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VOLUME 41 • NUMBER 4 • APRIL 2010 321
QUINTESSENCE INTERNATIONAL
Physiologic amounts of salivary secretion are
essential for oral health.1 Saliva influences
various events in the oral cavity such as
caries protective, digestive, and immunologic
processes. The ability to promote remineral-
ization and to reduce demineralization
makes saliva a major player in caries protec-
tion.2 Furthermore, this fluid is implicated in a
wide variety of digestive events including
lubrication of mucosa, bolus formation, and
enzymatic digestion of food.3 Saliva’s protec-
tive role to the human organism is exhibited
by delivering antimicrobial peptides and pro-
teins to the oral epithelium.4
Saliva is predominately secreted from
three major paired salivary glands: parotid,
sublingual, and submandibular (in all, about
90% of the total saliva production).3 In addi-
tion, hundreds of minor salivary glands (eg,
buccal, labial, palatal), which are spread over
all parts of the oral mucosa, contribute to
secretion of saliva. Regulation of salivary
secretion is reflex controlled by both the sym-
pathetic and parasympathetic divisions of
the autonomic nervous system.5 The impuls-
es, induced by action of gustation, mastica-
tion, or smell are forwarded from afferent
receptors to the salivary nuclei (salivation
center) in the medulla oblongata.3 The
Etiologic factors of hyposalivation and consequences for oral healthPeter Tschoppe, Dr Med Dent1/Michael Wolgin, Dr Med Dent2/
Nicole Pischon, Dr Med Dent Habil2/
Andrej M. Kielbassa, Dr Med Dent Habil3
Hyposalivation is represented by a reduced salivary flow rate and can be caused by etiolog-
ic factors such as systemic diseases and intake of various medications or by radiotherapy
following head and neck cancer. The aim of this review was to compile data about the
qualitative and quantitative changes of salivary components during hyposalivation, and to
summarize their consequences for oral health. A Medline/PubMed/Scopus search was con-
ducted to identify and summarize articles published in English and German that reported
on etiology of hyposalivation and changes in the salivary composition due to hyposalivation
of different origins. The search revealed 94 articles, 71 of which were original articles. Apart
from the reduction of the salivary flow rate, the quality of saliva is strongly altered because of
systemic diseases, medications, and radiotherapy, including increased viscosity and pH shift
to more acidic values and changes in salivary protein compositions. Furthermore, hypo -
salivation may be accompanied by pronounced shifts in specific microbial components, in
particular toward a highly acidogenic microflora. Moreover, therapy of hyposalivation is often
restricted to palliative treatment (ie, saliva substitutes or gels). To prevent tooth tissue de -
mineralization, clinicians should consider saliva substitutes that are supersaturated with
calcium and phosphates and contain fluoride. (Quintessence Int 2010;41:321–333)
Key words: caries, drugs, hyposalivation, microflora, periodontitis, radiotherapy, saliva
substitutes, Sjögren syndrome, xerostomia
1Assistant Professor, Department of Operative Dentistry and
Periodontology, CharitéCentrum 3, University School for Dental
Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
2Lecturer, Department of Operative Dentistry and Periodon -
tology, CharitéCentrum 3, University School for Dental
Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
3Professor and Head, Department of Operative Dentistry and
Periodontology, CharitéCentrum 3, University School for Dental
Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Correspondence: Dr Michael Wolgin, Abteilung für
Zahnerhaltungskunde und Parodontologie, CharitéCentrum 3
für Zahn-, Mund- und Kieferheilkunde, Charité-
Universitätsmedizin Berlin, Assmannshauser Strasse 4-6, 14197
Berlin, Deutschland. Fax: 49 30 450 562 932. Email: michael.
