**3.1 Lipid layer alteration**

Deficiency of this layer is the reason of more rapid evaporation and in the absence of increased tear production activates evaporative form of dry eye disease [58].

The most common reason of lipid layer deficiency is obstruction of the Meibomian glands. Meibomian gland disfunction (MGD) may be provoked by various local and systemic conditions, e.g. atopic keratoconjunctivitis, chronic blepharitis [59, 60], generalized dysfunction of sebaceous glands (rosacea, seborrheic dermatitis), chemical agents such as turpentine, present in the sick building environment [36, 61]. Tobacco smokers are prone to development of MGD [62], the more severe course of MGD was observed in type 2 diabetes mellitus [63].


#### **Table 2.**

*Dry eye classification [7, 23, 64–74].*


**7**

*Tear Film – Physiology and Disturbances in Various Diseases and Disorders*

A injections seem to increase lipid layer thickness [79].

Furthermore, the insufficient protein intake in bariatric patients negatively influences tear film lipids [75]. Also androgen deficiency (e.g. aging, anti-androgen therapy, congenital impairment or absence of the androgen receptor) hinders lipid production [76]. Incomplete blinking has been reported as the reason for lipid layer instability, because of inadequate lipid distribution [9, 77]. Some studies have revealed influence of medicines on the lipid layer: e.g. isotretinoin decreases Meibomian gland secretory ability [78], and on the contrary, botulinum neurotoxin

Aqueous layer deficiency is the most common reason of dry eye and is classified into two groups: Sjögren Syndrome dry eye and non-Sjögren Syndrome dry

Sjögren's syndrome (SS) is a rheumatic autoimmune disease in which exocrine glands (salivary and lacrimal glands) are involved that results in clinical symptoms of dry mouth and dry eye. SS can be primary-pSS (without any other accompanying symptoms) or secondary-sSS (with other autoimmune diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polyarteritis nodosa, systemic sclerosis, granulomatosis with polyangiitis (GPA), primary biliary cholangitis (PBC), mixed connective tissue disease, occult thyroid eye disease) [64, 66]. Some studies demonstrated coincidence of dry eye disease (DED) and SS in 46.7% cases [64, 67]. In non-SS dry eye reduced tear secretion is a result of senile hyposecretion, lacrimal excision, lacrimal duct obstruction, immune lacrimal gland damage in sarcoidosis or lymphoma, sensory or motor reflex block, scarring conditions of the conjunctiva (pemphigoid, chemical burns, trachoma, chronic ocular Graft-versus-Host Disease) [11, 57, 64, 68, 69]. Corneal hypoesthesia and due to it dry eye can be result of corneal refraction surgery [70], contact lens wearing [71], herpetic keratitis or as a side effect after surgical trigeminal neuralgia management [72]. Increased electrolyte concentration, loss of growth factors, presence of proinflammatory cytokines result in changes in composition of the aqueous part of the tear film. Such a disturbances in connection with slow tear turnover are secondary

There are some medicines reported to exacerbate tear secretion, e.g. thiazide diuretics, tricyclic and tetracyclic antidepressants, ß-blokers, anticholinergics, benzodiazepines, antihistamines, antihypertensives and anti-Parkinson's drugs

Disturbances of the mucin layer are connected with the goblet cell deficiency, which is observed in majority forms of dry eye [8, 80]. The leading reason of xerophthalmia connected with mucins the insufficiency of vitamin A is [8, 57, 81, 82]. The lack of vitamin A is usually connected with various forms of malnutrition or chronic malabsorption. Gastroenterological diseases (e.g. coeliac disease) impair vitamin A absorption [83–85]. Conditions affecting liver impair fat metabolism and decreases absorption of this fat-soluble vitamin [86, 87]. Pancreas insufficiency (e.g. cystic fibrosis) hinders vitamin A intake by its influence on fat digestion pathway [88, 89]. Alcoholism, restrictive diets (both in eating disorders and selective, like poor balanced vegans') and low-quality food consumption are the most common reasons of malnutrition and because of that vitamin A insufficiency [90–94]. There are some problems responsible for impairment of goblet cells function. Mucous membrane pemphigoid and its subtype – ocular cicatricial pemphigoid

*DOI: http://dx.doi.org/10.5772/intechopen.94142*

**3.2 Aqueous layer disturbances**

to ocular surface damage [8, 47].

**3.3 Mucin layer deficiency**

[8, 57, 73, 74].

eye [64, 65].

