to urea concentration in plasma ifl patients
was 1.78 while in controls the mean ratio
was 1.88. These values are in fairly close
agreement with the value of 1.75 obtained
Iw Schwartz et al.5 utilizing sweat
col-]ected under a vapor barrier after
intra-dermal Lecholvl stimulation. This ratio
was relatively constant regardless of a
large change in rate of sweating or a
25-fold increase in the concentration of urea in
plasma. His findings also agree with the
conclusion of \Veiner and van Fleyningen35
that the concentration of urea in sweat does
not change with rate of sweating, skin
temperature or concentration of chloride
and as others have also shown, is always
greater than the concentration of urea in
plasma.48#{176}
The concentration of lactic acid in the
sweat of four patients with cystic fibrosis
ranged from 100 to 143 mg/100 ml with an
average of 121. The lactic acid in sweat
in nine controls ranged from 45 to 290
mg/l00 ml with an average of 155.
Al-though the number of determinations is too
few to draw any definite conclusions, the
differences between normals and patients
are probably not significant and in no way
approach the differences in sodium or
chloride concentration. These values also
are of the same order of magnitude as
those obtained by Mickelsen and Keys in
normals.33
Skin temperature obtained from several
areas of the body were the same in patients
with cystic fibrosis as in controls. Likewise,
rectal temperatures taken at 20-minute
709
this laboratory have shown no unusual
variations between children with cystic
fi-brosis of the pancreas and those with other
diseases.
Discussion
The analyses of the whole body sweat
ob-tamed in this study confirm the findings of
di Sant’Agnese51 and Shwachmans2 who
col-lected sweat under an impermeable vapor
barrier. These authors found elevated
con-centrations of sodium and chloride in sweat
in 99% of living patients with pulmonary
signs characteristic of cystic fibrosis of the
pancreas and low or absent tryptic activity
in the duodenal juice; and in 100% of
pa-tients who at necropsy had characteristic
pancreatic lesions. The concentrations of
sodium in sweat in the present group of
patients were several fold higher than
those of the controls, with no overlapping
of values. The mean for patients was 79
mEq/l. The mean for controls was 18
rnEq/l. The batter value is somewhat lower
than that given by many authors using
different techniques for collection with
varying environmental conditions and rates
of sweating. This value, however, is within
the range reported by Pratt, Cooke and
Dar-row53 who used techniques similar to those
employed in the present study.
From data collected in these experiments
and from data in the literature, it is possible
to eliminate as causes of the abnormal
con-centrations of electrolytes in sweat of
pa-tients with cystic fibrosis of the pancreas
certain factors which are known to affect
concentrations of sodium chloride in sweat
in normals (Table II). Relative
hypoadrenal-ism is probably not responsible since
uri-nary excretion of sodium chloride is not
excessive during salt restriction. Likewise,
injection of ACTH into these patients leads
to a normal fall in circulating eosinophiles,
a normal rise in excretion of 17-ketosteroid
and an insignificant fall in sodium
concen-tration in sweat.3 Differences in degree of
acclimatization and diet between the two
groups were eliminated by the design of the
study and could not be responsible for the
high concentration of electrolyte in sweat.
Measurements of rectal and skin
tempera-ture, likewise, revealed no differences
be-tween the groups. The collection of whole
body sweat also eliminated the possibility
of an increased response of the patients
with cystic fibrosis of the pancreas to the
presence of a vapor barrier during
collec-tion of sweat. Rate of sweating was not
markedly different in the two groups under
standardized test conditions even though
profuse sweating is observed clinically in
many of these patients at times when
normal children do not sweat
signifi-cantly. After correction of the
concen-tration of chloride in sweat for differences in
rate of sweating by means of the equation*
of Locke
et
al.,24 an eightfold differencebetween patients and controls remained.
The mean sweat chloride rate index for the
controls in this experiment was 0.0075 which
falls within the range of normal summer
values obtained by Locke. The mean value
for our patients with cystic fibrosis of the
pancreas was 0.0606 which is within the
range of values for Locke’s patients with
hypoadrenocorticism (0.0348 to 0.1809).
The high concentration of sodium
chlo-ride in the sweat of patients with cystic
fibrosis of the pancreas, therefore, cannot
be explained by variations in the
parame-ters discussed above and other explanations
must be found.