© 2009 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
322 VOLUME 41 • NUMBER 4 • APRIL 2010
QUINTESSENCE INTERNATIONAL
Tschoppe et a l
parasympathetic and sympathetic nerve
bundles, which separately innervate the sali-
vary glands, form the efferent part of the
secretory reflex arch by using acetylcholine
as neurotransmitter.5
Saliva contains two major types of protein
secretion: amylase-containing serous and
mucin-containing mucous secretion. The
enzyme amylase takes part in initial diges-
tion, while mucin assists in lubrication and
serves to protect oral surfaces. The physical
and chemical characteristics of saliva vary in
different salivary glands. The sublingual
glands produce mucin-rich viscous saliva; in
contrast, the serous parotid glands secrete a
watery, amylase-rich fluid.6
The daily secretion of saliva normally
ranges between 1.0 and 1.5 L at a rate of on
average 0.5 mL/min (normal salivation; Table
1).7 The decreased flow of saliva is termed
hyposalivation (hypoptyalism), which can be
caused by water/metabolite loss, damage of
salivary glands and interference with neural
transmission (see Table 1). Common reasons
of decreased salivary secretion could be chron-
ic inflammation of the salivary glands, Sjögren
syndrome, radiation treatment, dehydration,
psychologic factors, and medications.5,8 The
increase of saliva is termed hypersalivation
(see Table 1). Hypersalivation has an
unknown origin; however, hypersalivation was
described in patients with herpetic stomatitis,
aphthous stomatitis, ulcerative gingivitis, and
those who wear dentures.9
The various components of saliva are
organic and inorganic substances, proteins/
poly peptides, hormones, and lipid mole-
cules. Whole saliva is composed mostly of
water, which contains ions, such as sodium,
potassium, magnesium, calcium, chloride,
carbonate, and phosphate ions.7 Small
amounts of organic nonprotein compounds
such as uric, amino, or fatty acids, and glu-
cose can be also detected in saliva.7 More
than 309 proteins, which include acidic and
basic proline-rich proteins, amylase, high-
and low-molecular-weight glycoproteins,
agglutinin, cystatins, histatins and statherin,
could be identified in saliva.10 Salivary pro-
teins have a wide range of functional proper-
ties. Different groups of saliva proteins take
part in immunologic reactions (lysozyme,
lactoferrin, lactoperoxidase, immu no globulin,
defensin),7,11–13 taste perception (carbonic
anhydrase),7 digestion (amylase),7 and many
other processes in the oral cavity. Saliva con-
tains steroid; nonsteroid; protein; and peptide
hormones, such as cortisol, testosterone,
progesterone, estradiol, and aldosterone.7
Numerous studies have shown correlations
between serum and saliva levels of different
hormones.14–16 The measurement of salivary
hormones for diagnostic aims is a widely
accepted, noninvasive, and stress-free
method compared to plasma and serum col-
lection.7,16–18
The purpose of the present review is to
summarize what is known about the qualita-
tive and quantitative changes of salivary com-
ponents during hyposalivation and to dis-
cuss the possibilities of their rational therapy.
DATA SOURCES AND STUDY SELECTION
A search of Medline/PubMed/Scopus data-
bases for articles written in English and
German from March to May 2009 was per-
formed. The following primary key words/
phrases were used in the search strategy:
hyposalivation / dry mouth / xerostomia /
saliva composition / qualitative changes /
quantitative changes / drugs / age / systemic
diseases, disorders / Sjögren syndrome /
Sicca syndrome / radiation, radiotherapy /
cariogenic microflora / periodontopathogen-
ic microflora / oral health. These terms were
used alone or were combined with each
other. A few older and/or basic references
were obtained by hand search and cross-ref-
erencing from the available literature.
UWS SWS
Hypersalivation > 1.0 mL/min > 3.5 mL/minNormal salivation 0.1–1.0 mL/min 0.5–3.5 mL/minHyposalivation < 0.1 mL/min < 0.5 mL/min
Table 1 Reference points for unstimulated (UWS)and stimulated (SWS) whole saliva inadults7,9
© 2009 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
VOLUME 41 • NUMBER 4 • APRIL 2010 323
QUINTESSENCE INTERNATIONAL
Tschoppe et a l
The authors examined the results
returned by the Medline/PubMed/Scopus
search to identify potentially relevant
abstracts. Publications that did not report
about etiology of hyposalivation or changes
in salivary composition due to hyposalivation
of different origins were not further consid-
ered. Finally, 94 full-text articles were select-
ed, 71 of which were original.
ETIOLOGY OF HYPOSALIVATION
Hyposalivation represents a reduced saliva
flow rate, and diagnosis of hyposalivation
can be made by means of saliva flow rate
measurements. The saliva flow rate varies
from person to person and is influenced by a
large number of factors, such as degree of
hydration, body position, exposure to light,
previous stimulation, circadian rhythms, or
gland size.10 However, when the conditions
during sampling of saliva are uniform, the
flow is remarkably stable for every individual.
