Oral medicine

Review article

The diagnostic uses of saliva

Irwin D. Mandel
Columbia University, School of Dental and
Oral Surgery, New York, USA

Mandel ID: The diagnostic uses of saliva. J Oral Pathol Med 1990; 19: 119-25.
It is becoming increasingly apparent to investigators and clinicians in a variety
of disciplines that saliva has many diagnostic uses and is especially valuable in
the young, the old and infirm and in large scale screening and epidemiologic
studies. The highly sensitive test procedures that are now commonplace makes
it practical to quantitate, despite very low concentrations, a large number of
hormones and drugs in saliva. Indeed, all steroids of diagnostic significance in
routine clinical endocrinology can now be readily measured in saliva. Drug
monitoring can include abusive as well as therapeutic agents. The concordance
between anti HIV antibodies in saliva and serum has stimulated application to
various other antiviral antibodies as well as to viral antigens per se. Saliva has
found use as a diagnostic aid in an increasing number of clinical situations and
in systemic diseases that can affect salivary gland function and composition
such as Sjogren's syndrome, cystic fibrosis and diseases of the adrenal cortex.
The list keeps growing.

SaHva is not one of the popular bodily

fluids. It lacks the drama of blood, the
sincerity of sweat and the emotional appeal of tears. Despite the absence of
charisma, however, a growing number
of internists, pediatricians, pharmacologists, clinical and forensic pathologists,
psychologists and dentists are finding
that saliva provides an easily available,
noninvasive diagnostic medium for a
rapidly widening range of diseases and
clinical situations (1, 2).
The limited utilization of saliva for
diagnostic purposes in the past may be
a reflection of the ambivalence that has
characterized both the public and professional view of the nature of saliva
over the ages. Prior to the 17th century
and the anatomic demonstrations by
STENSON and WHARTON of the ducts
that bear their name, salivary glands
were thought to be accessory excretory
organs, emunctories, that strained off
the evil spirits of the brain (3). With the
realization that the glands could generate an external secretion, physicians
who practiced medicine based on humoral pathology, the need to balance
the body humors (phlegm, blood, yellow bile and black bile), bled, blistered,
purged and stimulated salivation. It was
not uncommon to prescribe massive
doses of bichloride of mercury to
cleanse the system by causing saliva to
literally pour from the mouth. It was
the fortunate patient who survived both
the disease and the treatment.

This negative image of saliva, however, was not uniform. In the cosmologies of ancient Egypt, Thoth the wise is
said to have spat into the empty eye
socket of Horus, the sun god, to restore
his vision (4). The new testament (Mark
8: 23-25) tells us that Jesus took the
blind man by the hand and led him out
of town; and when he had spit on his
eyes, and put his hands upon him, he
asked him if he saw ought; and he was
restored and saw every man clearly.
The people who really appreciate the
"miracle" of saliva, however, are not
the blind, but those who suffer from
xerostomia (dry mouth) from a variety
of causes (5). They recognize belatedly
that saliva is a natural resource with
many functional capabilities that include food preparation, digestion, lubrication and protection of the teeth and
mucous membranes (6).
One function not bestowed by nature
is the use of saliva for diagnostic
purposes. Historically this diagnostic
value may have been recognized first
by the ancient judicial community who
employed salivary flow (or its absence)
as the basis for a primitive lie detector
test. The accused was given a handful
of dry rice. If anxiety (and presumably
guilt) so inhibited salivation that he or
she could not form an adequate bolus
to chew and swallow, than off with their
head. In more recent times, where the
vagaries of the secretory-motor system
have been replaced by those of the court

Key words: drugs in saliva; hormones in

saliva: saliva: salivary chemistry; salivary
diagnosis: salivary nnonitoring:
siaiochemistry.
irwin D. Mandei, Coiumbia University, School
of Dental and Oral Surgery, 630 West 168th
Street, New York, New York 10032, LISA.
Accepted for publication December 22, 1989.

