Etiologic factors of hyposalivation and consequences for

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


3Professor and Head, Department of Operative Dentistry and

Periodontology, CharitéCentrum 3, University School for Dental


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.

[email protected]

© 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


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




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.



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


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




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




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




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




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




Tschoppe et a l

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.




Tschoppe et a l

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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Etiologic factors of hyposalivation and consequences for