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Salivary secretion in health and disease

June 2018
Journal of Oral Rehabilitation 45(9)

DOI:10.1111/joor.12664

Authors:

Anne Marie Lynge Pedersen

University of Copenhagen

Christiane Elisabeth Sørensen

University of Copenhagen

Guy Carpenter

King's College London

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Saliva is a complex fluid produced by three pairs of major salivary glands and by hundreds of minor salivary glands. It comprises a large variety of constituents and physicochemical properties, which are important for the maintenance of oral health. Saliva not only protects the teeth and the oropharyngeal mucosa, it also facilitates articulation of speech, and is imperative for mastication and swallowing. Furthermore, saliva plays an important role in maintaining a balanced microbiota. Thus, the multiple functions provided by saliva are essential for proper protection and functioning of the body as a whole and for the general health. A large number of diseases and medications can affect salivary secretion through different mechanisms, leading to salivary gland dysfunction and associated oral problems including xerostomia, dental caries and fungal infections. The first part of this review article provides an updated insight into our understanding of salivary gland structure, the neural regulation of salivary gland secretion, the mechanisms underlying the formation of saliva, the various functions of saliva and factors that influence salivary secretion under normal physiological conditions. The second part focuses on how various diseases and medical treatment including commonly prescribed medications and cancer therapies can affect salivary gland structure and function. We also provide a brief insight into how to diagnose salivary gland dysfunction. This article is protected by copyright. All rights reserved.

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1

1 | INTRODUCTION

The saliva present in the oral cavity constantly covering the teeth

and oral mucosa is termed whole or mixed saliva. It is a complex

mixture of fluids secreted by 3 pairs of major salivary glands, the

parotid, submandibular and sublingual glands, and by numerous

minor salivary glands, but it also contains various amounts of gin-

gival crevicular fluid, microorganisms, desquamated epithelial cells

and food debris.1 Salivary glands are mostly regulated by neural

reflexes as part of the autonomic nervous system, but are also

under the influence of various centres in the brain and gastroin-

testinal hormones as well.1-15 Salivary output differs with regard

to volume and composition depending on differential activation of

glands by different types of stimuli.7,10,12-14,16-19 Saliva has multiple

functions, which are linked to its fluid characteristics and to spe-

cific components. Saliva protects the teeth and oropharyngeal

mucosa, it facilitates articulation of speech, it is imperative for

mastication and swallowing, it exerts digestive actions, and plays

an important role in maintaining a balanced microbiota.10,13,14, 20-32

Several diseases, medical conditions and medications can affect

salivar y gland function leading to a sensation of dry mouth (xe-

rostomia), usually caused by reduced salivary flow and altered

salivary composition.33-37 Salivary hypofunction increases the

risk of oral disease (dental caries, dental erosion and fungal in-

fections) but may also lead to changes in dietary intake resulting

in malnutrition and/or weight loss as well as impaired quality of

life.1,10,14,28 -34,3 8,39 This review ar ticle focuses on the salivary

gland structure, the neural mechanisms of salivary secretion, the

Accepted: 1 June 2018

DOI : 10.1111 /jo or.12664

REVIEW

Salivary secretion in health and disease

A. M. L. Pedersen1 | C. E. Sørensen2 | G. B. Proctor3 | G. H. Carpenter3 | J. Ekström4

1Oral Medicine, Oral Pathology & Clinical

Oral Physiology, University of Copenhagen,

Copenhagen, Denmark

2Oral Biochemistry, Cariology &

Endodontics, Department of Odontology,

Faculty of Health and Medic al

Sciences, University of Copenhagen,

Copenhagen, Denmark

3Mucosal & Salivary Biology Division, King’s

College London Dental Institute, London, UK

4Department of Pharmacology, Institute

of Neuroscience and Physiology, The

Sahlgrenska Academy at Universit y of

Gothenburg, Gothenburg, Sweden

Correspondence

A. M. L . Pedersen, Oral Medicine and Oral

Pathology, Department of Odontology,

Faculty of Health and Medic al Sciences,

University of Copenhagen, Copenhagen N,

Denmark.

Email: amlp@sund.ku.dk

Summary

Saliva is a complex fluid produced by 3 pairs of major salivary glands and by hundreds

of minor salivary glands. It comprises a large variety of constituents and physico-

chemical properties, which are important for the maintenance of oral health. Saliva

not only protects the teeth and the oropharyngeal mucosa, it also facilitates articula-

tion of speech, and is imperative for mastication and swallowing. Furthermore, saliva

plays an important role in maintaining a balanced microbiota. Thus, the multiple func-

tions provided by saliva are essential for proper protection and functioning of the

body as a whole and for the general health. A large number of diseases and medica-

tions can affect salivary secretion through different mechanisms, leading to salivary

gland dysfunction and associated oral problems, including xerostomia, dental caries

and fungal infections. The first part of this review article provides an updated insight

into our understanding of salivary gland structure, the neural regulation of salivary

gland secretion, the mechanisms underlying the formation of saliva, the various func-

tions of saliva and factors that influence salivary secretion under normal physiologi-

cal conditions. The second part focuses on how various diseases and medical

treatment including commonly prescribed medications and cancer therapies can af-

fect salivary gland structure and function. We also provide a brief insight into how to

diagnose salivary gland dysfunction.

KEYWORDS

autonomic nervous system, saliva, salivar y dysfunction, salivary glands, xerostomia

PEDERSEN Et al.

process of saliva formation, functions of saliva and the factors that

influence salivar y secretion and composition under normal phys-

iological and pathophysiological conditions. The latter includes

various diseases, medical conditions, commonly prescribed med-

ications and cancer therapy. The search for biomedical literature

on normal salivary gland structure and function and dysfunction

(years 1954 to 2017) was conducted in PubMed, Embase and Web

of Science databases. Articles from the primary, secondary and

tertiary literature were selected for inclusion on the basis of their

significance and relevance to the clinician.

2 | SALIVARY GLAND STRUCTURE

Salivary glands are categorised into the 3 pairs of major glands, in-

cluding the parotid, submandibular and sublingual glands and about

600 to 1000 minor salivary glands particularly located in the labial,

buccal, palatal, lingual and retromolar regions of the oral mucosa.40

The salivary glands consist of parenchymal and stromal components.

The parenchyma is composed of secretory end pieces (acini), which

make a primary fluid/saliva, connected to a system of ducts (inter-

calated, striated and excretory) which modify the saliva (Figure 1).

Each acinus consists of either serous or mucous cells, or mucous cells

capped by serous demilunes (only found in the submandibular gland),

arranged about a central lumen. The salivary glands are classified his-

tologically according to their structural composition and their secre-

tions1,5, 6,9,10, 12-14,2 2-28 (Table 1). The length and the diameter of the

duct system vary depending on the gland type. The major salivary

glands have long, branched ducts, the parotid and submandibular

glands contain all ductal segments (intercalated, striated and excre-

tory), whereas the sublingual and minor glands lack striated ducts.40

Myoepithelial cells are contractile cells with a stellate shape that

surround the acini and intercalated ducts variably in the different

glands. They are located between the basal lamina and the cytoplas-

mic membrane of acinar or ductal cells (Figure 1). The myoepithelial

cells are controlled by the autonomic nervous system and upon con-

traction they are believed to assist the flow of saliva by compressing

the acini and the ducts and also to provide structural resilience to

the parenchyma during secretion.41 Although they are contractile

there is no evidence to suggest they force saliva out of acini by in-

creasing intra- acinar pressure and indeed their presence is not re-

quired for secretion to occur.

The connective tissue capsule that surrounds the major salivary

glands forms septa, which divide the gland into lobes and lobules.

These septa contain large blood vessels, nerves and ducts, whereas

the acini, intercalated and striated ducts, small blood vessels and

nerves are located within the lobules. In the minor salivary glands,

the connective tissue merges imperceptibly with the surrounding

connective tissue.41 The parenchyma has a rich supply of blood

vessels, which form a capillary plexus, particularly adjacent to the

ducts. Sympathetic stimulation makes the blood vessels constrict,

whereas parasympathetic stimulation lead to vasodilation and in-

creased blood flow to the salivary glands.42 Virtually all protein in

“pure glandular saliva” is derived from the salivary glandular cells and

not the blood stream. Most of the about 2.500 different proteins

in whole/mixed saliva probably originate from exfoliating epithelial

cells and oral microorganisms, and only one- tenth is thought to be

of gland origin.26

The final saliva that enters the oral cavity is composed of more

than 99% water and less than 1% solids, including proteins and salts.

The normal daily production of saliva is approximately 0.6 L.3 7,4 3 The

major salivary glands produce about 90% of the fluid secretion and

FIGURE1 Secretory end piece (acinus) terminating into a duct system. An acinus consists of either serous or mucous acinar cells or

mucous cells capped with a serous demilune. The intercalated duct, consisting of a monolayered cuboidal epithelium, leads into the striated

duct, which consists of a monolayered columnar epithelium with several folds of the plasma membrane basally, and mitochondria between

the folds. The final segment of the duct system is the excretory duct (multilayered columnar epithelium), which leads the final saliva into the

main excretory duct into the oral cavity. Acini and intercalated ducts are surrounded by myoepithelial cells

Acinus Intercalated duct Striated duct Excretory duct Oral cavity

Surrounding blood vessels/capillary network

Myoepithelial cells

PEDERSEN E t al.

the minor glands less than 10%. However, the minor salivary glands

secrete a relative large fraction of the salivary mucins, providing lu-

brication to the oral surfaces.44 Table 1 details the contribution of

the various glands to the whole saliva volume under unstimulated

and stimulated conditions.