Most investigators have used the measure-
ments of unstimulated whole saliva (UWS) as
well as stimulated whole saliva (SWS) as cri-
teria to define hyposalivation or salivary gland
hypofunction.19 The reference values for
UWS and SWS secretion rates in adults are
depicted in Table 1.
Hyposalivation may be caused by different
etiologic factors (Fig 1). The developmental
causes of this symptom, such as aplasia or
agenesis of salivary glands, are rare.20
Although considerable structural age-related
changes in salivary glands (loss of secretory
epithelium) may occur,20 there is no strong evi-
dence that age is a significant cause of hypos-
alivation.21 In contrast, the variety of systemic
diseases, drugs, and particularly radiotherapy
of malignancies in the head and neck seem to
be significant factors of importance.22
Based on general clinical experience
reduced salivary flow is common in the eld-
erly compared to the younger age groups.23
However, as already mentioned, the aging
process itself does not seem to be the
primary cause of reduced salivary flow
rates.5,8,24–28 Although an age-related de-
crease in salivary flow rate of resting whole
and stimulated parotid and submandibular
saliva was reported,29,30 hyposalivation
seems to be caused secondary to various
diseases or medications.5
A variety of systemic diseases can be asso-
ciated with signs of hyposalivation (Table 2).5
Autoimmune diseases such as Sjögren syn-
drome, AIDS, lupus erythematosus, rheuma-
toid arthritis, scleroderma, as well as hormonal
(diabetes mellitus), neurologic (Parkinson dis-
ease), and psychogenic diseases (depression)
can irreversibly or temporarily cause a progres-
sive destruction of salivary glands.3,5,31 The rela-
tionship between hypertension and salivary
function is not clearly established. While sever-
al authors described lower salivary flow rates in
hypertensive compared to normotensive
patients,32,33 other investigators found no signif-
icant differences among these groups.34,35
More than 400 medications have been
reported to cause hyposalivation.36 The
prevalence of hyposalivation is positively
related to the total number of xerogenic and
nonxerogenic drugs in rates of up to 82%.37
Hyposalivation
Systemic disease
Radio
ther
apy
Irreversible or temporary destru
ction
of s
aliv
ery
gla
nds
Medication
Dev
elop
men
tal
caus
es
Age?
Anticho
linergic
effects
Dehy-dration
mim
eticeffe
ctsSympath
o
Ap
lasi
a or
agen
esis
of
sal
ivar
ygl
and
Lymp
haticFibrosis of
parenchyma
infiltration
Degeneration
of gland cells
Damag
e to
blood
ves
sels
Neuropathy changes
Fig 1 Various possible etiologic factors of hyposalivation.
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QUINTESSENCE INTERNATIONAL
Tschoppe et a l
In the American population 33% to 51.7% of
older individuals are taking at least one
potentially xerogenic medication.38,39 Various
medications such as antidepressants may
cause hyposalivation because of their inter-
ferences with transmission at the parasym-
pathetic neuroeffector junction.37,40,41
However, the inhibition of salivation can also
occur by action of drugs at higher centers of
the autonomic nervous system.5 The mecha-
nism of the xerostomic effect of diuretics can
be explained by dehydration. Diuretics can
affect the transport of water and electrolytes
through the cell membrane of salivary acinar
cells by causing vasoconstriction in salivary
glands.5,37,40 In addition, drugs may produce
mouth dryness without reducing salivary flow
rates. Inhaler medications can cause sensa-
tions of oral dryness by topical effects.37,41
Table 3 lists drugs and chemicals with well-
known potential to decrease salivary flow or
to cause mouth dryness.