The composition of sweat as analyzed
has been considered to be the result of the
elaboration at the base of the gland of a
secretion (precursor solution) which is
mod-ified as it passes through the sweat duct to
the skin surface. In these terms the high
concentrations of sodium chloride in the
sweat of patients with cystic fibrosis of the
pancreas can be accounted for by three
possible mechanisms:
1. Increased reabsorption of water in
ducts;
#{176}Sweat chloride rate index =
log 90 - log (90 - [Cl])
(mb/hr)/0.1 m2
[Cl] = concentration of chloride, mEq/l.
710
GOCHBERG
- SWEAT GLAND IN CYSTIC FIBROSIS2. Decreased reabsorption of sodium
chloride in ducts;
3. Increased concentration of sodium
chloride in the precursor solution.
The data collected in this study do not
indicate that there is increased
reabsorp-tion of water in the sweat ducts of these
patients. Schwartz
et
ai.38 havedemon-strated that the concentration of urea in
normal sweat is always approximately 1.7
times the concentration of urea in plasma
regardless of rate of sweating or increase
in urea concentration of plasma. These
authors suggest that urea, a freely
dif-fusible molecule, enters the precursor
solution at the same concentration as in
plasma and is raised to a higher
con-centration by reabsorption by the sweat
duct of a constant fraction of the secreted
water. Although this concept is probably
correct, the physiologic mechanism
respon-sible for reabsorption of a constant fraction
of water regardless of the volume of
se-cretion is difficult to visualize. In these
terms the finding of the same ratio of
urea in sweat to urea in plasma in patients
as in controls eliminates increased
reab-sorption of water as the mechanism
caus-ing the high concentration of sodium
chloride in sweat. In addition, the finding
of similar rates of sweating in the two
groups makes it unlikely that excessive
reabsorption of water by the sweat ducts
occurs.
The high concentration of sodium
chlo-ride in the sweat of patients with
hypo-adrenalism has been attributed by Conn23
and others2 to decreased reabsorption of
sodium chloride by the sweat ducts. This
concept is an obvious analogy to the
de-creased reabsorption of sodium chloride by
the renal tubules in adrenal insufficiency.
However, the recent studies of Schwartz
et suggest that reabsorption of sodium
by the sweat duct may actually be increased
in hypoadrenalism and decreased in
hyper-adrenabism. These authors noted that as
rate of sweating exceeded 5 gm/m2/min,
the rate of excretion of sodium increased in
a straight line relationship to the sweat rate.
When the line representing the regression
equation for this relationship is extrapolated
to zero rate, a negative intercept for the
output of sodium is obtained. The negative
intercept is interpreted as the amount of
sodium reabsorbed per square meter per
minute. Restriction of sodium chloride
in-take or administration of adrenal steroid
bed to a fall in concentration of sodium in
sweat as well as a decrease in the calculated
quantity of sodium reabsorbed by the sweat
duct. Exactly the same findings were noted
in the study o’f salivary secretion.56 These
findings imply but do not prove that
re-absorption of sodium is increased and not
decreased in states characterized by high
concentration of sodium in sweat. It is
therefore thought unlikely that decreased
reabsorption of sodium by the sweat duct is
responsible for the high concentration of
sodium in sweat in cases of cystic fibrosis
of the pancreas.
By exclusion the abnormal findings must
be due to an increased concentration of
sodium chloride in the precursor solution.
The exact significance of the elevated
con-centration of sodium chloride in the fluid
transported across the secretory cell is not
readily discernible. However, certain
possi-bilities must be considered.
The calculation from standard
thermody-namic equations57#{176} of the free energy
change (iG) required for the elaboration of
one liter of sweat reveals marked changes
with alterations in the concentration of
so-dium chloride. The relation between or
work and concentration of sodium in sweat
is revealed in Figure 5. The calculations
are based on alterations in concentration of
sodium, proportional changes in chloride
and resultant changes in the mole fraction
of water of sweat. Concentrations of
potas-sium, bicarbonate, lactate and urea in sweat
were assumed to remain constant. The
con-centrations of each. of these substances in
Cp
= n (1418.7) log
n = number of moles transferred
C p = concentration in plasma
180#{149}
S
f0.