3 | NEURAL REGULATION OF SALIVARY

SECRETION AND THE SECRETORY

ELEMENTS

Salivar y secretion is controlled by the autonomic nervous system

and regulated by reflexes. The reflex pathways consist of an afferent

component, the salivation centre and an efferent component, which

leads to activation of salivary gland cells (Figure 2).

The gustatory- salivar y reflex involves sensory signals from

taste- activated chemoreceptors in the taste buds in the lingual

papillae, in pharynx and larynx, transmitted along sensory fibres

of the facial, glossopharyngeal and vagal nerves to the nucleus of

the solitary tract.45 The masticatory- salivary reflex conducts so-

matosensory impulses, which are primarily induced by activation

of mechanoreceptors in the periodontal ligament during mastica-

tion, but also by activation of proprioceptors and/or nociceptors in

the oral cavity, along with sensory trigeminal and glossopharyngeal

nerves to the mesencephalic and spinal trigeminal nuclei.7,46 The

sensory nuclei convey these inputs to the salivation centre and to

higher brain structures. Thus, salivary reflex pathways situated in

the lower brainstem can in theory activate salivary secretion with-

out involvement of higher brain centres.47 Concomitantly, afferent

signals transmitted from the sensory nuclei along second and third

order ascending neurons activate higher brain centres, which then

via efferent inputs can modulate the reflexes. Accordingly, not

only masticatory and gustatory afferent impulses, but also olfac-

tory, nociceptive, thermoreceptive and psychic stimuli influence

salivation.8,48-50

Afferent sensory impulses are transmitted to the salivation

centre (comprising the parasympathetic superior and inferior

salivatory nuclei in the brainstem and the sympathetic saliva-

tion centre in the upper thoracic segments of the spinal cord)

and to higher brain structures, which may send both excitatory

and inhibitory efferent projections to the salivatory nuclei. The

inputs are integrated in the salivation centres, which induce

generation of nerve impulses in the parasympathetic and sym-

pathetic neurons inner vating the salivary glands. In the human

brain, the exact neuroanatomical pathways for connections be-

tween the salivation centre and forebrain structures have not yet

been fully explored, and most of the knowledge about projections

from higher brain centres to the brain stem derives from animal

studies.51-53

The efferent part of the reflex consists of parasympathetic and

sympathetic secretomotor neurons, which innervate the salivary

glands. Overall, the parasympathetic innervation of the salivary

gland cells is more abundant than the sympathetic innervation.

Upon stimulation, both parasympathetic and sympathetic nerves

cause secretion of fluid and protein, as well as contraction of myo-

epithelial cells, and the 2 divisions of the autonomic nervous sys-

tem interact synergistically. Since parasympathetic activity results

in large volumes of saliva and sympathetic activity results in small

TABLE1 Salivary gland structural features, parasympathetic innervation and contribution to whole saliva volume under unstimulated (in

the absence of exogenous stimuli) and under chewing- stimulated conditions1,1 0,12-14, 40

Acinar cell type Secretory product

Contribution (%) to

whole saliva volume

Parasympathetic

nerve supply

Ducts to the oral

cavity

Major salivary glands

Parotid glands Serous Watery, amylase- rich Resting: 25%

Stimulated: 50%

Glossopharyngeal

nerve

Stensen’s duct

Submandibular glands Mixed, mainly

serous

Viscous, mucin- rich Resting: 60%

Stimulated: 35%

Facial nerve Wharton’s duct

Sublingual glands Mixed, mainly

mucous

Viscous, mucin- rich Resting: 7%- 8%

Stimulated: 7%- 8%

Facial nerve Ducts of Rivinus

Bartholin’s duct

Minor salivary glands

Palatinal glands Mucous Mucin- rich Resting: 8%

Stimulated: 8%

Facial nerve Individual small

ducts

Buccal glands Mixed, mainly

mucous

Mucin- rich Facial nerve

Labial glands Mixed, mainly

mucous

Mucin- rich Facial nerve

Lingual glands Serous Watery, lipase- rich Glossopharyngeal

Retromolar glands Mucous Viscous, mucin- rich Facial nerve/

Glossopharyngeal

The sympathetic nerve supply is obtained from the superior cervical ganglion. Mixed means that the glands contain both serous and mucous acini, also

mucous acini capped with serous demilunes may be seen in these glands.

PEDERSEN Et al.

volumes, the parasympathetic saliva is characterised as protein- poor

(in terms of concentration) and the sympathetic saliva as protein-

rich.13 Under reflex secretion, the sympathetic nerve is thought to

act in a background of a parasympathetically induced flow of sa-

liva. Hormones, apart from adrenaline, do not seem to evoke fluid

secretion. However, recent findings indicate a possible secretory

role of gastrointestinal hormones.13,15 Gastrin, cholecystokinin and

melatonin (the latter found in large amounts in the intestines apart

from its traditional pineal localisation) induce protein secretion, but

not fluid secretion, in the rat parotid gland.11,15,5 4 Moreover, the 3

hormones stimulate protein synthesis in the experimental gland. In

addition, in vitro studies on human parotid tissue demonstrate acinar

exocytosis of protein storing granules upon stimulation with penta-

gastrin and melatonin.11,5 4 Thus, salivary glands and the secretion

may, like other digestive glands, be under the control of a cephalic

phase (nerves), a gastric phase (gastrin) and an intestinal phase (cho-

lecystokinin and melatonin).13

3.1 | Blood supply to the salivary glands

The blood vessels of the glands are supplied with parasympathetic

vasodilator fibres that upon stimulation cause the blood flow to in-

crease up to 20- folds, thus providing water for secretion.26,42 The

sympathetic innervation supplies the vessels with vasoconstrictor

fibres. Importantly, these vasoconstrictor fibres are separate from

those sympathetic secretomotor fibres for the gland cells and fur-

ther, they are activated in connection with a fall in blood pressure

such as in a situation of blood loss and not under normal conditions

such as during a meal.26,42

3.2 | Activation of salivary gland receptors

Beside the traditional transmitters of the parasympathetic and sym-

pathetic postganglionic nerves, acetylcholine and noradrenaline,

respectively, a number of co- transmitters may occur in cholinergic

FIGURE2 Regulation of salivary secretion illustration of the reflexes involved in salivary secretion. Afferent nerves carr y sensory inputs

that arise from taste activation of chemoreceptors (via the facial [VII], glossopharyngeal [IX] and vagus [X] nerves) or from activation of

mechanoreceptors or nociceptors (via the trigeminal [V] nerve) to the salivatory nuclei in the medulla oblongata. The salivatory nuclei also

receive impulses from higher brain structures, which thereby influence salivary secretion. Afferent inputs are integrated in the salivatory

centre, which then activate the efferent part of the reflex, comprising parasympathetic and sympathetic nerves. The parotid glands receive

parasympathetic signals from the glossopharyngeal nerve that synapse in the otic ganglion. The submandibular and sublingual glands

receive parasympathetic signals from the facial nerve that synapse in the submandibular ganglion. The sympathetic nerves run from to the

sympathetic trunk and synapse in the superior cervical ganglion. Postganglionic sympathetic nerves then follow the blood vessels to the

salivary glands which they innervate. Acetylcholine and noradrenaline are released from the postganglionic the parasympathetic and the

sympathetic nerve endings, respectively, and elicit salivary secretion. Other co- transmitters are released to which have a modulatory effect

on the formation of saliva

Cerebral cortex

Thalamus

Hypothalamus

Limbic system

Medulla oblongata

Salivatory nuclei superio

Salivatory nuclei inferior

Parotid gland

Sublingual gland

Submandibular gland

Otic ganglion

Submandibular ganglion

Superior cervical ganglion

Sympathetic trunk

Depression

Anxiety

Sleep

Smell

Sound

Masticatory stimuli

Gustatory stimuli

Nausea, vomiting,

distension

N. V

NN. VII, IX, X

Upper thoracic segment

of the spinal cord

PEDERSEN E t al.

and adrenergic axons, of which some induce secretion themselves or

potentiate the effects of the classical transmitters.18,55-59 Particular

attention has been paid to the parasympathetic innervation and a

number of neuropeptides as potential co- transmitters, one of which

is vasoactive intestinal peptide (VIP), causing secretion of proteins but

only a small fluid secretion, if any, and moreover, vasodilatation.18,57,59

Nitric oxi de of parasympat hetic origin is also invo lved in the vaso-

dilator response, and in the acinar cells, nitric oxide may be mobilised

upon stimulation, contributing to cAMP- mediated protein secre-

tion.13,26, 60 Substance P, another neuropeptide, causes a profuse sal-

ivation but only in some species and not in humans.18,59 In contrast

to the acinar cells of the human parotid and submandibular glands

FIGURE3 Model for acinar ion transport mechanisms involved in salivary fluid formation. A, Salivary secretion depends on increase

in the free intracellular calcium concentration [Ca2+]i in response to receptor stimulation to initiate key ion transport pathways necessary

for primary fluid formation. Stimulation of Gq/11- protein coupled, primarily the muscarinic M3 and M1 receptors by acetylcholine, leads

to phospholipase C (PLC)- mediated inositol 1,4,5- triphosphate (IP3) production, subsequent IP3 receptor activation on the endoplasmatic

reticulum (ER) and rapid Ca2+ release from the ER. Acinar cells further express α1- and β- adrenergic receptors, which bind noradrenaline

released from the glandular sympathetic innervation. Stimulation of β1- adrenergic receptors, coupled to Gs- protein, induces activation of

adenylyl cyclase (AC), followed by cyclic adenosine monophosphate (cAMP) production. cAMP activates protein kinase A (PKA), which via

phosphorylation events mediates exocytosis of proteins from acinar cells. β1- adrenergic receptor activation may also elicit fluid secretion.