Salivary gland dysfunction and mouth dry-
ness are serious adverse effects of radiother-
apy of head or neck cancer. Salivary glands,
primarily parotid and to some lesser extent
the submandibular, sublingual, and minor
glands, are extremely radiosensitive.42
However, the exact mechanism of hyposali-
vation development due to radiotherapy
remains to be elucidated. On the one hand,
the ionization may have an immediate effect
on the acinar cells of salivary glands42–44; on
the other hand, the radiation damage may be
caused by impairment and changes in struc-
ture of blood vessels or by interferences with
nerve transmission.5,42 With low-dose ranges,
damage seems to be reversible, although the
tolerance dose for the parotid gland above
which salivary gland function becomes irre-
versibly reduced is roughly 25 to 40 Gy,44
and with the usual cumulative tumoricidal
dose of 60 to 70 Gy, an extensive degenera-
tion of acini takes place.44 The occurrence of
these etiologic factors leads to quantitative
and qualitative changes of salivary compo-
nents with increased viscosity, reduced
buffering capacity, altered salivary electrolyte
concentrations, and changed nonimmune
and immune antibacterial system.44
324 VOLUME 41 • NUMBER 4 • APRIL 2010
Cause Diseases
Chronic inflammatory • Sjögren syndromeautoimmune • Systemic lupus erythematosus
• Scleroderma• Mixed connective tissue disease• Sarcoidosis• Amyloidosis• Crohn disease• Ulcerative colitis
Endocrine • Diabetes mellitus (labile)• Hyper- and hypothyroidism• Cushing syndrome• Addison disease
Neurologic • Mental depression• Narcolepsy• Parkinson disease• Bell palsy• Alzheimer disease• Holmes-Adie syndrome
Genetic and congenital • Ectodermal dysplasia• Cystic fibrosis• Prader-Willi syndrome
Malnutrition • Eating disorders• Anorexia nervosa• Bulimia• Anemia• Atrophic gastritis• Dehydration• Alcohol abuse
Infections • HIV/AIDS• Epidemic parotitis• Epstein-Barr virus• Bacterial sialoadenitis• Tuberculosis
Other conditions • Hypertension• Fibromyalgia• Chronic fatigue syndrome• Burning mouth syndrome• Compromised masticatory performance
Table 2 Diseases associated with signs of hyposalivation or xerostomia
© 2009 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
VOLUME 41 • NUMBER 4 • APRIL 2010 325
QUINTESSENCE INTERNATIONAL
Tschoppe et a l
Action/medication group Medicaments Action/medication group Medicaments
Sympathomimetic Synergistic mechanismAntidepressants Venlafaxine Opioids, hypnotics Opium
Duloxetine CannabisReboxetine TramadolBupropion Scopolamine
Anticholinergic DiazepamTricyclic antidepressants Amitriptyline Unknown
Clomipramine H2 antagonists, proton pump AmoxicillinAmoxapine inhibitors TetracyclineProtriptyline MetronidazoleDoxepin OmeprazoleImipramine Cytotoxic drugs FluorouracilTrimipramine Anti-HIV drugs, protease DidanosineNortriptyline inhibitorsDesipramineZimelidine
Muscarinic receptor antagonists OxybutyninAlpha-receptor antagonists Tamsulosin
TerazosinAntipsychotics Promazine
TriflupromazineMesoridazineThioridazineClozapineOlanzapineAzatadineBrompheniramineChlorpheniramineCyproheptadineDexchlopheniramineHydroxyzinePhenindamine
Antihistamines AzatadineBrompheniramineChlorpheniramineCyproheptadineDexchlopheniramineHydroxyzinePhenindamine
Anticholinergic, dehydrationDiuretics Furosemide
BumetanideTorsemideEthacrynic acid
SympathomimeticAntihypertensive agents Metoprolol
MonoxidineRilmenedine
Appetite suppressants SibutramineFenfluraminePhentermine
Decongestants PseudoephedrineCetirizineLoratadine
Bronchodilators TiotropiumSkeletal muscle relaxants TizanidineAntimigraine agents Rizatriptain
Table 3 Drugs with potential to cause hyposalivation or dry mouth
© 2009 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
326 VOLUME 41 • NUMBER 4 • APRIL 2010
QUINTESSENCE INTERNATIONAL
Tschoppe et a l
CHANGES OF SALIVARYCOMPOSITION AS CONSE-QUENCE OF HYPOSALIVA-TION CAUSED BY DIFFER-ENT ETIOLOGIC FACTORS
The decrease of salivary secretion leads to
changes in composition of saliva. These
changes could promote plaque accumula-
tion and increase the risk for caries, mucosal
and gingival infection, and inflammation.44
Changes of salivary compositioncaused by systemic diseasesSjögren syndrome is a chronic inflammatory