system, saliva found its widest use at

the race track where the saliva test for
drugs became the determinant of a
"fixed" horse race. It is interesting to
note that both the ancient and modern
use of saliva are different forms of lie
detection. Apparently ';";; saliva veritas'.
Sample collection

The fiuid most frequently employed for

salivary diagnostic purposes is expectorated whole saliva, a mix composed
largely of the secretions from the major
salivary glands, the right and left parotid, submandibular and sublingual
glands. There are also modest contributions from the minor salivary glands
(which are distributed inside the lips and
cheeks, on the palate and under the
tongue) and the gingival crevicular fluid
from the spaces between the teeth and
the gingiva. This latter Ouid is primarily
a serum transudate but can also contain
cells and products of the inflammatory
process when gingivitis or periodontitis
is present. Due to the presence of large
numbers of bacteria continually loosed
from tooth and soft tissue surfaces, as
well as shed epithelial cells, whole saliva
usually requires centrifugation to provide a clear sample. In some situations,
however, the bacteria or cells have diagnostic value.
Unstimulated or resting saliva is
usually collected by passive drooling
into a graduated tube or preweighed

120

MANDEL

vial so that fiow rate per unit time can

be measured. The concentration of
some salivary constituents is fiow rate
dependent (1). When volume measurement is not required the saliva can be
collected on cotton swabs, cotton rolls,
gauze or filter paper strips, then eluted
or centrifuged, or, aspirated directly
from the fioor of the mouth with plastic
pipettes.
For evaluating salivary gland function or when large volumes of saliva are
required for analytic purposes, saliva is
stimulated by a masticatory or gustatory stimulus, expectorated and handled
in a similar manner as the unstimulated
fluid. Softened paraffin wax or a
washed rubber band are the usual
masticatory stimuli and 2% citric acid
applied directly to the tongue the standard gustatory stimulus (1, 5).
In many situations separately collected secretions from individual glands are
preferable and this can be accomplished
in a non-invasive manner with suitable
collecting devices (1, 5). Parotid saliva
is best collected with plastic modifications of a simple cup first introduced
by CARLSON & CRITTENDEN in 1910

(7).

Disposable and individualized collectors have also been introduced (8, 9).
Submandibular-sublingual saliva can be
collected by customization of a basic
plastic collector (10, 11) or by aspiration
from the duct openings with a micropipette (5).
Oral diseases

For many years dental investigators

have been exploring changes in salivary
flow rate and composition as a means
of diagnosing and monitoring a number
of oral diseases (1, 2). The examination
of secretions collected from individual
glands has been especially valuable in
the differential diagnosis of local diseases of the salivary glands such as infiammatory and autoimmune diseases
and in evaluating the effects of pharmacologic agents and therapeutic regimens
which impact on salivary function (1,

5). Since individual gland secretions

contain some locally shed cells attempts
have been made to use saliva for cytologic examination as an aid in diagnosis
of tumors, but so far cytology is being
restricted to fine needle biopsy (12).
Shed buccal mucosal cells, however, are
being used as a simple, non-invasive
method for obtaining DNA for gene
analysis in cystic fibrosis and is applicable to other disease as well (13).
Saliva collected by expectoration
contains a fair representation of the
bacterial and fungal species that coat
the teeth, tongue and mucous membranes. By culturing a known volume of
saliva (in various dilutions) on selective
media a quantitative determination can
be made of specific organisms. Counts
of Streptococcus mutans and lactobacilli
are being employed for identifying children at high risk for enamel caries (14,
15) and older adults susceptible to root
surface caries (16). Oral candidiasis is
frequently found in people wearing
complete dentures, in people with a
marked diminution in fiow rate due to
a variety of therapies and medications,
and in HIV infection. Several recent
studies have shown that quantitation of
Candida (usually albicans) from whole
saliva can be used as an indicator of
infection (17-19).
System diseases affecting saliva