α1- adrenergic receptor stimulation evokes similar to M3 and M1 activation PLC/IP3- mediated [Ca2+]i increase, however, parasympathetic

muscarinic receptor activation by acetylcholine is the primary stimulus for production of the bulk of salivary fluid. Transepithelial movement

of anions is regarded the main driving force for acinar electroly te and fluid secretion. Both chloride and bicarbonate can drive salivary

secretion, and details primarily the chloride- dependent model. Increase in [Ca2+]i upon receptor stimulation immediately opens luminal,

calcium- activated chloride channels, consistent with TMEM/ANO- 1. In parallel, basolateral calcium- activated potassium channels are

opened, the molecular identities of which are the intermediate conductance KCa3.1 (IK1) and the large- conductance KCa1.1 (maxi- K)

channels. Basolateral potassium efflux leads to hyperpolarisation, which provides electrical driving force for the luminal chloride efflux. The

accumulation of chloride ions intraluminally creates a transepithelial lumen negative potential difference, which drives sodium paracellularly

into the lumen. The resulting high intraluminal sodium chloride concentration causes osmotic water movement to the lumen, both

transcellularly via aquaporin water channels as well as paracellularly. The final result is formation of isotonic primar y saliva with plasma- like

sodium chloride concentrations. To obtain sustained secretion from acinar cells, [Ca2+]i is maintained high due to extracellular calcium influx

induced by the mechanism of store- operated calcium entry, in which initial calcium release from intracellular stores leads to gating of plasma

membrane calcium channels. Resting conditions in acinar cells are rapidly reestablished after stimulation is terminated. Intracellular calcium

concentrations are reduced to the pre- stimulatory level by plasma membrane calcium ATPases, the Sarco/Endoplasmic Reticulum Calcium

ATPase- pump and by calcium binding proteins. B, Chloride secretion from acinar cells depends on basolateral ion transporters, which in

cooperation accumulate intracellular chloride above equilibrium. The Na+/K+ - ATPase creates an inwardly directed sodium gradient across

the basolateral membrane, and provides energy for this activity. The gradient is utilised for chloride uptake by the loop- diuretic sensitive

Na+/K+/2Cl− cotransporter NKCC1 and a coupled parallel pathway consisting of a basolateral Cl−/

HCO−

exchanger (AE2) and a Na+/H+

exchanger (NHE1). C, The secretory response from acinar cells is paralleled by transient intracellular acidification caused by the efflux of

HCO−

and H+ are produced by the carbonic anhydrase catalyzed conversion of CO2 and H2O.

HCO−

efflux can significantly contribute

to primary saliva formation, likely via a similar luminal conductance as Cl−, however, in many salivary glands Cl− secretion is sufficient to

drive fluid formation. Following

HCO−

efflux, the intracellular pH recovery is achieved by up- regulated activity of the basolateral Na+/H+

exchanger, which can use the Na+ gradient established by the Na+/K+ ATPase to export protons

(a) (b) (c)

Na+

H2O

Na+

H2O

NaCl

NaHCO3

H2O

2K+Na+

H+

Cl–

HCO3

–

Na/2Cl/K

K+

H+

Na+

Cl–

HCO3-

2K+

Cl–HCO3–

CO2 + H2O H2CO3 H+ + HCO3-

Transient decrease in pHi

followed by pHirecovery

3Na+

K+

H2O

α1

AQP5

HCO3–Cl–

Ca2+

IP3R

Ca2+

IP3

3Na+

β1cAMP

PIP2

ATP

DAG

PKC

Protein

PEDERSEN Et al.

which lack a substance P innervation,59 substance P- immunoreac tive

fibres are present in the human labial salivary glands, where stimu-

lation with substance P also induced a raise in intracellular calcium

suggesting that it is involved in fluid secretion in these glands.58

The receptors upon which the tr ansmitters act are located on the

basolateral part of the cell membrane. The cholinergic receptors are

of muscarinic M1- and M3- subtypes, whereas the adrenergic recep-

tors are of α1- and β1- subtypes.18,26, 55 VIP acts on so called VIP- ergic

receptors. Interestingly, with respect to the sympathetic response

noradrenaline evokes protein secretion particularly by β1- receptors,

while fluid secretion, serving as carrier for the proteins, is caused

by α1- adrenergic receptors. With respect to the parasympathetic

response, VIP is particularly responsible for protein secretion and

acetylcholine for fluid secretion, serving as carrier.18,26,55,61,62 Cross-

talk of these transmitter substances, via the intracellular messengers

cAMP (preferentially protein secretion) and Ca2+ (preferentially fluid

secretion), amplifies the neurotransmitter effects and is responsible

for augmented fluid and protein secretion under normal reflex con-

ditions. Several purinergic receptor subtypes have also been found

in salivary gland cells from various species, including human labial

salivary glands, which indicates additional modulation of salivary

gland function by extracellular nucleotides.18,58,63,64 Figure 3 illus-

trates the events occurring upon stimulation of the muscarinic, α1-

adrenergic (both Gq/11- protein- coupled receptors) and β1- drenergic

and VIP- ergic receptors.18,19,65-69

3.3 | Trophic effects of nerves on salivary gland size

The parasympathetic innervation is of particular importance for the

gland size and secretory capacity. A parasympathetic denervation is

followed by a marked fall in weight, which is gradually restored as

re- innervation progresses.57 However, denervation procedures are

not necessary to produce changes in gland size. Animal studies show

gland size, secretory capacity and neuronal synthesis of acetylcho-

line to decrease in response to decreased demands on reflex secre-

tion induced by liquid diet and to increase in response to increased

demands on reflex secretion induced by a chewing- demanding diet.70

Acetylcholine is not the likely transmitter responsible for changes in

gland weight, but rather a phenomenon involving neuropeptides.57

3.4 | Sensory gland innervation

Patients experience pain in the salivary gland region upon gland

swelling in response to gland inflammation or sialolithiasis. The pain

is often referred to stretching of the gland fascia and, as a conse-

quence, activation of afferent nerves of the fascia.71,72 However,

sensory nerves, containing the neuropeptides substance P and cal-

citonin gene- related peptide occur along the small ducts and close

to the vessels.73 Local release of these sensory peptides occurring

as a protective response may result in contraction of the myoepi-

thelial cells and release of ductal located antimicrobial agents as well

as vasodilation, protein extravasation and formation of oedema.74

Experimentally, increase in ductal pressure and, in particular,

exposing the ductal cells to noxious substances, activate impulse

activity in the glandular sensory nerves travelling in the parasympa-

thetic and sympathetic nerves of the glands.75

4 | FORMATION OF PRIMARY SALIVA

AND DUCTAL SALT REABSORPTION

Formation of saliva takes place in a 2- stage process.76 Upon stimula-

tion, the acini produce an isotonic, primary secretion with plasma-

like electrolyte composition. This primary saliva is then modified by

the striated ducts, where sodium and chloride ions are reabsorbed

and bicarbonate and potassium ions are added without further

changes in the water content due to the low water permeability of

the ductal epithelium. Thus, the final saliva that enters the oral cav-

ity is hypotonic and has low sodium concentration in comparison to

plasma. Figure 3 details the cellular mechanisms underlying forma-

tion of primary saliva.19, 62 ,76 -8 8

Salivar y duct epithelial cells express ion transport pathways

that enable reabsorption of sodium and chloride across the luminal

membrane. Sodium can enter the cells via the amiloride- sensitive,

epithelial sodium channel, ENaC89, 90 and chloride via the CFTR

(cystic fibrosis transmembrane regulator) chloride channel91-9 4

expressed in the luminal membrane. The driving force for sodium

reabsorption is provided by the inwardly directed sodium gradient

resulting from Na+/K+ - ATPase activity, which is abundantly ex-

pressed in the basolateral membrane foldings of striated ducts.91

The transporters involved in generation of driving force for lumi-

nal chloride uptake are not completely resolved, but may include

basolateral Cl− exit pathways, such as a K+/Cl− co- transporter,95

the AE4 member of the Cl−/HCO-

3 exchanger family,96 and the

hyperpolarisation- activated Clcn2 chloride channels.97 An alter-

native pathway possibly involved in luminal sodium and chloride

reabsorption is a luminal Na+/H+ exchanger (isoforms NHE2 and

NHE3,91 possibly operating in conjunction with a luminal Cl−/

HCO−

exchanger (isoforms SLC26A4 and SLC26A6,98 which promotes Cl−

import in exchange for

HCO−

. Nevertheless, a study on the effect

of knockout of the NHE2 or NHE3 isoform in mice did not reveal

a significant role of these in sodium reabsorption.99 Although sali-

vary duct epithelial cells contribute a large amount of bicarbonate

to the salivary secretion, neither the proportion contributed or the

underlying ion transport mechanisms are fully known. Sodium bi-

carbonate co- transporters (NBC) may be involved in ductal bicar-

bonate secretion. For instance, expression of 2 isoforms has been

described from the human parotid and submandibular glands, and

the cellular localisation differed between these two.100 Basolateral

expression of the NBCn1 isoform is in agreement with a supportive

role in ductal bicarbonate secretion, whereas the role of the lumi-

nally expressed NBC3 is less clear, but might include absorption

of bicarbonate under certain conditions.100 A further source for

bicarbonate release into the salivary secretion is the intracellular,

carbonic anhydrase catalysed conversion of CO2 and H2O. In co-

operation with the basolateral sodium/proton exchanger (NHE1),

PEDERSEN E t al.