autoimmune disorder that, next to xerosto-
mia, is characterized by keratoconjunctivitis
sicca. Sjögren syndrome is known to occur
with a variety of autoimmune diseases, such
as rheumatoid arthritis, systemic lupus ery-
thematosus, and primary biliary cirrhosis.45
The recently published European classifica-
tion suggests that at least four out of six cri-
teria (subjective oral and ocular symptoms,
keratoconjunctivitis sicca, focal sialadenitis
on biopsy, instrumental evidence of salivary
gland involvement, and presence of autoanti-
bodies) are needed to define patients with
primary Sjögren syndrome. Secondary
Sjögren syndrome is characterized by the
presence of one of the two subjective symp-
toms with at least two objective items of glan-
dular dysfunction.46
In patients with rheumatic diseases,
decreased secretion of saliva is often associ-
ated with focal sialadenitis. An increased
leukocyte infiltration of salivary glands can be
observed in primary Sjögren syndrome47 with
lymphocyte activation and autoantibody pro-
duction (ie, antinuclear antibodies).48 In spite
of normal potassium and phosphate con-
centrations of the saliva of patients with
Sjögren syndrome, the concentration of sodi-
um and chloride was reported to be higher,
and the concentration of bicarbonate and, as
a consequence, pH and buffer capacity
decreased compared to healthy subjects.49
Also, an increased salivary concentration of
calcium and proteins is found with Sjögren
syndrome.12,49 Proteins such as immunoglob-
ulin (Ig) A and IgG, lactoferrin, lysozyme,
matrix metalloproteinase, �2-microglobulin,
kallikrein, cystatin, and albumin were report-
ed to be higher in patients with Sjögren syn-
drome than in healthy subjects.12,50
Furthermore, oral lactobacilli and yeast
counts seem to be significantly higher
among patients with rheumatic diseases and
Sjögren syndrome.51 Decreased saliva flow
rates may be favorable for multiplication of
acidogenic microorganisms and yeasts.52,53
However, data are controversial since some
studies reported no difference in concentra-
tions of acidogenic microorganisms and
yeasts in Sjögren syndrome compared to
healthy conditions.52–54
Next to hyposalivation in rheumatic dis-
eases, diabetes mellitus is another example
affecting saliva flow rates and composi-
tions.55–57 Nevertheless, data about salivary
flow rates and compositions are controversial
and seem to depend on the type of saliva as
well as the type of diabetes mellitus (insulin-
dependent or non-insulin-dependent).55–57
Further more, decreased salivary flow rates
and pH values as well as impaired salivary
gland function were reported in type 1 as well
as in type 2 diabetes. Elevated levels of glu-
cose have been found in saliva57; moreover,
higher potassium, calcium, and total protein
concentrations were detected in patients with
diabetes.55,56 These findings might be due to
hyperaldosteronism or to impaired sodium-
potassium pump (Na+-K+-ATPase [adenosine
triphosphatase]) activity leading to altered
transport of potassium in the salivary
glands.55 However, a former investigation
showed reduced salivary potassium concen-
trations in diabetic patients compared to
healthy age-matched controls as well as
decreased concentration of magnesium and
zinc,56 while the salivary concentrations of
innate antimicrobial defense factors, such as
lysozyme, lactoferrin, and peroxidase obvi-
ously were not affected.57 In contrast, the sali-
vary concentrations of IgG and IgA were
found to be elevated in whole saliva of dia-
betic patients.57
In addition, it is widely accepted that high
salivary glucose levels in diabetic patients
favor oral yeast growth. The accumulation of
glycosylation products on the epithelial sur-
face may favor the adhesion of pathogens. It
is likely that the decrease in salivary flow
© 2009 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
VOLUME 41 • NUMBER 4 • APRIL 2010 327
QUINTESSENCE INTERNATIONAL
Tschoppe et a l
rates following diabetes in addition to
impaired immune response may enhance
candidal colonization.58 In contrast, peri-
odontal bacteria have not been shown to be
elevated in the saliva among patients with
diabetes.58
Several systemic diseases that primarily
