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VOLUME 30 AUGUST 1962 NUMBER 2
COMMENTARY
THE
SWEAT
TEST
N INCREASED interest in the physiology
of sweating’ was precipitated by the
demonstration of markedly elevated
elec-trolyte levels in sweat of patients with
cystic fibrosis. 21 Indeed, the determination
of sweat electrolytes has become the most reliable single diagnostic test for cystic fi-brosis, replacing the more difficult, time consuming, uncomfortable, and less reliable procedures of duodenal fluid aspiration and assay. The marked reduction or absence cf proteolytic activity of duodenal fluid no longer serves as the cornerstone of diag-nosis, since fully 15% of patients with cystic fibrosis have sufficient exocrine pancreatic ftnnction to yield normal or nearly normal enzyme values. Nevertheless, study of duo-denal fluid is still of considerable value when dealing with cases difficult to diag-nose, in instances of borderline sweat elec-trolyte levels, or for special study purposes. The duodenal fluid of patients with cystic
fibrosis may contain substances, such as
a water insoluble protein fraction precipi-tated by equal parts of ethanol and ben-zene,5 and possesses properties which are independent of enzyme activity, such as in-creased viscosity.6
The nature of the sweat gland defect in cystic fibrosis remains unknown. Neverthe-less, the abnormality of function can he demonstrated in approximately 98% of pa-tients. Unlike the progressive changes that may occur in the lungs, liver, and pancreas, the defect in the sweat glands is not an ac-quired one as it may be detected as early
as one day of age.7 Markedly elevated sweat electrolytes have not been encountered in other diseases seen by pediatricians,
al-though values above normal have been
claimed for children with allergic manifesta-tions5 and in some healthy siblings of patients with cystic fibrOsis.4 These claims have been either discreditedt or questioned.’#{176}’ ‘ To
make a diagnosis of a disease based on one diagnostic test is fraught with danger. In
establishing a diagnosis of cystic fibrosis
the following considerations must be kept
clearly in mind.hl
1. The initial step is a high degree of clinical suspicion. WTe must discard the false concept that the patient looks too well to have cystic fibrosis, and recognize the great variation in the severity of the disease and in the degree of organ involve-ment.
2. The presence of elevated electrolytes
in the absence of symptoms does not
es-tablish the diagnosis of cystic fibrosis, for a small percentage of normal individuals have elevated electrolytes. This number increases with age. Careful study of some of these in-dividuals revealed that they were either (a) the most mildly affected patients with cystic fibrosis in families with more severely ill siblings or (b) rarely encountered individuals with suspicious clinical manifestations of cystic fibrosis who upon repeated testing
showed a decline to normal values with an
amelioration of the original complaints. 3. Many factors can influence the result of the sweat test. The physician responsible
for the care of the patient should be familiar with the reliability of the laboratory
per-forming sweat tests before he places
confi-dence in the report. The sweat test report should include the amount of sweat
col-lected and the values of sodium and
chlo-ride in meq/l. Small amounts of less than 50 mg are usually insufficient for accurate
assay. The determination of both sodium
and chloride concentrations serves as a
check on the reliability of the test. Large discrepancies, such as over 30 meq/l
be-tween the sodium and chloride, should
sug-gest a repeat examination. Screening tests should not be used as a final diagnostic procedure.
4. The establishment of a diagnosis is a severe blow to any family as it affects them emotionally, socially, and economically.
Hence the diagnosis should not be made
lightly but only after careful appraisal of the patient, the family history and labora-tory evidence.
A number of factors influence the level of electrolytes in sweat. Many of these fac-tors are listed in Table J12
Of practical importance in the general agreement of many workers using a multi-tude of techniques, that infants and chil-dren with cystic fibrosis have markedly elevated sweat sodium and chloride levels, although the amount of sweat collected ap-pears to be the same as in control subjects.