bicarbonate generated from this reaction can leave the cells via the

luminal Cl−/

HCO−

exchanger. In addition to the ductal bicarbonate

contribution, a certain amount of salivary bicarbonate may also

originate from acinar cells, as for instance expression of the NBCe1

transporter was observed in human parotid acini.101 It has been

shown that the luminal membranes of ducts in mouse submandib-

ular glands express potassium channels, which may play a role in

ductal potassium secretion.102 Although the bulk protein secretion

occurs from the acini, the ductal cells also release various proteins,

including growth factors (eg nerve growth factor and epithelial

growth factor), immunoglobulin (IgA) and kallikrein.88

The final salivar y electrolyte composition is dependent on the

flow rate, which in turn depends on the stimuli that activate neu-

rotransmitter release from the glandular autonomic neurons. In the

human parotid gland, sodium and chloride are largely reabsorbed at

low or unstimulated secretion rates.103,104 Upon stimulation of the

submandibular glands, the salivary concentrations of sodium, bicar-

bonate, chloride, calcium, and protein, the ionic strength, and pH

increase with increasing flow rates, whereas potassium concentra-

tions only slightly decline with increasing flow.16 Testing the effect

of the duration of stimulation at different constant flow rates, for

instance, on bicarbonate and chloride concentrations, revealed that

after an initial increase of both anion concentrations, bicarbonate

concentration continued to increase, whereas chloride concentra-

tion decreased during prolonged stimulation, resulting in an inverse

relationship between these ions with time.16,103,10 4 Moreover, pa-

rotid salivary pH followed the pattern of bicarbonate and increased

with stimulation duration and higher flow rates.103 Overall, this un-

derlines the importance of the salivary flow rates and duration of

stimulation for the final electrolyte concentrations, ionic strength,

tonicity and pH of saliva, which are important for the functions of

saliva.

5 | FACTORS INFLUENCING SALIVARY

SECRETION

Salivar y gland function is under the influence of various factors and

stimuli, which can alter the volume, flow, and composition of saliva.

For instance, unstimulated saliva flow rates display circadian varia-

tion, with a peak level in the afternoon and a time span of 12 hours

between highest and lowest secretory rates.105-109 Salivary protein

displayed a similar pattern, whereas salivary sodium and chloride

concentrations followed the reverse rhythm, with highest levels in

the early morning.105,106,10 8 Labial salivary glands also show some

daytime- dependent variation, with highest secretory rates in the

evening, and a diurnal pattern different from the rhythm of unstimu-

lated whole saliva.110 A recent publication has demonstrated expres-

sion of certain key clock genes involved in regulation of circadian

rhythms and of aquaporin 5 in mouse submandibular gland cells,

which both followed a regular rhythmic pattern.111 Thus, evidence

suggests that normal salivary secretion is under influence of a circa-

dian clock mechanism, which may also play a role in different salivary

gland pathologies.112 In addition, it is important to take variations in

salivar y secretion due to circadian rhythms into consideration, when

saliva flow rates are measured and saliva composition is analysed in

a clinical context or for research purposes.

The level of hydration of the body also influences salivar y

secretion.109 It has been shown that parotid saliva flow rates de-

creased significantly in both younger and older healthy adults after

a 24 h period of fluid and food abstinence,113 and conditions of

acute dehydration are also associated with reduction in salivary

flow rates.114,115 Gland size is another factor related to saliva flow

rates.116-118 With respect to ageing, a number of studies have in-

vestigated whether it is associated with decrease in salivary flow

rates, since both major and minor salivary glands undergo age-

related structural, degenerative changes, such as loss of secre-

tory acini and stromal alterations.1 19-1 25 In this regard, results are

contradicting, showing stable113,126-133 or declining salivary gland

function with age.134-136 This variability may be ascribed to differ-

ences in sampling conditions and methods used, and in the health

status of study participants, since in older people, reduced salivary

flow is often associated with diseases and medication intake.128

A recent meta- analysis revealed that unstimulated and stimulated

whole as well as submandibular/sublingual, but not parotid and

minor salivary gland flow rates were lower in older than in younger

persons.137 However, the difference was not significant for stim-

ulated whole saliva flow rates after exclusion of the medicated

subgroup in the analysis.137 Results indicating that unstimulated

whole saliva flow may be more prone to decline in older people

suggest that the degree of functional glandular impairment with

age may vary despite consistently observed age- related loss of se-

cretory tissue in all salivar y glands. For instance, the function of

the parotid gland, which contributes most to chewing- stimulated

secretion, remains stable during ageing in healthy, non- medicated

persons.126

6 | FUNCTIONS OF SALIVA

Saliva serves multiple functions, which are important for the main-

tenance of oral and general health. Saliva lubricates and cleanses the

teeth and oral mucosa, maintains neutral pH through its buffering

capacity, prevents tooth demineralisation, exerts antimicrobial ac-

tions, aids in taste and bolus formation, initiates enzymatic diges-

tion of starch and is imperative for mastication and swallowing and

articulation of speech (Table 2).10,13,14,20-29 It also plays an important

role in the formation of the acquired enamel pellicle and the mucosal

pellicle, which apart from having a protective function also deter-

mine the initial adhesion and colonisation of microorganisms and the

composition of the resident oral microbiota.30-32 Saliva contains sev-

eral proteins and peptides with specific biological functions, a pro-

portion of which are of microbial origin.26,138 There is a large panel

of host salivary proteins and peptides, which range in abundance

and a core group of proteins.139 Table 2 shows the functions of the

most abundant salivary proteins. Salivary proteins are involved in a

PEDERSEN Et al.

TABLE2 Functions of saliva related to its components and their mode of action (for reviews1,10,13,14, 20-3 2)

Function Component Mode of action

Maintenance of oral health

Lubrication of oral surfaces Mucins Mucins are large, highly glycosylated proteins that form a hydrophilic

network

Glycosylated proline- rich

proteins

MUC5B is the primar y gel- forming mucin, MUC7 is less efficient as

lubricant

Water Moisten and lubricate oral surfaces, give saliva its texture and viscosity

Oral clearance Water Elimination of microorganisms, dietary sugars and acids by dilution and

swallowing

Buffer capacity Bicarbonate Buffer acids from dietary intake and acids produced by bacterial fermenta-

tion of sugars, thereby maintaining pH in the neutral range, decreasing

the tooth demineralisation rate and promoting/maintaining a balanced

oral microbiota

Phosphate

Proteins

Salivary pellicle formation Salivary proteins Salivary proteins, eg mucins, proline- rich proteins, α- amylase, cystatins,

statherins, lysozyme, lactoferrin, sIgA a.o. interact with dental and

mucosal surfaces, each other, and oral microorganisms, thereby altering

their properties and ability to modulate the microbial colonisation in the

oral cavity. MUC1 and MUC4, which play a role in cell signalling, also

interact with other salivary proteins

Tooth mineralisation Proline- rich proteins High affinity to hydroxyapatite, bind to calcium, inhibit spontaneous

precipitation of calcium phosphate salts from the dental surfaces,

important for the integrity of the teeth

Cystatins

Statherins

Antimicrobial actions Mucins Mucins, promote aggregation of microorganisms, especially MUC7;

antibacterial, antifungal and antiviral

Histatins Antifungal, moderate antibacterial

Cystatins Antibacterial, antifungal and antiviral

Statherins Antibacterial, antifungal and antiviral

Proline- rich proteins Antibacterial (Gram- negative), antiviral

Peroxidases Catalyse oxidation of thiocyanate to hypothiocyanite by hydrogen

peroxide; antibacterial and antifungal

α- amylase Antibacterial, provide nutrition for certain bacteria via hydrolysis of starch

Lysozyme Hydrolysis of the polysaccharide layer of the gram- positive bacterial cell

wall; antibacterial, antifungal and antiviral

Lactoferrin Binding and sequestering of iron, depriving microorganisms of iron;

antibacterial, antifungal and antiviral

Immunoglobulins, mainly sIgA Inhibit microbial adhesion, enhance phagocytosis, aggregate microorgan-

isms in interactions with other proteins

Antibacterial, antifungal and antiviral

Defensins Antimicrobial peptides

Tissue repair Growth factors Epidermal growth factor (EGF) promotes proliferation and migration of oral

epithelial cells for wound healing; fibroblast growth factor (FGF)

promotes wound healing and tissue repair

Water, mucins Protects oro- oesopharyngeal mucosa from injury

Digestive functions

Tas te Water, mucins Dissolution and transport of taste substances to taste buds

Gustin Growth and development of taste buds, integrity of taste sensitivity

Salivary proteins Salivary composition influences the perception of fat, saltiness, bitterness,

and the perception of texture

Electrolytes

Proline- rich proteins Precipitate tannins and thus contribute to the sensation of astringency