do not impair the salivary flow rate can
indeed affect the composition of saliva and
incite oral pathologic processes. One exam-
ple is celiac disease, where no changes in
salivary secretion rates were evident but sig-
nificant elevation of total protein concentra-
tion, such as albumin, IgG, IgA, as well as
peroxidase, were found in saliva.59
Influence of medication on salivacompositionOne major group of medication affecting sali-
va composition includes tricyclic antidepres-
sants, such as imipramine, which produce a
significant decrease in saliva pH.60 Also,
imipramine and higher doses of zimelidine
produce an increase in buffer capacity, and
in sialic acids and hexoses.60 Contrary, no
qualitative changes in saliva composition are
produced by lower doses of zimelidine (100
mg/day).60 No changes in the concentration
of sodium, potassium, calcium, phosphate,
and protein were reported after administra-
tion of these tricyclic antidepressants.60
Another investigation reported a strong
increase in the activity of amylase and the
content of proteins, glycoproteins, calcium,
potassium, and hexose in saliva, indicating a
strong agonistic effect on noradrenaline
transmission after administration of amitripty-
line.20 Also, single doses of maprotiline
increase salivary amylase activity and protein
content.61
The effects of psychotropic drugs (eg, flu-
oxetine, sertraline, paroxetine, citalopram,
clonazepam, and lorazepam) on the concen-
trations of salivary components such as total
proteins, urea, and calcium, as well as �-amy-
lase activity, pH, and buffer capacity have
been evaluated.62 Psychotropic users pre-
sented a significant decrease of 33.85% in
stimulated salivary flow rate compared to
controls. However, the biochemical composi-
tion of saliva was found to be not significant-
ly affected by the use of psychotropics.62
Diuretics such as furosemide and ben-
droflumethiazide demonstrate during chron-
ic treatment a pronounced effect on saliva
composition, especially on sodium and
chloride concentration in stimulated and
unstimulated saliva.63 Another group of anti-
hypertensive drugs, angiotensin-converting
enzyme (ACE) inhibitors and calcium chan-
nel antagonists, seem to generate no
alterations in the salivary composition.64 In
contrast, the concentrations of calcium,
phosphate, chloride, and magnesium were
reported to be altered in saliva during active
treatment periods with �-adrenoreceptor
antagonists (atenolol and propranolol).65
These results suggested that the ductal sodi-
umand chloride transport is controlled by the
�-adrenoreceptor.65 The same study group
also reported a decline of salivary total pro-
teins, decreased amylase activity, as well as
changes of the calculated ratios of sialic
acid/hexosamine and hexosamine/total pro-
tein during treatment with �-adrenoreceptor
antagonists.66
Additionally, significant increases in albu-
min secretion into saliva and salivary
lysozyme, but significant decreases of total
salivary IgG, IgA, and IgM concentrations,
were observed during cancer therapy with
cytostatic drugs.67
Changes of salivary compositiondue to radiotherapyRadiation-induced hyposalivation is the com-
mon and most serious adverse effect in
patients after radiotherapy of malignant
tumors in the head and neck region. The
exposition of these regions to high doses of
radiation can lead to not only hyposalivation
but also to other clinical consequences for
oral health, such as mucositis, taste loss, tris-
mus, and osteoradionecrosis (Fig 2).42,44,47
Apart from the reduction of salivary flow rates,
the quality of saliva undergoes significant
changes due to radiation therapy, including
increased viscosity and pH shift to more
acidic values.68,69 During the early phase of
radiation therapy, the concentrations of antimi-
crobial proteins, lactoferrin, lysozyme, salivary
peroxidase, and myeloperoxidase in saliva
were found to be elevated.70 However, it is dif-
ficult to estimate what proportion of these
© 2009 BY QUINTESSENCE PUBLISHING CO, INC. PRINTING OF THIS DOCUMENT IS RESTRICTED TO PERSONAL USE ONLY. NO PART OF THIS ARTICLE MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM WITHOUT WRITTEN PERMISSION FROM THE PUBLISHER.
