Maxfacts

Xerostomia (dry mouth) is not a disease but a symptom, and yet we have included it in the A-Z of diagnoses as a separate entry. This is for several reasons:

• it is a common problem affecting an estimated 10 to 30 % of the population and is related to a variety of underlying conditions, the most common cause being medications;
• if severe xerostomia persists for extended periods of time, it can lead to further oral and systemic health issues (including dysphagia (difficulty swallowing);
• radiotherapy applied to the head & neck region can cause severe and lasting xerostomia;
• autoimmune disorders such as Sjögren’s syndrome cause particularly severe and lasting forms of xerostomia, with significant negative impact on quality of life and general health.

Xerostomia is by definition a symptom and thus subjective in nature. Patients are likely to approach clinicians with complaints of a constantly dry mouth that doesn’t go away with drinking water. Diagnosing dry mouth by measuring the resting salivary flow is difficult as the pre-complaint flow rate is often unknown. Normal salivary flow rates vary widely so dry mouth cannot be excluded if subjects have a flow rate in the normal range. However, extremely xerostomic patients may have flows of less than 0.1 ml/min (measured over 5 minutes). Persistent dry mouth can cause noticeable effects on the mouth and these have been calibrated in the Challacombe scale which can be useful in charting the severity and progression of dry mouth.

Below we give an overview of the various causes of xerostomia: medications, diseases and high-energy radiation. In the majority of cases the cause(s) for dry-mouth problems can be identified but there is a minority of cases where no specific cause can be firmly established (idiopathic xerostomia).

Xerostomia and medications

Several hundred prescription and non-prescription medications are known to cause or exacerbate xerostomia, indeed over 50 % of all medications list dry mouth as a possible side-effect. These include some of the most common prescription drugs such as antidepressants, analgesics, antihistamines and anti-hypertensives, cytotoxic drugs used in chemotherapy, as well as recreational drugs such as caffeine, cocaine or nicotine and commonly used over-the-counter herbal remedies (for example, gingko and capsicum extracts or St. John’s wort preparations). There are different mechanisms by which medications cause dry mouth problems, affecting both the quantity and composition of saliva. Medications potentially responsible for causing or exacerbating xerostomia should be identifiable from recording a thorough medical history.

The severity of dry-mouth problems are usually related to the dose of medications and number of different medications (polypharmacy). Sometimes the duration of usage can also affect dry mouth. Dry mouth related to medications usually has a rapid change and is therefore more noticeable. Fortunately, in most cases medication-related xerostomia is a temporary and a reversible symptom once the medication is no longer taken.

The mechanisms by which cytotoxic drugs cause xerostomia as an unwanted side-effect of chemotherapy by damaging the cells in salivary gland tissue are broadly the same mechanisms by which these substances damage or destroy malignant cells, in addition to the indirect effects on salivary glands by damage to the mucosa (lining) of the mouth commonly caused by cytotoxic drugs.

Drugs that are prescribed to deplete fluids from the body (diuretics) can lead to xerostomia by reducing the salivation rate, similar to the effects of dehydration from insufficient fluid intake (common in elderly people, or with excessive exercise) or fever. This occurs because of the effect of diuretics on the concentration of electrolytes in body fluids, which in turn is closely related to the fluids ‘management’ of the body.

It may seem surprising that so many widely used drugs, in particular anticholinergic and sympathomimetic drugs (see below and Table 1) cause dry-mouth problems. Many drugs are used to ‘normalise’ or ‘regulate’ involuntary body functions such as blood pressure or heart rate. Many drugs achieve these effects by directly interfering with the autonomic nervous system that governs all involuntary body functions, including salivation; other drugs have indirect effects on the autonomic nervous system.

Of the three strands of the autonomic nervous system, mainly the parasympathetic and the sympathetic sub-systems matter here in this context. These two, in part complementary, sub-systems of the autonomic nervous system are sometimes referred to as the ‘rest and digest’ or ‘feed and breed’ system (parasympathetic system) and the ‘fight or flight’ (sympathetic) system. The cooperation between these two strands of the autonomic nervous systems is governed by specialised centres in a particular region of the brain (the medulla oblongata).