With the increase in investigator interest

it is becoming apparent that many systemic diseases affect salivary gland
function and/or salivary composition
(Table 1) (1). Although the study of
these effects have been valuable in the
understanding of the pathogenesis of
the diseases, their use as diagnostic
markers have been more limited, but
none the less helpful in some situations.
In Sjogren's syndrome, an autoimmune disease which affects several million people, one of the main diagnostic
procedures is biopsy of the minor salivary glands of the lip (the labial glands)
to assess the presence of and the extent

Table 1. Systemic diseases affecting salivary glands and saliva

Sjogren's syndrome
Rheumatoid diseases
Graft VS host disea.se
Sarcoidosis
Cystic fibrosis
Hypertension
Hyperlipidemia
Alcoholic cirrhosis
Malnutrition

Hromonal dysfunction
Diabetes
Pancreatitis
Adrenal-cortical diseases
Thyroiditis
Acromegaly
Neurological diseases
Parkinsonism
Bell's palsy
Cerebral palsy

of the lymphocytic infiltration characteristic of this disease (20). Siaiochemistry provides a helpful screening
procedure to determine whether the biopsy is indicated. A number of studies
have shown that if the disease is developing in the salivary glands the periductal infiltrate and its products (cytokines)
can have a profound effect on the resorptive, transport and synthetic function of the striated duct cells which results in: a) elevated sodium and chloride
concentration and a decreased phosphate concentration despite reduced
fiow rate (1, 21); b) elevation in lactoferrin (21-24); c) elevation in beta 2-microglobulin (25, 26) and in d) kaUikrein
(27). Parotid lysozyme was found to be
elevated in patients with primary Sjogren's syndrome (dry eyes, dry mouth
but no rheumatoid disease) but not in
secondary Sjogren's syndrome (with an
accompanying rheumatoid disease)
(28). The alteration in glandular structure produced by the disease resulted in
a marked impact on the lipid content of
saliva with a 20 fold elevation in the
concentration of phospholipids (29). If
confirmed in a larger group of subjects
this could be the basis of a valuable
diagnostic test. Salivary gland chemistry
in Sjogren's syndrome is not only potentially useful for diagnostic purposes but
for following disease development and
monitoring therapy (1, 26).
Cystic fibrosis affects all of the exocrine glands to varying degrees. The impact on salivary gland function at a clinical level is minimal, but there are very
definite effects on the composition of
saliva (1, 30, 31). The most dramatic
changes reported have been an elevation
in calcium and proteins, especially apparent in the submandibular-sublingual
glands and minor salivary glands. In the
former these elevations result in a very
apparent turbidity in the fluid secreted
due to formation of a calcium-protein
complex (32) and possibly of hydroxyapatite as well (33). In the minor salivary glands the precipitate physically
obstructs the narrow excretory duct and
markedly reduces the rate of secretion
to virtually zero. This phenomenon can
be used as a diagnostic test by measuring the fiow from the readily accessible
labial glands on the lower lip with a
capillary tube (34).
Although many hormones influence
the composition of saliva, the most dramatic changes have been noted in diseases of the adrenal cortex. The sodium
and potassium concentration is markedly affected by corticosteroids, especially