140.
120.
L\G=
[J5
20 60 100 i4o
[Na]5
FIG. 5. The free energy change or work required for the elaboration of one liter of sweat. The ordinate
represents the calories expended for the elaboration of one liter of sweat at the concentration of sodium
represented on the abscissa. The details of the calculations are given in the text.
711
the plasma were also considered to remain
constant. Although the exact composition of
the precursor solution is unknown because
of unmeasurable reabsorption of water and
salt b the sweat duct, Figure 5 reveals
that the patient with cystic fibrosis of the
pancreas elaborates a sweat of such
com-position that a minimum expenditure of
energy is required for elaboration of the
final sweat. It is possible therefore that
the abnormality in sweat in cystic fibrosis
of the pancreas may result from an
altera-tion in the quantity of energy available for
secretion. When readily available energy is
limited, a rise in concentration of solute
may occur. If concentration has attained
an optimal level, maximal secretory rate
may be reduced. Such findings have been
noted in prolonged stimulation of the
sweat glands leading to “fatigue” as well
as after arterial occlusion producing local
anoxia.3#{176}
If such a concept is applied to other
glands which respond to cholinergic
trans-mitters, a general theory for the disturbed
1
Enn
(deficient)
C
+
DL__L.-7E
+
F
Acetyl
C2ioliz
+ I
j1A
+Fier
4’
Secretion
Fic. 6. Theoretical representation of possible genetic defect in secretory cells of patients with cystic
fibrosisof the pancreas.
712
GOCHBERG
- SWEAT GLAND IN CYSTIC FIBROSISSchematic Representation of Defect
in
Cholinergic Glandular
Systems
(Dyscholinergia)
A
+B
Adrenal
pancreas may be formulated (Fig. 6). It is
postulated that there is a genetically
deter-mined deficiency of an enzyme, coenzyme
or substrate in secretory cells so that the
release of energy is altered. As a result the
composition of secretions is abnormal.
Al-though such a scheme is completely
con-jectural, it may serve to stimulate
funda-mental research on the energetics of
secre-tion in normals and patients with cystic
fibrosis of the pancreas.
The source of energy for secretion of
sweat is thought to be the glycogen of the
secretory cells.8 The breakdown product of
this glycogen is probably lactic acid which
may diffuse into the sweat. The preliminary
finding that the concentration of lactic acid
in the sweat does not differ markedly
be-tween normals and patients with cystic
fibrosis of the pancreas casts some doubt
on the hypothesis that the quantity of
secretory energy is altered significantly.
Furthermore, recent studies of parotid
secretion in the dog indicate that the
con-centration of sodium in the saliva rises with
increase in rate.58 However, calculation of
the osmotic work performed per
unit
time
did not show that limitation of secretory
energy was responsible for a rise in
concen-tration of electrolyte with increasing rate
of secretion. However, calculation of the
free water transport or clearance (FWC)
with increasing rate of salivary secretion
revealed that the transport of water without
solute approached a maximum
asymptoti-cally. Because of the high concentration of
the major solute, sodium chloride, in sweat
of patients with cystic fibrosis of the
pan-creas, FWC#{176} is considerably less than in
the normal (107 ml/m2/2 hr versus 201
ml/m2/2 hr). Since the transport of water
without solute probably requires the major
portion of secretory energy in many
glan-dular systems, investigation of this
funda-mental problem would seem worthwhile in
relation to cystic fibrosis of the pancreas.
#{176}Free Water Clearance (F\VC) =
SOs.
Vol. (1---) Pos.
S os.= osmolarity of sweat
P os.= osmobarity of plasma
Vol. = ml/m2/2 hr
Calculations of sweat osmobarity are based on the
concentrations of sodium, potassium, chloride,
lac-tate and urea representing 90% of the osmotically
713
Summary
Electrolyte concentrations of total body
sweat were determined in nine patients
with cystic fibrosis of the pancreas and in
six controls. The sodium concentration in
the patients averaged 79 mEq/l; the
con-trols averaged 18 mEq/l. There was no
difference between the two groups in rate
of sweating, skin and rectal temperature,
ratio of urea in sweat to urea in plasma and
lactic acid concentration of sweat.