(Continues)

PEDERSEN E t al.

range of functions, for example acidic proline- rich proteins, histatins,

cystatins and statherins have a high affinity for hydroxyapatite as

they bind to calcium. Statherin in particular inhibits precipitation of

calcium phosphate salts from saliva and thereby plays a central role

in tooth integrity.140 Some of the more abundant salivar y proteins

display multifunctionality and act in synergy, for example, histatins

are a group of basic proteins which play a role in wound healing, have

antimicrobial activity and bind to enamel.140,141

Physiological factors, for example reflex stimulation, circadian

rhythms and age influence the composition of proteins, and inor-

ganic constituents in whole mouth saliva. As mentioned above, the

composition of both glandular and whole mouth saliva is highly de-

pendent o n the flow rate, and the concentr ations of sodium, chloride

and bicarbonate are higher, and the co ncentrations of pot assium and

total phosphate are lower in stimulated compared to unstimulated

saliva.16,17,19,76,7 7 The salivary buffer capacity includes the bicarbon-

ate, phosphate and protein systems and is much higher in stimulated

saliva due to the higher concentrations of bicarbonate.142-145 In the

unstimulated state, the bicarbonate and phosphate buffer systems

contribute almost to the same extent to the overall buffer capac-

ity, whereas the bicarbonate buffer system is responsible for more

than 90% of the total buffer capacity in stimulated whole saliva. At

very low saliva flow rates and at pH below 5.0 it is mainly proteins

that contribute to the buffer capacity.144-146 Salivary pH and sali-

vary concentrations of calcium and phosphate are important factors

for the maintenance of saturation with regard to hydroxyapatite in

the saliva. The salivary buffer capacity, and its ability to keep pH

within a neutral range, is also important for the promotion and

maintenance of a balanced oral microbiota.31,32 ,147 The bicarbonate

is an ideal buffer in the oral cavity as it also contributes with a phase

buffering effect, due to the carbon dioxide phase conversion from

the dissolved state to the volatile gaseous phase, resulting in loss

of the acidic end product from the oral cavity. Carbon anhydrase

VI, which is secreted into human saliva by the serous acinar cells of

the parotid and submandibular glands, catalyses this conversion of

carbonic acid to water and the volatile gas carbon dioxide.148

Recent studies have revealed several hundred fatty acids, pep-

tides, amino acids and other low molecular weight metabolic deriv-

atives constituting the human salivary metabolome. Components of

the human salivary metabolome are derived from and provide bio-

markers of both human and microbial metabolic activity and their

functional significance is being studied.149, 15 0

7 | SALIVARY GLAND DYSFUNCTION

Salivar y gland dysfunction is defined as any quantitative and/or

qualitative change in the output of saliva. It can either be a reduc-

tion in salivary secretion ranging from mild to severe hypofunc-

tion or an increase in salivary secretion (hyperfunction). The latter,

called sialorrhea is relatively uncommon in adults. Drooling may

occur as the result of genuine salivary hyperfunction (primary

sialorrhea), but most commonly drooling is associated with an

overflow of saliva from the mouth due to impaired neuromuscular

control with dysfunctional voluntary oral motor activity or distur-

bances in sensory ability (secondary sialorrhea).151 In Parkinson’s

disease drooling is attributed to a swallowing disorder and not to

an increase in salivary flow rate.152 In fact, both unstimulated and

stimulated salivary flow rates have been found decreased and the

frequency of xerostomia increased in patients with Parkinson’s

disease.153-155

Of note, the side- effects of treatment of schizophrenia with

clozapine, the flagship of the second generation of antipsychotics,

are often both dry mouth and sialorrhea.37 Clozapine is a dopamine

receptor antagonist but it acts also as a partial agonist on muscarinic

M1 receptors and as antagonist on muscarinic M3 receptors and α1

adrenergic receptors explaining mixed actions of the drug.156 The

following section is focused on the most common problem, namely

salivar y gland hypofunction and the associated changes in saliva

composition and oral consequences.

Salivar y gland hypofunction is often associated with a per-

sistent sensation of dr y mouth (xerostomia). Xerostomia usually oc-

curs when the unstimulated whole saliva flow rate falls by 40- 50%

of its normal value in any given person, indicating that more than

one major salivary gland must be affected.109 However, xerostomia

may also occur without objective evidence of salivary gland hypo-

function.157 Thus, xerostomia may be a result from changes in sal-

ivary composition or function, particularly of lubricating mucins.21

Xerostomia is a common complaint estimated to affect at least 10%

of an adult population.158,159 The prevalence of xe rostomia, however,

varies from 5.5% to 46% depending on the method of assessment

used and the population cohorts studied.160 ,161 Generally, women

and older people suffer more from xerostomia and have lower sali-

vary flow rates than men and younger people due to a higher num-

ber of diseases and a higher intake of medication among women and

older people.159,162-168 Salivary gland hypofunction may develop into

Function Component Mode of action

Initial digestion α- amylase, lipase α- amylase cleaves the α- 1,4- glycosidic linkages of starch into maltose,

maltotriose and dextrins

Mastication Hydrolyses triglycerides into partial glycerides and free fatty acids

Food bolus formation,

swallowing

Water, mucins Promotes and facilitates bolus formation and swallowing

Articulation of speech Water, mucins Facilitates articulation of speech

TABLE2 (Continued)

PEDERSEN Et al.

hyposalivation, a term that is based on objective measures of the

salivary flow rate (sialometry).

8 | CONSEQUENCES OF SALIVARY GLAND

HYPOFUNCTION

Patients with salivary gland hypofunction, irrespective of the ae-

tiology, often complain of oral dryness that is present throughout

the day, but it can also lead to disturbed sleep at night. Persistent

and severe salivary gland hypofunction commonly results in mu-

cosal changes, an increased activity of caries with lesions on

cervical, incisal and cuspal tooth surfaces and oral fungal infec-

tions.1,10,14,21-32 ,38 ,39,109,168-171 Disturbed taste sensation, impaired

lubrication and dysphagia may lead to behavioural changes avoiding

certain foods. In turn, changes in dietary intake may result in nu-

tritional deficiencies and atrophy of the masticatory muscles and

decreased masticatory ability.23,172-176 Consequently, salivary gland

hypofunction and its related symptoms and clinical consequences

often have negative effects on social functioning and quality of

life.34,157,159,177-179 Table 3 shows the various consequences of per-

sistent salivary gland hypofunction. Of note, the feeling of oral mu-

cosal dryness may be associated with dryness in other regions of the

body indicating common underlying factors for dryness.180

9 | CAUSES OF SALIVARY GLAND

HYPOFUNCTION

Intake of medications, especially of antidepressants, anxiolyt-

ics, opiates, antihypertensives, diuretics and antihistamines, is the

most common cause of salivary gland hypofunction and xerostomia.

Drugs can affect the salivary secretory mechanisms in various ways.

Some drugs, like benzodiazepines and opioids, affect the central

neural regulation of salivary secretion, while others act on the pe-

ripheral neuro- effector site via interaction with the binding of neu-

rotransmitters to receptors on the plasma membranes of the salivar y

gland cells, including atropine, which binds to muscarinic cholinergic

receptors and α- and β- blockers, which bind to adrenergic receptors.

Other drugs like diuretics can indirectly affect the salivary secretion

via their action on the salt and water transport and water balance. In

addition, polypharmacy, that is a regular daily intake of more than 4

different medications, is associated with xerostomia and salivary hy-

pofunction. The adverse effects of medication on salivary secretion

are reversible and salivary gland function will usually recover after

withdrawal of the pharmacotherapy.159,168,181 ,182

Numerous diseases and medical conditions can cause salivary

gland dysfunction, including hypofunction and altered salivary

composition (Table 4).33,35,36 Some systemic diseases like Sjögren’s

syndrome and cystic fibrosis permanently affect the salivary gland

tissue and function,177,1 83 while other conditions, eg salivary gland

infections, sialoliths, dehydration, depression and anxiety, have tem-

porary effects.33,35,36 Other diseases act on the autonomic pathway

involving t he trigeminal, facial and glossophar yngeal nerve s, the cen-

tral brain structures and/or the salivation centre, eg brain tumours,

neurosurgical traumas, diseases of the autonomic nervous system

like Holme’s- Adie syndrome.35,36,184 The latter is assumed to be the

result of a viral infection that causes inflammation and damage to

neurons in the ciliary ganglion, and the dorsal root ganglion, an area

of the spinal cord involved in the response of the autonomic ner-

vous system.184 Finally, diseases can also indirectly affect salivary

secretion, which is the case in hormonal disturbances, inflammatory

gastrointestinal diseases, and malnutrition.33,35,36

Xerostomia and salivary gland hypofunction is extremely com-

mon in patients having received radiotherapy to the head and neck

region.34 The development of salivary gland dysfunction depends

on the cumulative dose of radiation and the volume of salivary gland

tissue included in the field of radiation.34 Although the turnover

rate of the salivary gland tissue is rather slow (approx. 60 days), sal-

ivary dysfunction already occurs within the first week of treatment,

and the salivary secretion continues to decrease at 1–3 months

after radiotherapy. Doses higher than 60 Gray (Gy) usually lead to

TABLE3 Symptoms and clinical manifestations related to

salivary gland hypofunction

Oral mucosal and dental problems

Oral mucosal dryness and discomfort, oral burning sensation

Dry vermillion border, cracked lips, the tongue sticks to the

palate

Adherence of food and dental plaque to dental surfaces

Sensation of thirst, frequent sipping of liquid

Difficulty in wearing removable dentures

Atrophic, glazed, dry and red oral mucosa

Dorsal part of the tongue lobulated or fissured, atrophy of the

filiform papillae

Halitosis

Mucosal ulcerations, denture stomatitis

Increased frequency of oral candidiasis, angular cheilitis

Increased number of caries lesions on cervical, incisal and cuspal

tooth surfaces

Dental erosions

Problems related food intake

Difficulty in swallowing (dysphagia)