In spite of a lack of standardization of test-ing methods it is indeed remarkable that there is so general an agreement on what
constitutes an elevation of sodium and
chloride. Most workers would consider a
value of chloride above 60 meq/1 and
sodium of above 70 meq/l as significant and consistent with the diagnosis of cystic fibrosis. Fortunately, borderline values with chloride concentration of 50 to 60 meq/l and sodium of 60 to 70 meq/l are only
oc-casionally encountered and when noted
cause considerable concern. Repeat tests
should be done whenever in doubt. The
laboratory in which sweat tests are done should have adequate controls and a uni-form procedure which is carried out ideally
by the same experienced technician. The elevation of sweat sodium and chloride in
cystic fibrosis is so great that a number of
factors that play only a minor role in in-fluencing the sweat electrolyte level can
be safely neglected. For diagnostic testing,
it matters only little whether the salt in-take of the patient is 1 or 5 gm/day, whether mild thermal stress or drugs such as pilocarpine or mecholyl are used to in-duce sweating, whether the sweat is col-lected from the forearm, abdomen, back, or thigh areas, or whether the collection pe-nod is 20 minutes or 60 minutes. However, a large salt intake of 20 to 25 gm/day may artificially increase the sodium and chloride
concentrations in sweat by 10%. Likewise, with a deficit in salt intake the salt
con-tent of sweat may diminish.13 Also the
collection from the hand may yield signifi-cantly higher values than body sweat since the concentration of salt in sweat from the palms may be as much as from two to five times greater. This is the case in controls as well as in patients with cystic fibrosis. The highest chloride concentration in palm sweat was 587.0 meq/l in a patient with cystic fibrosis. The average concentration in a study of 13 patients was 308 meq/l as contrasted with an average concentration
of 59 meq/l for 13 non-cystic fibrosis
con-trol cases. The highest chloride concen-tration reached in the control group was 165 meq/l.12 Emotional and mental stimuli may significantly increase the salt content of palmar sweat while having no effect on body sweat. Unlike the sweat glands else-where, those of the palms and soles dis-charge continuously even with the subject at rest at ordinary room temperature.04
The moist hands and soles in the patient with cystic fibrosis, although of frequent and striking occurrence, have not received sufficient attention in the description of the clinical features of cystic fibrosis. Other observations of a similar nature are (a) the excessive and spontaneous sweating from other areas of the body especially in infants
with cystic fibrosis, (b) the formation of
TABLE I
THE SWEAT TEST: SOME FACTORS THT INFLUENCE THE LEVEL OF ELECTROLYTES0
The Patient
Nature of disease-characteristic elevation of sweat electrolytes in cystic fibrosis (CF.). Volume of
sweat collected under similar testing conditions is the same as in controls.
Sweat electrolytes are not uniformly elevated to the same degree in any other disease studied to date. Elevated values are claimed for some heterozygotes or carriers of the gene for systic fibrosis. Not so
in our experience.
Elevated values have been noted in some patients with adrenal insufficiency, ectodermal dysplasia, malnutrition and allergic disease; and in some adults with cylindrical bronchiectasis and diabetes.
However these conditions rarely cause confusion in diagnosis of CF.
Genetic stock-higher values found in some families.
Individual variation noted on repeated testing. This may be of considerable magnitude in some
mdi-viduals, although fairly constant values are usually noted in the majority of people tested. Age-higher values found with increasing age except in newborn period.
Condition of patient-dehydration, circulatory failure, hypoglycemia, respiratory distress,
hypothy-roidism, malnutrition, edema, etc.
Time of day and season of year.
Diet-especially salt intake.Salt loading may increase sweat electrolyte levels.
Sex-no difference noted in childhood. Adult females sweat less than males with heat stimulus. Exhaustion of glands. Repeated stimulation of same area causes reduced volume and elevation of
electrolyte levels. Acclimatization.
Activity of patient.
Unknown or unrecognized factors.
Sweat Induction and Collection
Heat vs.drug or combined.
Environmental and body temperature.
Rate of sweating.
Duration of sweat period. Humidity and effect of evaporation. Area of body
Total body sweat vs. local collection
Drug Used
Pilocarpine, furmetide, mecholyl
Method of application of drug. I.M. injection or by iontophoresis
Analytical Factors Size of sample
Weight determined in analytical balance by weighing sweat absorbed on gauze pads, cotton, flutes
paper
Volume measured directly with volumetric pipette
Method of determining chloride-semi-quantitative, electrometric, titremetric, polarographic
Flamephotometric analysis for Sodium and Potassium
Dilution factor
Contamination
Technical-personal factor
o Table reproduced with permission.”
line in some patients with cystic fibrosis, food heavily, or showing a preference for
(c) mothers’ comments regarding the salty salty foods and drinks.
method of Gibson and Cooke.1 When
com-paring this method with the bag method of
collecting sweat the values for sodium and
chloride are lower for both controls and patients with cystic fibrosis.’’ ‘ Since the
volume of sweat collected over a given
pe-nod of time by the bag method is greater
than by the pilocarpine method we
postu-late a greater rate of sweating to explain the higher electrolyte levels by this method.
Widely divergent values of sweat
chlor-ide have been reported, and the chief
rea-son for this is the variation in chloride
con-centration with changes in the rate of se-cretion. The chloride concentration is not conditioned by the duration of sweating,
but increases in later stages of sweating in association with an increase in the rato of sweating.14 The problem of measuring rate of sweating as a continuous function has not been solved technically. A satis-factory procedure is to study frequent
samples, for example, every 5 minutes, as was done by Kuno, and to plot the results
in relation to time. The shorter the time
interval the more exact is the measurement
of rate of secretion. Additional and difficult
problems arise, such as the density of
sweat glands in the area selected for study
and the number of glands responding to
the stimulus. The accepted method of ex-pressing sweat rates is in grams per square meter per minute. This may eloquently
ex-press results in adult subjects after a
thermal or work stimulus when total body sweat is measured at short intervals. In small subjects with a very small area of skin stimulated and with one collection
over a long period, the expression appears
inadequate and potentially misleading.