#### **Table 3.**

*Signs and symptoms of dry eye disease [1, 7, 23, 64].*

#### *Tear Film – Physiology and Disturbances in Various Diseases and Disorders DOI: http://dx.doi.org/10.5772/intechopen.94142*

Furthermore, the insufficient protein intake in bariatric patients negatively influences tear film lipids [75]. Also androgen deficiency (e.g. aging, anti-androgen therapy, congenital impairment or absence of the androgen receptor) hinders lipid production [76]. Incomplete blinking has been reported as the reason for lipid layer instability, because of inadequate lipid distribution [9, 77]. Some studies have revealed influence of medicines on the lipid layer: e.g. isotretinoin decreases Meibomian gland secretory ability [78], and on the contrary, botulinum neurotoxin A injections seem to increase lipid layer thickness [79].

#### **3.2 Aqueous layer disturbances**

*Ocular Surface Diseases - Some Current Date on Tear Film Problem and Keratoconic Diagnosis*

**3. The influence of various diseases and conditions on the tear film**

Tear film stability can be disturb in tear film layers deficiencies, defective spreading of the tear film, in some general diseases and during application of some general and/or topical medications. In the wake of it dry eye disease evolves

Deficiency of this layer is the reason of more rapid evaporation and in the absence

**Dry eye**

Endogenous

Exogenous

**Dry eye disease**

Low blinking Systemic medicines

Contact lens wear Ocular surface diseases Topical medicines Vitamin A deficiency

tion, trichiasis, symblepharon

filaments, mucus clumping

matory mediators

Meibomian gland dysfunction (MGD) Disorders of lids and lid aperture

• Eyelids: blepharitis posterior, Meibomian gland disfunc-

• Cornea: epithelial defect (dyeing with the fluorescein),

• Potential complications: persistent epithelial defect, keratomalacia, corneal perforation, corneal ulcer

• Conjunctiva: hyperemia, keratonization, persistent inflammation, dyeing with the lissamine green(rose bengal) • Tear film: debris, reduced meniscus, instability(reduced break-up time), elevated osmolarity and level of inflam-

of increased tear production activates evaporative form of dry eye disease [58]. The most common reason of lipid layer deficiency is obstruction of the Meibomian glands. Meibomian gland disfunction (MGD) may be provoked by various local and systemic conditions, e.g. atopic keratoconjunctivitis, chronic blepharitis [59, 60], generalized dysfunction of sebaceous glands (rosacea, seborrheic dermatitis), chemical agents such as turpentine, present in the sick building environment [36, 61]. Tobacco smokers are prone to development of MGD [62], the more severe course of MGD was observed in type 2 diabetes mellitus [63].

Aqueous deficient dry eye (ADDE) Evaporative dry eye (EDE)

functioning, thereby ocular surface health [3].

[11, 36, 57] (**Tables 2** and **3**).

Sjőgren syndrome dry eye (SSDE)

Non- Sjőgren Syndrome dry eye Lacrimal deficiency

*Dry eye classification [7, 23, 64–74].*

• Discomfort: itching, stinging, burning, "foreign body sensation" occasionally pain, photophobia • Visual fluctuations (especially during reading- blinking recover vision) • Tear film instability (potential dam-

age of ocular surface)

*Signs and symptoms of dry eye disease [1, 7, 23, 64].*

Lacrimal gland duct obstruction

Signs Symptoms

Primary Secondary

Reflex block Systemic medicines

**Table 2.**

**3.1 Lipid layer alteration**

the tear film production, retention and elimination acts the crucial role in its proper

**6**

**Table 3.**

Aqueous layer deficiency is the most common reason of dry eye and is classified into two groups: Sjögren Syndrome dry eye and non-Sjögren Syndrome dry eye [64, 65].

Sjögren's syndrome (SS) is a rheumatic autoimmune disease in which exocrine glands (salivary and lacrimal glands) are involved that results in clinical symptoms of dry mouth and dry eye. SS can be primary-pSS (without any other accompanying symptoms) or secondary-sSS (with other autoimmune diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polyarteritis nodosa, systemic sclerosis, granulomatosis with polyangiitis (GPA), primary biliary cholangitis (PBC), mixed connective tissue disease, occult thyroid eye disease) [64, 66]. Some studies demonstrated coincidence of dry eye disease (DED) and SS in 46.7% cases [64, 67].

In non-SS dry eye reduced tear secretion is a result of senile hyposecretion, lacrimal excision, lacrimal duct obstruction, immune lacrimal gland damage in sarcoidosis or lymphoma, sensory or motor reflex block, scarring conditions of the conjunctiva (pemphigoid, chemical burns, trachoma, chronic ocular Graft-versus-Host Disease) [11, 57, 64, 68, 69]. Corneal hypoesthesia and due to it dry eye can be result of corneal refraction surgery [70], contact lens wearing [71], herpetic keratitis or as a side effect after surgical trigeminal neuralgia management [72].