328 VOLUME 41 • NUMBER 4 • APRIL 2010
QUINTESSENCE INTERNATIONAL
Tschoppe et a l
changes is caused primarily by tumor or sec-
ondarily by oral inflammatory diseases, such
as mucositis, in this phase of radiation thera-
py.42,44,70,71 According to other investigations,
decreases in the activity of �-amylase, flow
rate, and protein levels were observed in
patients after 6 weeks of radiation treatment.69
In addition, the concentration of acidic and
basic proline-rich proteins, like cystatins, his-
tatins, and statherins also seems to be
reduced in irradiated patients.68 The low sali-
vary concentration of these components
could be caused by reduction in the number
of acinar cells, incomplete tissue regenera-
tion, and late stromal effects such as delayed
radiation-induced vascular damage.42,68,69
The radiation-related changes in salivary
concentrations of immunoglobulins have
also been investigated. Salivary IgA is con-
sidered to play an important role in protec-
tion against dental caries. Whole saliva and
serum samples collected from patients with
oral cancer display significantly elevated lev-
els of IgA and IgG even before radiation ther-
apy.70,72 Ratios of IgA and IgG to total protein
were reported to be greatly increased during
radiation therapy, but decreased notably
thereafter.72 The elevation of IgA was con-
fined largely to the first 2 weeks of irradiation,
after which it remained quite constant.72 The
elevated concentrations of these compo-
nents may provide some protection against
radiation-induced infections, at least in the
first phase of radiation therapy. According to
another study, the secretory IgA titer was sig-
nificantly higher in patients with fully irradiat-
ed major salivary glands even more than 6
months after radiation therapy.73
Even though total bacterial concentrations
in saliva of irradiated subjects seem to be rel-
atively unchanged,74 radiation-induced hypo -
salivation is accompanied by pronounced
shifts in specific microbial components, espe-
cially highly acidogenic microflora.72,74–76 The
number of cariogenic microorganisms such
as Lactobacillus, Streptococcus mutans, and
Staphylococcus was found to be extremely
elevated following radiation therapy.74–76 In
contrast to the high colonization with strepto-
cocci, lactobacilli, and candida species, peri-
odontal pathogens do not seem to be affect-
ed.74,75 During and following radiation therapy
the incidence of periodontal pathogens (such
as Aggregatibacter actinomycetemcomitans
or Porphyromonas gingivalis) was not found
to be significantly changed.75,77 Therefore, it
was suggested that in contrast to “radiation
caries,” there seems to be no microbiologic
evidence for “radiation periodontitis.”77
CONSEQUENCES OF ALTERED SALIVA COMPONENTS FOR ORAL HEALTH
Generally, objective hyposalivation of differ-
ent origins results in a change of salivary
composition, with increased viscosity,
reduced buffering capacity, altered salivary
electrolyte concentrations, and changed
nonimmune and immune antibacterial sys-
tems (Fig 3). These alterations can lead to
serious consequences for oral health. For
example, the average pH falls from about 7.0
to 5.0, which is considered cariogenic.42,44
Because of the lowered pH and buffering
Fig 2 Direct and indirect consequences of hyposalivation of differentorigins. (Modified from Kielbassa44 with permission.)
Systemic disease
Hyposalivation
Marginal/apical periodontitis, pulpitis
Medication
Dietary changes
Frequentmeals
Increase of cariogenic and periodontopathogenic microorganisms
Sticky foodSweet food
Reduced bufferAcidic plaque
Insufficient self-cleaning
Rampant caries
Radiotherapy Miscellaneous
Accelerated demineralizationReduced remineralization
Periodontitis
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capacity, the minerals of enamel and dentin
could easily dissolve. This event will not be
followed by the usual remineralization of the
dental hard tissue, because the conditions of
the oral environment of patients with hypos-
alivation are especially prone to demineral-
ization.42,44 As a consequence, remineraliza-
tion capacity of saliva is considerably ham-
pered.