Age is a factor in influencing the level of sweat electrolytes as determined by local drug stimulation.’#{176} 12 The interest in this
method is relatively new so that no observa-tions are available in the same group of in-dividuals at different ages. In healthy per sons and in sick controls there is an increase in the sodium and chloride concentrations
with increasing age, except in the newborn period where the values are higher than
in infancy and childhood. The rise in values
at and above age 17 years appears most
striking. The concentration of ptassiun
shows a slight decline with increasing age.
There is no apparent difference in the
electrolyte concentration in the different age ranges of those patients with cystic fibrosis so far studied. The values reported for parents of children with cystic fibrosis are no different from those for our
con-trol parents, when studied by the same
method.hu, 12. 17 The ability to detect the
heterozygote by the pilocarpine iontophore-sis method has not been accomplished. However, the discovery of proper stress conditions to bring out a difference in the heterozygote for cystic fibrosis is attracting the attention of a number of observers and a proper solution may not be too far off. A
number of investigators have observed
ele-vated electrolyte levels in adults ill with a variety of conditions such as bronchiectasis, pulmonary emphysema, peptic ulcers, and diabetes. The relationship of these condi-tions to cystic fibrosis is not clear, and further study is needed.
HARRY SH\VACHMAN, M.D. The Children’s Hospital
Medical Center Boston, Massachusetts
REFERENCES
1. Lobeck, C. C., and Huebner, D.: Effect of
age, sex, and cystic fibrosis on the sodium
and potassium content of human sweat.
PEDIATRICS, 30:172, 1962.
2. Darling, R. C., et a!.: Electrolyte abnormalities
of the sweat in fibrocystic disease of the
pancreas. Amer.
J.
Med. Sci., 225:67, 1953. 3. di Sant’Agnese, P. A., et al.: Abnormalelec-trolyte composition of sweat in cystic fibrosis of the pancreas. PEDIATRICS, 12:549, 1953.
4. Shwachman, H., Leubner, H., and Catzell, P.: Mucoviscidosis. Adv. Pediat., 7:249, 1955. 5. Dische, Z., and di Sant’Agnese, P. A.:
Composi-hon of mucoprotein fractions from duodenal fluid of patients with cystic fibrosis of the
pancreas and from controls. PEDIATRICS, 24:
74, 1959.
6. Shwachman, H., Dooley, H., and Evans, A. C.:
Cystic fibrosis of the pancreas without pan-creatic enzyme deficiency. Amer. J. I)is.
Child., 92:520, 1956.
Intestinal obstruction of the newborn in-fant. Ne’ Engi. J. Mcd., 264:13, 1961. 8. Usia, I). Y., et a!.: Abnormal sweat electrolytes
in patients with allergies. Amer. j. Dis. Child., 96:685, 1958.
9. Kulczvcki, L. L., Mueller, Fl., and Shwach-mali, 11.:Respirators’ allergy in patients with
cystic fibrosis. J.A.\1.A., 175:358, 1961.
10. Anderson, C.
M.,
and Freeman, M.: “Sweattest” results in normal persons of different ages compared with families with fibrocystic disease of the pancreas. Arch. Dis. Child., 35:581, 1960.
11. See literature prepared for physicians by the
Medical Education Committee of the
Na-tional Cystic Fibrosis Research Foundation,
521 Fifth Ave., New York, N.Y. Dr. Ken-neth S. Landauer, Vice-president for Medical Affairs.
12. Shwachman, H., and Antonowicz, I.: The sweat test in cystic fibrosis. Ann. N.Y. Acad. Sci.,
93:12, 1962.
13. \IcCance, R. A.: The effect of salt deficiency in
man on the volume of the extracellular fluids, and on the composition of sweat, saliva,
gas-tric juice and cerebrospinal fluid. j. Physiol., 92:208, 1938.
14. Kuno, Y: Human Perspiration. Springfield,
Illi-nois, Thomas, 1956.
15. Gibson, L. E., and Cooke, R. E.: A test for concentration of electrolytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis. PEDIATRICS, 23:545, 1959. 16. Huang, N. N., and Librenjak, K.: Sweat
chlo-rides in cystic fibrosis: comments on variable
results in families according to methods.
Pre-sented at Cystic Fibrosis Club, Atlantic City, May 7, 1962.
17. Kohner, D., et al.: A study of 60 parents of
cystic fibrosis children and controls. Presented
at Cystic Fibrosis Club, Atlantic City, May 7,