The diagnostic uses of saliva 121

ical depression. In more than a dozen
studies the data supported the view that
patients with affective disorders secrete
significantly less saliva than normal. A
more recent study noted a similar trend
(43). However, another study found no
difference between depressed patients
and controls (44). Apparently widescale
use of psychoactive drugs with xerostomia as a side effect makes quantitation of flow rate in these patients more
unreliable than in the past (1). An alternative, showing great promise, is the
measurement of sahvary prostaglandins
(PGD2, PGEj and PGF2a). In the saliva
of patients with major depressive disorder the concentrations of immunoreactive PG's were significantly higher than
cortex (36, 37). WOTMAN et al. (38) those of healthy controls (45). In pashowed that the ratio had value pre- tients with minor depressive or neurotic
and post-surgically as an early index of disorders the values were comparable to
prognosis and recovery as well as a those of controls. Salivary PG levels
means of differentiating the adenoma may be a good indicator of major defrom "pseudoprimary aldosteronism", a pressive disorders.
hyperplastic disease of the cortex (39).
One of the unhappy consequences of
cancer chemotherapy with such agents
as high-dose methotrexate and cycloDiagnostic aids for ciinical
phosphamide is the induction of an
problems
acute, severe mucositis with severe disIn several diverse clinical situations comfort and the high risk of fatal infec(Table 2) salivary analysis has provided tion. IzuTSU et al. (46) found that the
valuable information for both the clini- loss of epithelial barrier function and
cian and the investigator. The common- increased vascular penneability results
ly used cardiac glycosides have a rela- in a marked increase in the albumin
tively narrow margin of safety and de- concentration in the whole expectorated
termining if a patient is manifesting saliva. The parotid secretion is not aftoxic effects has critical clinical implica- fected, hence the elevation is purely lotions. WOTMAN et al. (40) demonstrated cal in origin. The increase in albumin
in 1971 that both potassium and calci- always preceeded the stomatitis and
um concentration in whole saliva was could be a useful predictor of the clinmarkedly elevated in toxic patients and ical problem. Monitoring whole saliva
that the calcium-potassium product albumin is "useful in establishing treatprovided a very easy and sensitive ment schedules for chemotherapy promeans of identifying these patients. tocols that have stomatitis as the limitThere have been a number of affirm- ing factor in treatment" (46).
ations of these findings (1, 2). The curChronic respiratory infection, esperent view is that cardiac glycosides not cially in children, is often associated
only affect monovalent cation transport with specific secretory IgA deficiency
in cardiac cells, but also modify cation (47). Secretory IgA is the major immuATPase systems in erythrocytes and sal- noglobulin of exocrine gland secretions
ivary gland cells (41).
(48) and detennination of complete or
There is an extensive literature (re- near-cotnplete IgA deficiency can readiviewed by BROWN) (42) on the relation- ly be made with a whole saliva sample,
ship between salivary flow rate and clin- aspirated from the floor of the mouth in
young children or expectorated in older
children. With a cooperative child a parTable 2. Clinical problems in which saliva
otid saliva sample is preferable and flow
contributes to diagnosis
rate should be determined for the most
Digitalis toxicity
precise measure of IgA level since saliAffective disorders
vary IgA concentration varies inversely
Stomatitis in cancer chemotherapy
with fiow rate (49).
Immunodeficiency of secretory IgA
Cigarette usage
The thiocyanate concentration in
Dietary nitrates, nitrites and gastric cancer
saliva is appreciably higher in smokers
Ovulation time
than non-smokers (50). Advantage has

aldosterone, via their impact on the

NaK/ATPase in the striated duct cells
where resorption of the primary secretion occurs. FRAWLEY & THORN (35)
were the first to demonstrate the value
of the sodium to potassium ratio of paraffin - stimulated whole saliva in diagnosing and monitoring Cushing's syndrome and Addison's disease. The mean
Na to K ratio of Addisonian patients
was 5.0 and decreased to 1.8 following
treatment with corticosteroids. In normal subject the ratio was 1.3; in Cushing's syndrome, 0.5.
Several investigators have demonstrated the diagnostic value of salivary
Na to K ratio in primary aldosteronism,
a hormone-producing adenoma of the