Impaired masticatory function

Taste disturbances (dysgeusia or hypogeusia)

Pharyngitis, laryngitis

Oesophagitis, oesophageal dysmotility

Acid reflux, hear tburn and nausea

Malnutrition, constipation, weight loss

Change in diet, eg avoiding dry, spicy foods

Psychosocial problems

Impaired quality of life, depression, social isolation

Other problems

Difficulty in speech, sleep disturbances

PEDERSEN E t al.

irreversible salivary gland hypofunction and xerostomia, while doses

of 30- 50 Gy may be reversible. Radiotherapy causes direct damage

to the acinar cells, and initially mainly the serous acini, but also the

surrounding blood vessels and nerves. It has been shown that parot-

id- and submandibular- sparring intensity- modulated radiotherapy

(IMRT) can reduce the prevalence and severity of salivary gland hy-

pofunction, which also increase patient’s quality of life.185 However,

it may be difficult to spare the minor salivary glands, which con-

tribute significantly to secretion of mucins and thereby lubrication.

The prevalence of xerostomia in patients receiving chemotherapy

is about 50% and salivary gland function usually restores 6 months

to 1 year after treatment. It is unknown whether concomitant ra-

diotherapy and chemotherapy affect the risk of developing salivary

gland dysfunction.34

10 | DIAGNOSIS OF SALIVARY GLAND

DYSFUNCTION

The diagnosis of salivary gland dysfunction requires a careful and

systematic evaluation of the patient. It includes a detailed history

of present symptoms, oropharyngeal functions, systemic and oral

diseases, type and number of medications, previous therapies in-

cluding surgery, radiotherapy in the head and neck region and/or

chemotherapy (Tables 3 and 4). Several questionnaires have been

developed for the identification of patients with xerostomia and

salivar y gland hypofunction, and for assessment of their sever-

ity157,158,166 ,186-189. The following scientifically validated questions

are simple to use in a clinical setting and may be helpful in iden-

tifying these patients: (i) Does your mouth feel dry when eating a

meal?, (ii) Do you have any difficulty swallowing?, (iii) Do you sip

liquids to aid in swallowing dry food?, and (iv) Does the amount of

saliva in your mouth seem to be too little, too much or you do not

notice it? Positive responds to these questions are highly predictive

of salivar y gland hypofunction.157

The second step is a thorough facial and intraoral examination,

including inspection and palpation of the salivary glands, expulsion

of saliva from the major salivar y duct orifices, and inspection of the

oral mucosa, the dentition and gingivae. It is impor tant to stress that

there are no specific clinical signs that make it possible to discrimi-

nate between the various causes of salivary gland dysfunction, and

patients with xerostomia and/or may present with some or none of

the symptoms and clinical signs mentioned in Table 3. Apart from

being indicative of Sjögren’s syndrome, salivary gland enlargement

may also be related to medication- induced sialadenosis, sodium re-

tention syndrome, malignancies or parotitis.190

The third step is measurement of salivary flow rates. There are

various methods for assessment of the unstimulated and stimu-

lated flow rates for whole saliva and for the parotid, subman-

dibular/sublingual and minor salivary glands. Whole saliva flow

rates may be measured by means of the draining, spitting, swab

(absorbent), and suction methods.191, 192 The most commonly used

method is the “draining method,” which is internationally accepted

as a standard for measuring unstimulated whole saliva in relation

to the diagnosis of Sjögren’s syndrome. Furthermore, it is simple

and can easily be conducted in the dental office.191,192 As salivary

flow and composition are influenced by the time of day and du-

ration of collection, standardisation of the saliva collecting pro-

cedure is extremely important. Sialometry should be performed

2 hours after a meal (ideally after breakfast) or after overnight fast

and unstimulated saliva should be collected for at least 10 minutes

and chewing- stimulated for at least 5 minutes.193 For measure-

ment of stimulated whole saliva flow, the patient is instructed to

chew a standard piece (1- 2 g) of paraffin wax or unflavoured gum

base at a fixed chewing rate (eg 60- 70 chews/minute).192 Citric acid

at a concentration of 2%, applied to the tongue every 30 seconds,

can also be used for measuring stimulated flow. However, citric

acid may interfere with subsequent sialochemical analysis. Under

normal conditions, the average unstimulated whole saliva flow rate

is in the range of 0.3- 0.4 mL/min, and flow rates below <0.1 mL/

min are considered pathologically low and designated hyposaliva-

tion.194,195 The mean chewing- stimulated whole saliva flow rates

range from 1.5 to 2.0 mL/min, and flow rates below 0.50- 0.70 mL/

min are considered abnormal (hyposalivation).194,195 In cases of

medication- induced salivary gland hypofunction, the unstimulated

whole saliva flow rate is usually significantly reduced, whereas

the chewing- stimulated flow rate is within the normal range.128 ,196

However, intake and/or prolonged use of drugs with anticholiner-

gic effect and centrally acting analgesics often cause diminution

TABLE4 Causes of salivary gland dysfunction33-37

Iatrogenic

Intake of certain medications, polypharmacy

Radiation therapy for cancer in the head and neck region

Graft versus host disease

Radioiodide treatment

Surgical trauma

Musculoskeletal diseases, eg chronic inflammatory connective tissue

diseases, including Sjögren’s syndrome, rheumatoid arthritis,

systemic lupus erythematous, scleroderma, mixed connective

tissue disease

Neurological diseases, eg CNS trauma, cerebral palsy, Bell’s palsy,

Parkinson’s disease, Alzheimer’s disease, autonomic dysfunctions

like Holmes- Adie syndrome

Gastrointestinal diseases, eg Crohn’s disease, ulcerative colitis,

coeliac disease, autoimmune liver diseases

Endocrine diseases, eg type 1 and type 2 diabetes mellitus (especially

when dysregulated), hyperthyroidism, hypothyroidism, Cushing’s

syndrome, Addison’s disease

Infectious diseases, eg parotitis, HIV/AIDS, hepatitis C, Epstein- Barr

virus, tuberculosis, bacterial sialadenitis

Genetic disorders, eg salivar y gland aplasia, cystic fibrosis, ectoder-

mal dysplasia, Prader- Willi syndrome

Eating disorders, eg bulimia nervosa and anorexia nervosa

Additional causes: depression, anxiety, stress, dehydration,

malnutrition, vitamin and mineral deficiencies, mouth breathing

PEDERSEN Et al.

of both unstimulated and chewing- stimulated whole saliva flow

rates.128,162 Assessment of the parotid, the submandibular/sublin-

gual saliva flow rates and minor salivary gland secretions requires

special equipment and techniques and still primarily used for re-

search purposes.120 ,192, 193,196

An additional number of tests may be necessary for adequate

diagnosis of salivary gland dysfunction and its underlying cause in-

cluding sialography, scintigraphy, ultrasound, magnetic resonance

imaging (MRI), Cone Beam CT and/or endoscopy of the salivary

glands as well as blood tests.

Although analysis of the organic and inorganic constituents in

saliva may be promising and valuable tools in the diagnosis of many

diseases, it is still not applicable for regular, daily use in a dental

practice. However, through recent advances in technology including

development of molecular biological methods that can be applied

to saliva samples containing human cells, bacteria, DNA, RNA and

proteins, novel ways to detect oral and systemic diseases at an early

stage are rapidly emerging. Thus the field of saliva proteomics has

expanded significantly the last decade, and presently a number of

these potential salivary biomarkers are being tested for identifica-

tion and monitoring diseases including periodontitis, dental caries,

oral cancer, but also systemic diseases like Sjögren’s syndrome197-2 05

Also the emerging fields of transcriptomics and metabolomics open

for new possibilities for using saliva in the diagnosis and assessment

of various diseases.

11 | CONCLUSION

It is important for oral health professionals to have a thorough

knowledge and understanding of the normal structure and func-

tion of salivary glands including the normal neural control of salivary

secretion, normal salivary flow and composition and functions of

saliva. Such knowledge facilitates recognition of symptoms or signs

related to salivary gland dysfunction at an early stage, and thus pro-

vide appropriate diagnosis (or referral). A comprehensive diagnostic

evaluation is important in order to determine the cause of xerosto-

mia and salivary gland dysfunction, and consequently initiate proper

prevention and treatment.

ACKNOWLEDGMENTS

Ethical approval(s) was not necessary for this study. The study has

not received any funding.

CONFLICT OF INTEREST

The authors have stated explicitly that there are no conflicts of in-

terest in connection with this article.