The parasympathetic nervous system is involved in the regulation of sexual arousal, secretion from various glands (salivation and lacrimation), digestive functions and the slowing of the heart rate. Its main neurotransmitter (messenger molecule) is acetylcholine (ACh) which binds to muscarinic receptors that are found all over the body. Anticholinergic drugs competitively inhibit this binding of the neurotransmitter molecule ACh to its target receptors both centrally in the brain and peripherally in salivary glands to cause reduced salivation.

The sympathetic nervous system is mainly involved in the regulation of the requirements of fast body action – ‘fight and flight’ (but in addition it also controls and stabilises various physiological activities in order to maintain a stable equilibrium for the body’s functions (homeostasis) under all circumstances). Its actions include the increase of heart rate and blood pressure, constriction of blood vessels and activation of the sweat glands. When activated, neurons release the relevant messenger molecules (dopamine, norepinephrine or epinephrine), these bind to their target receptors where they initiate the various ‘fight and flight’ physiological effects. Drugs that mimic the actions of the sympathetic nervous system are called sympathomimetics, others that inhibit adrenergic receptors are often called blockers eg beta blockers (beta adrenergic antagonists); both of these can act either centrally or peripherally to cause hyposalivation and therefore dry mouth.

Table 1 gives some examples of drugs known to cause dry-mouth problems, there are many more drugs with such side effects.

Xerostomia and diseases

As well as a wide range of medications, several diseases are associated with xerostomia of different degrees of severity. Autoimmune conditions and diabetes mellitus are the most common among these diseases. Identifying and confirming a particular disease or disorder as the cause of dry-mouth problems usually requires some detective work and may involve a variety of blood or urine tests, microbiological laboratory investigations or taking a biopsy. Depending on the suspected cause(s), some X-ray, ultrasound or MRI imaging may be included in the diagnostic toolbox.

Endocrine diseases

Diabetes mellitus (type 1and type 2) results in hyperglycaemia (enhanced glucose levels in the blood and other body fluids) and concomitant changes in metabolism. Type 1 diabetes is caused by insufficient or absent insulin production and belongs to the broad category of autoimmune diseases (see below). Type 2 diabetes is related to insulin resistance and has a strong element of behavioural (poor diet and life style) and environmental risk factors. Xerostomia is commonly reported for untreated or poorly treated diabetes where it occurs alongside polyuria (increased volume of urine output, due to glucose in the urine (osmotic diuresis)) which leads to dehydration. In fact, xerostomia is often the symptom which leads to a diabetes diagnosis.

Thyroiditis is the umbrella term for inflammatory disorders of the thyroid gland that lead to reduced activity of the gland. The most common types of thyroiditis belong to the broad category of autoimmune diseases (see below) but there are also medication- or radiation-related disorders of the thyroid gland. Thyroiditis commonly occurs in conjunction with other autoimmune conditions such as Sjögren’s syndrome (see below). Inflammation of the thyroid gland is often associated with xerostomia.

Viral and bacterial infections

Oral lesions of all kinds as well as xerostomia commonly occur in human immunodeficiency virus (HIV) infections, with xerostomia related both to antiviral medications and structural changes of the salivary gland tissues as a consequence of the infection.

Infections with Epstein-Barr virus, hepatitis C virus, cytomegalovirus and T-lymphotropic virus (type 1) have all been implicated with xerostomia in some way. However, these findings about cause and effect are not entirely clear as it appears more likely that all of these viral infections in some way are related to and/or cause or trigger autoimmune diseases (cytomegalovirus and hepatitis C virus: Sjögren’s syndrome; Epstein-Barr virus: a whole host of autoimmune disorders) or T-cell leukaemia in adults (T-lymphotropic virus), where all of these conditions have a very well established role in causing xerostomia.

Bacterial infections that affect the salivary glands can cause reduced salivary gland activity. Organisms include  mycobacterium and actinomycosis (caused by an anaerobic bacterium, actinomyces as well as much more common oral pathogens such as streptococci species

Nutritional causes

The most obvious condition here is dehydration, common in elderly people but insufficient fluid intake is not restricted to this demographic. Dehydration can also occur in the course of intense exercise, or can be induced by medications (diuretics, see above) or be related to swallowing difficulties, dysphagia (difficulty swallowing liquids is a common form of dysphagia).