been taken of this observation to confirm or reject self-reporting of cigarette

usage among children and adolescents
(51). The test is somewhat limited, however, by the impact of exposure to
smoke from heavy smokers in the home
environment (52). A more sensitive indicator of exposure to tobacco smoking
is measurement of salivary cotinine (53).
It strongly correlated with urinary levels
and with number of cigarettes smoked
per day (54). Salivary cotinine is a useful
measure in both compliance and epidemiologic studies.
There is increasing interest in the relation of dietary factors to various types
of cancer. One such association is between ingested nitrate, its conversion to
nitrite and nitrosamines and the development of oral and gastric cancer (55).
Since the amount of nitrate secreted by
the salivary glands is directly related to
the amount ingested (56), measuretnent
of salivary nitrate can provide a convenient index for epidemiologic studies.
Development of methods for determination of time of ovulation and the
fertile period has been an active research
area for many years (57). A recent multicenter study indicated that measurement of salivary estradiol was a promising method of prediction (58). The
method requires the services of a clinical
laboratory, however, and is not readily
applicable to home testing. Since the
composition of human saliva is altered
during the menstrual cycle many simpler methods of using saliva have been
explored (1). These involved measurement of a variety of enzymes, sialic acid,
glucose and electrolytes. None of the
methods appear to be sufficiently reliable for routine use. A new approach
has recently been introduced which has
considerable potential - the measurement of electrical resistance (59). A special device which provides a digital
measurement of the electrical resistance
of saliva has been shown to predict ovulation on average of 5.3 ( 1.9 SD) days
in advance. With further confirmation
this could prove to be a very useftjl
method.
Hormone monitoring

Since the pioneering studies of SHANNON et al. (60) it has generally been
recognized that the lipid-soluble unconjugated steroids pass readily into saliva
and that their concentrations in saliva
are proportional to the concentrations
of free, unbound steroids in plasma (2).
The conjugated steroids diffuse with

122

MANDEL

Table 3. Hormones whose salivary levels reflect serum levels

Cortisol
Aldosterone
Dehydroepiandrosterone
Testosterone
5a-Dihydrosterone
17p-hydroxyprotesterone

Progesterone
I7p-Estradiol
Estriol
Estrone
Insulin
Melatonin

great difficulty because of their low lipid-solubility and high molecular weight
(62). An exception has recently been
noted for corticosteroid binding globulin (CBG) and some modification of the
assay may be required (63). A workshop
on the immunoassay of steroids in saliva
concluded that, "All steroids of diagnostic significance in routine clinical endocrinology can now be measured in
saliva" (67). The list of steroid hormones currently being assayed in saliva
includes cortisol, aldosterone, dehydroepiandrosterone, testosterone, 5adihydrotestosterone, 17P-hydroxy-progesterone, progesterone, 17P-estradial,
estriol and estrone (2, 65) (Table 3).
The literature on the clinical utilization of salivary monitoring of steroid
hormones is rapidly expanding. According to RIAD-FAHMY et al. (66) salivary

progesterone is being used for: 1) assessing the functional capacity of the corpus
luteum in both normal women and
those with defects in the hypothalamicpituitary-ovarian axis; 2) studies of
subfertile women; 3) studies of pregnant
women; 4) examining the effect of contraceptive steroids on ovarian activity
and 5) assessing hormonal changes during adolescence. Salivary estriol measurement during pregnancy has been
shown to be an excellent means of detecting fetal growth retardation (67) and
the estriol to progesterone ratio shows
promise as a predictor of preterm labor
(68).
Some investigators have found that
salivary cortisol is a better measure of
adrenal cortical function than serum
cortisol (69) and is particularly useful in
studies with children (70-72). In many
instances the children have been taught
to collect their own saliva (71). Measurement of salivary cortisol at 11 P.M.

Table 4. Drugs curently monitored in saliva

Phenytoin
Primidone
Ethosuximide
Carbamazepine
Theophylline
Caffeine

Lithium
Methadone
Cyclosporine
Marijuana
Cocaine
Alcohol

has been reported to be a reliable and

practical index of hypothalamic-pituitary-adrenai axis activity in depression,
especially in outpatients (73).
Recently hormones other than steroids have been found to be refiective
of their plasma levels and could be considered for salivary monitoring. MARCHETTi et al. (74) found a positive linear
relationship between plasma and salivary insulin during the oral glucose tolerance test in Type 2 diabetic patients,
in obese non-diabetic subjects and in
normal volunteers. Further study by
these investigators in a large group of
non-diabetic subjects affirmed the highly significant correlation between sahvary and plasma insulin and indicated
the potential of salivary insulin measurement in clinical practice (75). Excellent correlation has also been found between salivary and plasma levels of melatonin (76-78) and several clinical
applications have been suggested (78).