A possible mechanism for the altered
composition of sweat is suggested in terms
of the present knowledge of sweat
physi-obogy.
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SUMMARIO IN INTERLINGUA
Physiologia
del
Glandula
Sudoripare
in
Cystic
Fibrosis
del
Pancreas
Altere autores ha trovate elevate
concentra-tiones de natrium e chboro in be sudor de 100
pro cento de patientes qui monstrava al
necrop-sia be lesiones characteristic de cystic fibrosis
del pancreas. Un deficientia del hormon adrenal
de sal e aqua causa elevate concentrationes de
ebectrolvto in be sudor, sed il ha essite
demon-strate que il ha nuble insufficientia adrenal in
patientes con cystic fibrosis. In plus, elevate
electrolytos del sudor es etiam producite per
vane factores non-endocrin, corno elevation del
temperatura rectal, elevation del temperatura
intradermab, augmentate sudation, probongate
sudation (fatiga), occlusion arterial, un barriera
a vapor (corno ilbo formate per be banda de
gaza sub be qual be majoritate de specimens de
sudor local es cobligite) e be region mesme ubi
le sudor es cobligite.
Nove infantes de 6 a 13 annos, con cystic
fibrosis del pancreas, e sex fraternos de
con-trobo con nulle stigmas del morbo, esseva
studi-ate in re br total sudation corporee in un
camera de constante temperatura e humiditate.
Le subjectos esseva pesate, lavate con aqua
distillate, e facite seder se pro duo horas in
un cupa libere de electrolytos.
Subsequente-mente illes esseva eluite con 2 o 3 litros de
aqua distillate e pesate de novo. Le analyse de
br total sudation corporee monstrava in be
patientes con cystic fibrosis un distribution de
concentrationes inter 42 e 87 mEq/l con un
valor medie de 79. In be infantes de controbo
be distribution esseva inter 1 1 e 35 mEq/l con
un valor medie de 18. Le concentrationes de
chioro esseva ben correlatate con be
concentra-tiones de natriurn, distribuite inter 51 e 137
mEq/l in be patientes, con un valor medie de
80, durante que be vabores de controbo esseva
distribuite inter 10 e 35 mEq/l con un valor
rnedlie de 16. lb habeva nulle area commun de
vabores in be concentrationes de natrium e
chboro, sed ii habeva un considerabile area
commun in be vabores de kalium in be total
sudation corporee con be patientes inter 5 e 29
mEq/b con un valor medie de 10, e be infantes
de controlo inter 4 e 8 mEq/l con un valor
medie de 6. In be patientes con cystic fibrosis
del pancreas be sudation total esseva inter 267
e 406 gm/m2/2 hr con un valor medie de 299;
be vabores de controbo esseva inter 224 e 368
gm/m2/2 hr con un valor medie de 257. Iste
differentias non esseva considerate corno
sig-nificative.
Ii es suggerite per Schwartz que be
constata-tion de un constante proportion de 1,7 inter le
urea del sudor e del plasma, nonobstante
cambi-amentos in le concentration de urea del plasma
o del prorata de sudation, es be resultato final
de reabsorption intra be ducto sudoripare de
un constante fraction del aqua secretate post
que be biberemente diffusibile urea entra, ab
concentration del plasma, in be solution
pre-cursori in be gbanduba sudoripare. Si isto es
correcte, be abterate electrobytos del sudor in
cystic fibrosis non es causate per augmentate
reabsorption de aqua intra be tububos
sudori-pare, proque in be infantes de controbo le valor
medie del urea del sudor esseva 55 mg/100
ml, e in be patientes con cystic fibrosis ilbo
esseva 58 mg/100 ml.
Ii ha essite demonstrate, per medio de
stand-ard equationes thermodynamic, que le carga de
libere energia (G) requirite pro be elaboration de
un litro de sudor cambia marcatemente con
alterationes in be concentrationes de natrium e
chloro in be sudor. Le cambiamento minimal de
libere energia occurre con be elevate
concentra-tiones de ebectrobyto in be sudor que es trovate
in patientes con cystic fibrosis del pancreas. Nos
presenta le hypothese que in iste condition be
anormalitate in be secretiones glandular pote
resultar de un alteration in be quantitate de