Eating disorders such as anorexia nervosa (avoiding eating) and bulimia nervosa (binge eating and induced vomiting) cause a range of metabolic disturbances. These, together with the effects of abuse of diuretics and laxatives (see above) associated with eating disorders, explain why eating disorders are often associated with xerostomia.

Neurological conditions

The central nervous system, including the brain, controls the autonomic nervous system (see above), which in turn is responsible for the regulation of salivation, amongst many other body functions. Accordingly, brain trauma from fractures of facial bones, from surgical interventions or from stroke may all cause dry-mouth problems.

Paralysis of the facial nerve, Bell’s palsy, is usually a temporary condition of unknown cause(s). One of the functions of the facial nerve is to carry parasympathetic information to the salivary glands, so an impaired facial nerve leads to reduced function of the salivary glands. Bell’s palsy can occur in conjunction with a number of other conditions, including autoimmune diseases (see below), diabetes (see above) or herpes zoster viral infection.

Parkinson’s disease is a neurodegenerative disease of unknown cause. It mainly afflicts older people. The most prominent symptoms are various motor dysfunctions but reduced function of the salivary glands is also common with this condition (in part this is related to medication used to treat Parkinson’s disease; see above and Table 1). Excessive drooling is a feature of later stages due to loss of control of swallowing muscles.

Autoimmune diseases

Autoimmune diseases include a group of nearly 100 syndromes and conditions, mostly of unknown cause(s), where the body’s immune system attacks and often destroys, healthy body tissues. The usual trio blamed for autoimmune conditions are genetic disposition, environment and some infections. Often several of these autoimmune syndromes and conditions (with similar symptoms) occur simultaneously, women are more often affected than men.

Sjögren’s syndrome is one of the autoimmune disorders for which the precise aetiology (cause) is not known although infection by the Epstein-Barr virus has been implicated in the development of the disorder. Sjögren’s syndrome is not a rare condition, it affects about half as many people as rheumatoid arthritis does. Sjögren’s syndrome is characterised primarily by a dry mouth and dry eyes. It occurs most commonly in middle or old age, with women being affected ten times as often as men. When dry mouth and eyes occur in isolation it is termed primary Sjögren’s syndrome. When these symptoms occur in combination with a connective tissue disease it is termed secondary Sjögren’s syndrome. It is of interest that the ocular (eye) and oral (mouth) symptoms are usually more severe in primary Sjögren’s syndrome. The most commonly associated connective tissue diseases are rheumatoid arthritis and systemic lupus erythematosus (see below). Of those patients with rheumatoid arthritis, 15 % report symptoms consistent with secondary Sjögren’s syndrome; for those with systemic lupus erythematosis the figure is 30 %.

A particular type of white blood cell, the lymphocytes, is crucial for the body’s immune system. Lymphocyte T cells, produced in the thymus (a small gland at the base of the neck), and lymphocyte B cells, made in the bone marrow recognise and identify invaders, foreign pathogens such as bacteria or viruses, and trigger an immune response to eliminate the pathogen. Some sub-species of T cells (the T helper cells) are responsible for triggering a direct immune response to invaders while other T cells produce enzymes that kill infected body cells.

In Sjögren’s syndrome the salivary (and lacrimal) glands are infiltrated by T and B lymphocyte cells. Initially the infiltration is focussed around blood vessels or ducts, but increasingly over time the whole gland tissue becomes affected. The mistaken attack of these T and B cells and the resulting inflammation have been said to be mainly responsible for irreversible destruction and loss of functioning salivary gland tissue. However, clinical observations and laboratory research suggest that straightforward inflammatory response of the gland tissues is likely to be not the only cause for reduced saliva production. The various specific roles of several types of T helper cells, as well as the presence of particular antibodies have been further investigated, and there are some indications that immune-system mediated destruction of muscarinic receptors (see above; anticholinergic medications) leads to reduced parasympathetic function and thus further reduced salivary flow. These searches for causes and mechanisms have not yet identified a particular aetiology; genetics, hormones, environmental factors, and viral and bacterial infections have all not been ruled out. However, recent research suggests the exploration of promising routes for future treatments of this (and similar) autoimmune disorders. The rare malignant transformation of B cells is thought to be responsible for the increased risk of non-Hodgkin lymphoma in people diagnosed with Sjögren’s syndrome.