ing on this basis can overcome this difficulty. Monitoring for salivary lithium in
manic depressive patients is also subject
to the problem of individual variation
in the ratio and can be dealt with in the
same way (88).
Salivary monitoring is being used for
patients on methadone, (84) for assay
of cyclosporine in kidney-transplant patients (85) and for detection of marijuana smoking (86, 87) and cocaine use (88,
89). It also is a very practical way for
determining alcohol concentration (90).
Salivary caffeine levels can be accurately
measured and overnight caffeine clearance appears to be a simple, safe test
for measuring liver function (91). There
are numerous other examples.

Screening for antivirai antibodies

and viral antigens

The proliferation of new technologies

and their application to large-scale
screening for presence of HIV antibody
Drug monitoring
has not only stimulated research into
Over the past 15 yr there has been a the use of saliva for this specific purburgeoning interest in the use of saliva pose, but into the whole area of viral
in pharmacokinetic studies of drugs in diagnosis and screening (92-95). Invesgeneral and in therapeutic drug moni- tigators in both the United States (92)
toring in a variety of clinical situations and Great Britain (94) have shown the
(Table 4). The salivary/plasma ratio has complete concordance between salivary
been established for a long list of drugs and serum findings for HIV positive
(79) and the list has been continually people. Indeed with the use of the Ig
expanded. As with hormones, lipid solu- capture radioimmunoassay (GACRIA)
bility is a determining factor in their the low level of IgA, IgG and IgM antisalivary excretion. For lipid soluble body in whole saliva (relative to serum)
acidic or basic substances the diffusibili- is not a limitation, since "the proportion
ty is dependent on degree of ionization of specific to total immunoglobulin is
in plasma and saliva. Only the un-ion- similar in the saliva and serum of each
ized fraction can cross biologic mem- individual and the signals from capture
branes and hence the degree of acidity assays on the two sorts of specimen are
or basicity of a drug will determine its much the same and almost independent
salivary/plasma ratio. Drug levels in of immunoglobulin concentration" (95).
saliva, (like hormone levels) reflect the PARRY et al. (93) have shown the applifree, non-protein-bound portion in plas- cation of this method for salivary monima and hence may have a greater thera- toring of hepatitis A and B infection
peutic implication than the total blood and rubella as well. Salivary assay of
antiviral antibodies has also been used
levels.
Currently therapeutic drug monitor- as an indicator of rotavirus infection in
ing is most effectively used when the neonates (96).
saliva to plasma concentration ratio is
In addition to measuring antibody, it
constant over a wide range. This is espe- is possible to identify a number of specially so with anticonvulsant drugs such cific viral antigens in saliva. This has
as phenytoin, primidone, ethosuximide been put into clinical practice as a
and carbamazepine, (79, 80) and has screening procedure for feline leukemia
special applicability to dose adjustment virus in vetinary medicine (97) and
in children (81). Theophylline monitor- could be applied to mumps virus, cytoing for asthmatic children has also megalo-virus and probably several
proven helpful, (82) although there are others as well in humans.
often differences among individuals in
Identification of salivary antibodies
the S/P ratio (79). Establishing the ratio and antigens need not be confined to
for the individual patient and monitor- viral diseases, although they have re-

The diagnostic uses of saliva 123

ceived the most attention to date.
GRANSTROM et al. (98) used saliva for
rapid diagnosis of pertussis by measuring the specific immunoglobulin A response to Bordetella pertussis antigens.
Because of the common mucosal effect
secretory IgA antibodies in saliva could
be especially useful in measuring response to other infectious diseases of the
nasopharyngeal and tracheo-bronchial
surfaces. However, with the antibody
capture technique (95) salivary screening could be used for measuring response to any bacterial infection be it
IgG, IgM or IgA.

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