ORCID

A. M. L. Pedersen http://orcid.org/0000-0002-6424-5803

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https://doi.or g/10.1111/joor.12664

Acupuncture in Dental Medicine: Practical Applications

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May 2024

Acupuncture, rooted in Traditional Chinese Medicine (TCM), has garnered attention within dental care for its multifaceted therapeutic applications. This review explores the diverse roles of acupuncture in addressing various dental concerns, including postoperative pain management , inflammation reduction, anxiety alleviation, temporomandibular joint (TMJ) disorders, myo-fascial pain, atypical facial pain, xerostomia, and neural disorders. Acupuncture presents a promising adjunctive therapy, offering effective pain relief, anti-inflammatory effects, and anxiety reduction with minimal adverse effects. Additionally, it shows potential in improving salivary secretion and managing neural conditions like facial palsy and trigeminal neuralgia. While further research is needed to refine acupuncture protocols and establish standardized practices in dental care, its integration holds significant promise in enhancing patient well-being and satisfaction.

Saliva as a Diagnostic Tool for Systemic Diseases—A Narrative Review

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MED LITH

Saliva has emerged as a powerful diagnostic tool due to its non-invasive collection, straightforward storage, and ability to mirror systemic health. This narrative review explores the diagnostic potential of salivary biomarkers in detecting systemic diseases, supported by examples such as salivary proteomics’ role in monitoring endocrine disorders, cancer, and viral infections. Advances in technologies like microfluidics, biosensors, and next-generation sequencing have enhanced the sensitivity and specificity of salivary diagnostics, making it a viable alternative to blood-based diagnostics. The review also evaluates challenges such as the need for standardized collection protocols, variability in salivary composition, and the integration of these technologies into clinical workflows. The findings emphasize the transformative potential of saliva in personalized medicine, especially for early disease detection and real-time health monitoring. Practical applications include its use in mass screenings and public health crises, highlighting saliva as a cornerstone for future advancements in non-invasive diagnostics.

Androgen suppression protects against hyposalivation and salivary gland damage in mice with type 2 diabetes

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Mar 2025

Objective Hyposalivation is one of the most common oral complications of type 2 diabetes (T2D). Sex hormone levels, which have been associated with hyposalivation, salivary gland atrophy, and inflammation, can be altered in T2D. However, the relationship between androgen levels and hyposalivation in the context of T2D is unknown. Therefore, this study investigated the role of gonadal androgen suppression on the function and histomorphometry of salivary glands in mice with T2D. Methods Four-week-old male C57BL/6 mice were divided into four groups: control, orchiectomy (ORQx), T2D, and ORQx-T2D. Orchiectomy was performed at eight weeks of age, and T2D was induced using a high-calorie diet and low-dose streptozotocin. At 20 weeks of age, the blood glucose levels, saliva secretion and quality, and serum testosterone were measured. The parotid and submandibular glands were retrieved, processed for histology, and sections were stained with hematoxylin and eosin, Sirius Red or immunohistochemically stained for α-amylase, interleukin (IL)-1, IL-6, IL-10, IL-17, and tumor necrosis factor-α. Results Mice with T2D exhibited decreased saliva secretion and quality, reduced α-amylase expression, and the number of acini. They also developed glandular fibrosis and acinar hypertrophy, along with increased in proinflammatory cytokines in both salivary glands. Androgen suppression in mice with T2D reduced hyperglycemia, normalized saliva secretion, decreased glandular fibrosis and acinar hypertrophy, increased α-amylase expression, and reduced proinflammatory cytokine expression in both glands. Conclusions Androgen suppression in mice with T2D reduces the development of hyposalivation and histomorphometric changes in the parotid and submandibular glands by modulating the inflammatory microenvironment.

Saliva: A Potential Biological Fluid to Assess High-Altitude Associated Consequences

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Feb 2025

High-altitude acclimatization has always been a major concern to humans as it is directly related to the performance of travelers at high-altitude. However, acclimatization to high-altitude varies among individuals. The exposure of high-altitude to humans can cause moderate to severe symptoms like headache, vomiting, dizziness, fatigue, high-altitude cerebral edema, high-altitude pulmonary edema and if not treated timely may lead to death. These symptoms appear due to physiological, biochemical and metabolic changes and are generally assayed using blood, plasma or serum, but it is an invasive method and require technical expertise. Therefore, looking for an alternative biological fluid which is noninvasive and easily accessible will be advantageous. In this regard, saliva bears the potential to be an excellent biological fluid to assess high-altitude associated consequences as it offers a simple mode of collection, multiple sampling, noninvasive procedure, and also ensures the patient’s comfort. In the present review, we have emphasized the role of saliva, different collection methods, and salivary biomarkers responsive to high-altitude exposure. The review could be insightful for researchers as it contemplates saliva collecting strategies and diagnostic devices.

Change and significance of connexin 43 in saliva extracellular vesicles from oral lichen planus patients

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Feb 2025
ARCH ORAL BIOL

The complexity of managing oral dryness in general dental care

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Interrelationship between oral and colon diseases: a systematic review

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Jan 2025

Relevance . Recent studies from researchers worldwide have confirmed that the coexistence of dental and intestinal diseases disrupts the structural and functional regulation within the gastrointestinal tract (GIT), including the oral environment. Оbjective. To analyze data from domestic and international scientific literature on the oral health conditions in relation to colon diseases. Materials and methods . A systematic search and analysis of domestic and international literature were conducted, with 89% of the selected studies published within the last 10 years. The search utilized electronic databases such as PubMed, Google Scholar, and eLibrary. Inclusion criteria encompassed studies involving patients with GIT diseases, including colon disorders (constipation, hemorrhoidal disease, colitis, diverticulosis, colon polyps, and colon cancer), where the oral environment or the maxillofacial region was examined in relation to at least one of these conditions. A total of 2,473 scientific sources were initially identified. After removing duplicates and reviewing titles and abstracts, 985 studies were deemed eligible for further analysis. Ultimately, 59 publications met the inclusion criteria and were included in the systematic review, providing data for quantitative comparisons. Results . The analysis revealed a negative correlation between the level of C-terminal telopeptide of type I collagen and alveolar bone resorption, as measured by Fuchs' bone index (r = -0.633; p < 0.05). Additionally, a statistically significant positive correlation was observed between reduced osteocalcin levels in salivary fluid and disease severity (r = 0.589; p < 0.05). These findings suggest that salivary fluid analysis in patients with ulcerative colitis and irritable bowel syndrome may indicate the presence of periodontal inflammatory disease. There is a growing consensus among researchers that autoimmune reactions triggered by inflammatory processes in the mucosa of different GIT sections negatively affect oral tissues. For example, a 2019 study by a Japanese research group utilized 16S rRNA gene sequencing to investigate the salivary microbiome. The study found significantly increased salivary bacterial diversity in patients with GIT cancer compared to the control group: operational taxonomic units (OTU), P = 0.02; Shannon index, P < 0.01; Chao1 index, P = 0.04. Conclusion . The current body of global scientific literature highlights pathological changes in oral tissues associated with colon diseases, which could aid in the diagnosis and monitoring of colorectal disease activity. This growing interest underscores the importance of further research into the interconnection between colon diseases and oral health. However, the topic remains underexplored, with only a limited number of studies available. Notably, there are few reports on pathological oral changes in patients with hemorrhoidal disease, emphasizing the need for more comprehensive and in-depth investigations.

Integrating Oral Health in Palliative Medicine

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Jan 2025

THE ROLE OF SALIVARY GLANDS IN ORAL REHABILITATION: FUNCTIONS, IMPORTANCE, PATHOLOGY AND THERAPEUTIC APPROACHES

Article

Mar 2024

The salivary glands are essential for oral health, providing not only environments for digestion and taste, but also protection from pathogens. This review examines the functions of salivation, the importance of salivary glands in the context of oral pathology, and therapeutic approaches for their dysfunctions. Pathologies of the salivary glands range from minor conditions, such as sialadenitis, to severe conditions, such as cancer of the salivary glands. These conditions can affect quality of life, the ability to eat and speak, and have systemic implications. Treatment of salivary gland dysfunctions includes pharmacological therapies to stimulate salivary secretion, the use of saliva substitutes, and physical therapies such as ultrasound therapy. Management is aimed at relieving symptoms and improving the function of affected glands. Antioxidant supplements, depending on your circadian rhythm, may help reduce oxidative stress associated with glandular pathologies.

The Effects of Alexithymia on Self-Reflection and Insight in Major Depressive Disorder

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Salivary biomarkers and proteomics: Future diagnostic and clinical utilities

Article

Full-text available

Apr 2017

Saliva testing is a non-invasive and inexpensive test that can serve as a source of information useful for diagnosis of disease. As we enter the era of genomic technologies and –omic research, collection of saliva has increased. Recent proteomic platforms have analysed the human salivary proteome and characterised about 3000 differentially expressed proteins and peptides: in saliva, more than 90% of proteins in weight are derived from the secretion of three couples of “major” glands; all the other components are derived from minor glands, gingival crevicular fluid, mucosal exudates and oral microflora. The most common aim of proteomic analysis is to discriminate between physiological and pathological conditions. A proteomic protocol to analyze the whole saliva proteome is not currently available. It is possible distinguish two type of proteomic platforms: top-down proteomics investigates intact naturally-occurring structure of a protein under examination; bottom-up proteomics analyses peptide fragments after pre-digestion (typically with trypsin). Because of this heterogeneity, many different biomarkers may be proposed for the same pathology. The salivary proteome has been characterised in several diseases: oral squamous cell carcinoma and oral leukoplakia, chronic graft-versus-host disease Sjögren’s syndrome and other autoimmune disorders such as SAPHO, schizophrenia and bipolar disorder, and genetic diseases like Down’s Syndrome and Wilson disease. The results of research reported herein suggest that in the near future human saliva will be a relevant diagnostic fluid for clinical diagnosis and prognosis.