Rheumatoid arthritis is a systemic chronic inflammatory disease of unknown cause(s); it affects an estimated 1 % of the world population (with a three-fold higher incidence in women than in men). The inflammation mainly affects the lining of multiple joints, primarily small joints in the hands and feet. In rare cases rheumatoid arthritis affects the temporomandibular joint (jaw joint). Dry-mouth problems are commonly reported in about 50 % of rheumatoid arthritis cases. About a third of rheumatoid arthritis cases occur together with Sjögren’s syndrome (see above).

Systemic lupus erythematosus is an umbrella term for a range of systemic chronic inflammatory diseases which affect women more commonly than men. Systemic lupus erythematosus causes inflammation of joints, skin, kidneys and other body parts, including the oral mucosa (lining of the mouth). The majority of patients with this condition report problems associated with sore mouth and xerostomia. The condition leads to reduced salivary flow as well as to changes in the composition of saliva. About a third of systemic lupus erythematosus cases occur together with Sjögren’s syndrome (see above).

Scleroderma is a progressive disease leading to excessive deposition of collagen in the skin and other organs. Oral manifestations of the condition include fibrosis (scarring) of the ducts of the salivary glands, alongside destruction of the saliva-producing cells in the glands. The condition is more common in women than in men. In the majority of cases there is severe xerostomia, in about 20 % of scleroderma cases the condition occurs together with Sjögren’s syndrome (see above).

Primary biliary cirrhosis is an autoimmune inflammatory liver disease of unknown cause(s) and frequently occurs together with other autoimmune conditions. Reduced salivary flow is commonly reported for this condition.

Miscellaneous Conditions

The cause(s) of sarcoidosis are unknown. It is an inflammatory disease that leads to the presence of multiple granulomas (small areas of inflamed tissue) most commonly in the lungs, lymph nodes, skin, eyes and salivary glands. The condition may be without symptoms and resolve spontaneously. However, in some cases where the salivary glands are involved, over time some of the saliva-producing cells may be lost, resulting in dry-mouth problems. The condition is more prevalent in women than in men.

Cystic fibrosis is a genetic disease that mainly affects the function of lungs, pancreas and liver; the condition leads to malfunction of secretions. This may include reduced quantity and altered quality of saliva secretion, often exacerbated by the side effects of medications used in the treatment of cystic fibrosis.

The ectoderm is the outer tissue layer of the early embryo. Ectodermal dysplasias are inherited disorders that affect body parts and tissues that originate from the ectoderm (hair, skin, teeth, salivary, lacrimal and sweat glands) when this early period of the embryonal development had been disturbed.

Haemochromatosis is a disorder where abnormally large amounts of iron compounds (ferritin) are deposited in various organs, such as liver, heart and endocrine glands (glands that produce hormones). Deposition in the salivary glands leads to reduced salivary flow.

Amyloidosis describes a range of conditions where abnormal protein polymers (amyloid) are deposited in a range of organs and tissues, often affecting the tongue, thyroid gland, heart, lungs or kidneys, and sometimes leading to reduced salivary flow. Amyloidosis conditions often occur together with other chronic diseases (secondary amyloidosis).

With renal disease in its final stages, irreversible loss of kidney function (possibly dialysis), xerostomia is often reported. This is related to the accumulation of toxic metabolic products in the body as a consequence of renal failure, which leads to a severe imbalance of electrolytes.

Graft-versus-host disease is a serious possible complication after a bone marrow or other blood stem cell transplant from a genetically different individual. It occurs when the donated tissue cells (the graft) recognise the host’s cells as foreign and attack these – essentially the graft rejects the host. The damage that evolves from this immune reaction primarily affects the liver, intestines and oral mucosa (lining); chronic forms of graft-versus-host disease often include dysfunction of the salivary glands with concomitant dry-mouth problems.