Additionally, the reduced salivary flow rates
result in a substantial immunoprotein defi-
ciency.42,44 Accompanied by the reduced oral
clearance, these effects result in tremendous
changes of the oral flora in patients with
hyposalivation (particularly radiation induced)
with an increase in acidogenic and cariogenic
microorganisms.42,44 Undoubtedly, the shift in
oral microflora toward cariogenic bacteria, the
reduced salivary flow (oral clearance), and the
altered saliva composition (buffer capacity,
pH, immunoproteins, and oral clearance)
clearly result in an enormous increase of
caries risk in patients with hyposalivation,
especially after radiation therapy in the neck
and head area (Fig 4).42,44
In addition, if salivary flow is objectively
reduced, oral function (speech, chewing, and
swallowing) is hampered, because wetting
and lubrication of the mucosal surfaces and
moistening of food items will not be suffi-
cient.42,44 The previously mentioned loss of
taste is due not only to the effect of irradiation
on the taste buds but is also related to hypos-
alivation of another origin.44 A reduced sali-
vary flow inhibits transport and solubilization
of gustatory stimulants, thus leading to
decreased gustatory stimuli and a reduced
excitability of the taste buds.44
Under these conditions and without pre-
ventive measures (oral hygiene) and support-
ive therapy (ie, fluoridation), the dentition can
be destroyed within a few months (see Fig
3).22,78 Providing moisture to the oral mucosa
helps to relieve the symptoms of hyposaliva-
tion in patients.22,78
TREATMENT OPTIONSFOR HYPOSALIVATION
In case of a remaining functional salivary
gland parenchyma it is possible to treat hypos-
alivation with the administration of choliner-
gics (ie, pilocarpine hydrochloride), but sys-
temically acting sialogogues need to be used
with caution since adverse effects are often
observed.79 Locally acting stimulants of sali-
vary flow may be useful by way of masticatory
and/or gustatory stimulation of the salivary
glands.80 When it is impossible to stimulate
minimal salivary gland activity, saliva substi-
tutes can be prescribed.81 However, not all
functions of saliva can be adequately replaced
by artificial products; saliva substitutes often
lack sufficient lubrication and antimicrobial
Fig 3 Schematic diagram of time of onset and duration ofradiation-induced oral sequelae. (Reprinted from Kielbassa44
with permission.)
0 20 40 60
Gy
Taste loss
Mucositis
Hyposalivation
Radiation caries
Susceptibility to osteradionecrosis
0 1 2 3 4 5 6 10 14 18 32 64 110
During radiotherapy (d) After radiotherapy (wk)
Fig 4 Radiation-related damages to dentition.
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activity.82 Therefore, various thickening agents
(eg, carboxymethylcellulose [CMC], linseed,
ptyalin, or mucin) have been added to saliva
substitutes to improve their viscoelastic prop-
erties.82 However, some artificial salivas con-
taining these thickeners (Ptyalin, ptyalin based,
TMP Tüshaus; Salinum, linseed based,
Sinclair) have recently been withdrawn from
the (German) market because of pH instabili-
ties and occasionally observed bacterial
growth.81 Although it is not a natural lubricant,
CMC still seems to be a good clinical choice
as a basis of a saliva substitute. A recent
prospective crossover study showed that
most patients suffering from xerostomia pre-
ferred a CMC spray (Glando sane, Cell
Pharm) compared to solutions based on cel-
lulose gel, oil, or mucin, because of taste and
handling.83 None theless, preference of saliva
substitutes by various groups of patients has
been discussed controversially.84–88 Because
Glandosane revealed a high demineralizing
potential in several in vitro studies, it has not
been recommended for dentate patients.78,89,90
As mentioned above, saliva substitutes often
have a demineralizing potential or are at the
utmost neutral; only a few offer a remineralizing
potential.78,91,92 For example, Saliva natura (poly-
saccharide based, Medac) was introduced to
substitute Saliva medac (Medac) in 2006.
However, a demineralizing effect on dentin,92
and also on enamel after longer storage peri-
ods,78,93 could be observed. Remineralization
could be achieved in vitro with an experimen-
tally modified Saliva natura solution slightly
supersaturated with octacalcium phosphate
and dicalcium phosphate dihydrate.92,94 In con-
clusion, a stable remineralizing saliva substitute
preventing dental caries has been found in
vitro, and these results should be verified in clin-
ical studies.
CONCLUSION
Hyposalivation is common among patients
with different systemic autoimmune, hormon-
al, neurologic, and psychogenic diseases, but
also after intake of various medications or after
exposure to radiation therapy directed against
the head and neck region. The occurrence
of these etiologic factors can be accompa-
nied with quantitative and qualitative
changes of salivary components including
increased viscosity, reduced buffering
capacity, altered salivary electrolyte concen-
trations, and changed nonimmune and
immune antibacterial system. These alter-
ations can lead to serious consequences for
oral health such as hyposalivation, rampant
caries and oral yeast infection, reduced ability
to ingest food, speech impairment, and
many others. Providing moisture to the oral
mucosa helps to relieve the symptoms of
hyposalivation in patients. For this purpose,
saliva substitutes have been developed. To
date, clinical studies evaluating the effect of
saliva substitutes on dental hard tissues are
still missing. With the results of several in vitro
studies in mind, clinicians should consider
saliva substitutes that contain fluorides, and
those that are supersaturated with calcium
and phosphate.
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