In Defense of the Oral Cavity: Structure, Biosynthesis, and Function of Salivary Mucins

Article

Full-text available

Jan 1995

Lawrence A Tabak

The oral microbiome - An update for oral healthcare professionals

Article

Full-text available

Nov 2016

For millions of years, our resident microbes have coevolved and coexisted with us in a mostly harmonious symbiotic relationship. We are not distinct entities from our microbiome, but together we form a ‘superorganism’ or holobiont, with the microbiome playing a significant role in our physiology and health. The mouth houses the second most diverse microbial community in the body, harbouring over 700 species of bacteria that colonise the hard surfaces of teeth and the soft tissues of the oral mucosa. Through recent advances in technology, we have started to unravel the complexities of the oral microbiome and gained new insights into its role during both health and disease. Perturbations of the oral microbiome through modern-day lifestyles can have detrimental consequences for our general and oral health. In dysbiosis, the finely-tuned equilibrium of the oral ecosystem is disrupted, allowing disease-promoting bacteria to manifest and cause conditions such as caries, gingivitis and periodontitis. For practitioners and patients alike, promoting a balanced microbiome is therefore important to effectively maintain or restore oral health. This article aims to give an update on our current knowledge of the oral microbiome in health and disease and to discuss implications for modern-day oral healthcare.

A Guide to Medications Inducing Salivary Gland Dysfunction, Xerostomia, and Subjective Sialorrhea: A Systematic Review Sponsored by the World Workshop on Oral Medicine VI

Article

Full-text available

Nov 2016
DRUGS R&D

Background Medication-induced salivary gland dysfunction (MISGD), xerostomia (sensation of oral dryness), and subjective sialorrhea cause significant morbidity and impair quality of life. However, no evidence-based lists of the medications that cause these disorders exist. Objective Our objective was to compile a list of medications affecting salivary gland function and inducing xerostomia or subjective sialorrhea. Data SourcesElectronic databases were searched for relevant articles published until June 2013. Of 3867 screened records, 269 had an acceptable degree of relevance, quality of methodology, and strength of evidence. We found 56 chemical substances with a higher level of evidence and 50 with a moderate level of evidence of causing the above-mentioned disorders. At the first level of the Anatomical Therapeutic Chemical (ATC) classification system, 9 of 14 anatomical groups were represented, mainly the alimentary, cardiovascular, genitourinary, nervous, and respiratory systems. Management strategies include substitution or discontinuation of medications whenever possible, oral or systemic therapy with sialogogues, administration of saliva substitutes, and use of electro-stimulating devices. LimitationsWhile xerostomia was a commonly reported outcome, objectively measured salivary flow rate was rarely reported. Moreover, xerostomia was mostly assessed as an adverse effect rather than the primary outcome of medication use. This study may not include some medications that could cause xerostomia when administered in conjunction with others or for which xerostomia as an adverse reaction has not been reported in the literature or was not detected in our search. Conclusions We compiled a comprehensive list of medications with documented effects on salivary gland function or symptoms that may assist practitioners in assessing patients who complain of dry mouth while taking medications. The list may also prove useful in helping practitioners anticipate adverse effects and consider alternative medications.

The Functions of Saliva

Article

Feb 1987

I. D. Mandel

Nature's demands on salivary glands are extensive and diverse and range from the reptilian need for a venomous drop to incapacitate its prey to the 100 quarts that ruminants require to digest a day's grazing. Other species depend on saliva not for survival, but for improving the quality of life, using the fluid for functions varying from grooming and cleansing to nest-building. Humans can manage without saliva; its loss is not life-threatening in any immediate sense, but it results in a variety of difficulties and miseries. Oral digestion per se is only of marginal importance in humans, but saliva is important in preparing food for mastication, for swallowing, and far normal taste perception. Without saliva, mealtimes are difficult, uncomfortable, and embarrassing. The complex mix of salivary constituents provides an effective set of systems for lubricating and protecting the soft and hard tissues. Protection of soft tissues is afforded against desiccation, penetration, ulceration, and potential carcinogens by mucin and anti-proteases. Saliva can encourage soft tissue repair by reducing clotting time and accelerating wound contraction. A major protective function results from the salivary role in maintenance of the ecological balance in the oral cavity via: (1) debridement/lavage; (2) aggregation and reduced adherence by both immunological and non-immunological means; and (3) direct antibacterial activity. Saliva also possesses antifungal and anti-viral systems. Saliva is effective in maintaining pH in the oral cavity, contributes to the regulation of plaque pH, and helps neutralize reflux acids in the esophagus. Salivary maintenance of tooth integrity is dependent on: (I) mechanical cleansing and carbohydrate clearance; (2) post-eruptive maturation of enamel; (3) regulation of the ionic environment to provide a remineralizing potential without spontaneous precipitation; and (4) pellicle deposition and limitation of acid diffusion. Saliva also plays a role in water balance, can serve in a limited way in excretion, and has possible hormonal function in the gastro-intestinal tract.

Electrophysiological study on sensory nerve activity from the submandibular salivary gland in rats

Article

Dec 2017
BRAIN RES

To evaluate the role of afferent information from the salivary gland, we analyzed the neural activity of the sensory nerve innervating the submandibular gland in anesthetized rats. The sensory nerves running through the parasympathetic nerve supply responded to mechanical pressure applied to the surface of the main duct and the body of the gland, whilst those in the sympathetic nerve supply responded only to the body of the gland. The sensory nerves in the sympathetic and parasympathetic nerve routes responded to pressure in the duct system produced by a retrograde injection of saline into the main duct. The threshold pressure for production of afferent discharges was higher than the maximum secretory pressure evoked by electrical stimulation of the parasympathetic secretory nerve. The retrograde ductal injection of drugs related to the inflammatory process (capsaicin and bradykinin) evoked intense multi-unit discharges in the sensory nerves of both routes. The sensory nerve in the sympathetic route was responsive to ligation of the artery to the gland. These results suggest that sensory nerves in the sympathetic and parasympathetic routes mainly conduct noxious information, and that those in the sympathetic route are responsive to ischemia and may control blood flow of the gland.

Factors associated with mucosal dryness in multiple regions and skin: A web-based study in women: Factors for dryness in multiple regions

Article

Apr 2017

Aim: We hypothesized that feeling mucosal dryness in one body region and the skin may be associated with dryness in other regions and that there are common background factors for dryness. In an earlier web-based survey, we reported prevalence figures of dry eyes, nose, mouth, skin, and vagina. In the present study, additional analyses were made to investigate the factors associated with dryness in each region, and simultaneous dryness in multiple regions. Methods: A web-based questionnaire was completed by 310 Japanese women. The questions included dryness of the eyes, nose, mouth, vagina, and skin. Menopausal and other symptoms were also addressed. Multiple logistic regression modeling was performed to identify factors associated with dryness in each region and in multiple dry regions. Results: Dry eyes were associated with dryness in the nose and with headache; dry nose was associated with dryness in the vagina and eyes; dry mouth was associated with sticky mouth symptom and dryness of the nose; dry skin was associated with use of xerogenic medications and vaginal discharge; and dryness of the vagina was associated with vaginal itchiness and dry nose. Vaginal discharge (odds ratio, 9.64; 95% confidence interval, 3.15-29.51) and sticky mouth (odds ratio, 6.35; 95% confidence interval, 1.29-31.29) were further associated with dryness in multiple regions. Conclusion: The present results confirmed our study hypothesis by showing that dryness in one region was clearly associated with that in another or in multiple regions. The result implies the need for holistic diagnosis and counseling for patients with dryness complaints.

Mechanisms of secretion by salivary glands

Article

Jan 1996

P.M. Smith

Secretion by major salivary glands.

Article

Jan 1987

Diseases Causing Oral Dryness

Chapter

Sep 2015

Anne Marie Lynge Pedersen

Saliva is important for the maintenance of oral health and also plays an essential role in a number of oral and gastrointestinal functions. Consequently, patients with reduced salivary secretion and changes in their saliva composition are more susceptible to dental caries, oral infections and mucosal lesions and often have symptoms of a dry and sore mouth, burning and itching oral mucosa, difficulties in chewing and swallowing dry foods, impaired sense of taste, difficulty in speaking and problems with acid reflux. These distressing consequences of salivary hypofunction also have a significant negative impact on quality of life and general health status. Several diseases and medical conditions as well as the medications used for treating them are associated with salivary gland hypofunction (objective evidence of diminished salivary output) and xerostomia (subjective sensation of dry mouth). In autoimmune diseases like Sjögren’s syndrome, salivary gland dysfunction is largely related to structural changes in the salivary glands and in endocrine and metabolic disorders mainly related to pathophysiological changes that affect the formation of saliva. Other diseases affect the autonomic outflow pathway involving the salivary gland innervation, the central nervous system and the salivation centre. This chapter reviews systemic diseases and medical conditions associated with salivary gland hypofunction and xerostomia.