Malignancies of the salivary glands are rare. Lymphoma and some forms of leukaemia of adults are rare amongst these overall rare salivary gland malignancies; they may present with xerostomia as one of the early symptoms.

Xerostomia and high-energy radiation

Radiotherapy either as a single modality or in combination with surgery is a common treatment option for head and neck malignancies. Despite improved, more selective irradiation schemes for external beam radiotherapy (IMRT) and better irradiation planning methods aiming to minimise unwanted radiation dose delivered to the salivary glands, xerostomia remains a serious long-term consequence of high-energy irradiation in the head and neck region (together with osteoradionecrosis and trismus). More often than not, it is not possible to spare the salivary glands (or the mandible) from high-energy irradiation to the extent where no or little long-term damage will occur. This is mainly because of the anatomical position of the glands (and mandible) – often they simply are in the way of irradiation aiming at the target volume. This is also true when the source of high-energy radiation is, for example, a set of implanted radioactive ¹⁹²Ir wires in brachytherapy (internal radiation source) treatments.

It is commonly accepted that radiotherapy in the head & neck region has a number of unwanted and lasting effects on salivary glands, oral mucosa, jaw bones and jaw joints, cheek muscles and dentition. The extent of all of these effects depend on the total dose of radiation delivered to the various tissues, the volume of irradiation and the delivery and fractionation schemes used (in addition to the type of radiation used).

The typical curative total irradiation dose for a head and neck malignancy is 50 to 70 Gy (Gy, gray, is the unit for measuring ionising radiation). It is generally accepted that irradiation levels of less than 25 Gy delivered to the salivary glands in the process lead to little long-term damage and good chances of recovery. The peak of salivary-gland damage occurs typically around 6 months after radiotherapy, and chemotherapy in addition to irradiation is known to exacerbate xerostomia effects. It is thought that modulated irradiation schemes (such as IMRT) cause slightly less long-term damage to the salivary glands than conventional irradiation schemes. It is difficult to compare quantitatively such effects as the different schemes irradiate different volumes and areas.

It is not completely understood why the salivary glands are so vulnerable to the effects of high-energy radiation, and why there is little recovery long term once the glands are damaged by high-energy radiation. Common wisdom and arguments about the curative effects of high-energy radiation rely on the idea that cells and tissues with a high rate of turn-over and growth (such as malignant cell lines) are more vulnerable to the effects of high-energy radiation on DNA. The oral mucosa belongs to this group of tissues with fast turn-over. Accordingly, the oral mucosa is severely affected by radiotherapy and painful mucositis, inflammation of the mucosa, invariably starts soon after the beginning of a course of radiotherapy applied to the head and neck region. In contrast, the tissues of the salivary glands do not have a particularly rapid turn-over rate and thus should be less susceptible to radiation damage according to this argument. Clearly some additional mechanisms must be at work.

The current thinking about the mechanisms underlying the lasting damage to the salivary glands caused by high-energy radiation favours a two-stage model. There are two distinct forms of cell death: necrosis and apoptosis. DNA damage from high-energy radiation initiates an inflammatory cell-death process, necrosis. Apoptosis is a non-inflammatory, genetically rooted cell-death process, sometimes called ‘programmed cell death’. It is thought that the initial effects of high-energy radiation on the salivary gland tissues, the early destruction and loss of saliva-producing cells, are due to apoptosis. A later onset of inflammatory tissue response, leading to further loss of, and/or damage to salivary-gland tissue is thought to be due to necrosis. This model accounts for the observed effects over the course of radiotherapy but it does not completely explain the lack of long-term recovery of the salivary-gland tissues. This lack of recovery is, in part, thought to be related to additional damage to ducts where the stem/ progenitor cells lie, nerve cells and blood vessels in the glands. The two-stage model for the development of radiation damage to the salivary glands forms the basis for some ideas about and attempts to prevent radiation-induced xerostomia.