Increased electrolyte concentration, loss of growth factors, presence of proinflammatory cytokines result in changes in composition of the aqueous part of the tear film. Such a disturbances in connection with slow tear turnover are secondary to ocular surface damage [8, 47].

There are some medicines reported to exacerbate tear secretion, e.g. thiazide diuretics, tricyclic and tetracyclic antidepressants, ß-blokers, anticholinergics, benzodiazepines, antihistamines, antihypertensives and anti-Parkinson's drugs [8, 57, 73, 74].

#### **3.3 Mucin layer deficiency**

Disturbances of the mucin layer are connected with the goblet cell deficiency, which is observed in majority forms of dry eye [8, 80]. The leading reason of xerophthalmia connected with mucins the insufficiency of vitamin A is [8, 57, 81, 82]. The lack of vitamin A is usually connected with various forms of malnutrition or chronic malabsorption. Gastroenterological diseases (e.g. coeliac disease) impair vitamin A absorption [83–85]. Conditions affecting liver impair fat metabolism and decreases absorption of this fat-soluble vitamin [86, 87]. Pancreas insufficiency (e.g. cystic fibrosis) hinders vitamin A intake by its influence on fat digestion pathway [88, 89]. Alcoholism, restrictive diets (both in eating disorders and selective, like poor balanced vegans') and low-quality food consumption are the most common reasons of malnutrition and because of that vitamin A insufficiency [90–94].

There are some problems responsible for impairment of goblet cells function. Mucous membrane pemphigoid and its subtype – ocular cicatricial pemphigoid

via recurrent inflammation destroy goblet cells and promote subepithelial fibrosis, resulting in changes ranging from xerophthalmia to conjunctival keratinization and blindness [95–99]. Stevens-Johnson Syndrome, trachoma and severe burns (both thermal and chemical) impair mucin production by decreasing the number of active goblet cells [8, 100–103].

Moreover, some medications (e.g. mucolytics, antihistamines) and preservatives influence the ocular surface and modify mucous layer [8, 57, 104].

#### **3.4 Multilayer disturbances**

Although three layers of the tear film are investigated, all of them remain in strict dependence of each other and many conditions cause disturbances of the tear film as a whole. The most common problem impairing ocular surface is progression with age; decreased tear production, tantalic problems, hormonal changes, medications and other diseases affect tear production, its' ingredients and spreading over the ocular surface [8, 57, 105, 106]. Tantalic dry eye seems to be one of the most important conditions influencing all three layers: eyelid incongruency (entropion, ectropion, lid margin irregularities, exophthalmos), epitheliopathy (e.g. corneal scars) and evaporation are the reason of tear loss. Neurological problems (both afferent and efferent part of the reflex loop) directly affect tear secretion [8, 57, 105].

Hormonal changes (androgens, estrogens, prolactin, thyroid hormone, insulin resistance/deprivation, ACTH resistance, adrenal insufficiency, multiple endocrine deficiency) influence tear stability as well [105, 106]. Meanwhile, the newest metaanalysis revealed no correlation between hormonal replacement therapy or oral contraceptives and tear film – it seems to be speculative [107, 108]. Dry eye disease due to hormonal disorders often connect both aqueous tear deficient and evaporative mechanism. Thyroid associated diseases result usually in autoimmune condition (impaired thyroid hormone activity, autoantibodies against THS receptors present in lacrimal glands, autoantibodies against thyroid hormone and/or their receptors) but the final effect of dry eye is connected also with ocular surface disturbances due to enhanced environment exposure, lid mechanical impairment (reduced lipids secretion, eyelid retraction, eye globe proptosis, impaired blinking) and therapy (thyroid hormone replacement, iodine suppression, immunomodulators specific for orbit and ocular disease, local radiotherapy and surgical procedures) [106]. In patients with diabetes mellitus the frequency of dryness varies from 15.4 to 82%. The mechanism of dry eye disease in diabetic patients is multifactorial: insulin resistance or deprivation is responsible for lacrimal gland size reduction, histological and molecular changes of it, polyneuropathy and nerve-conduction abnormalities that reduce secretion. Peripheral microvascular disease and insulin reduced input in target tissues are the other reasons of lacrimal gland and ocular surface disorders. Tear film instability and higher osmolarity are probably the result of higher glucose and protein levels in the tears and changes in the protein profile [106, 109].

In literature there are examples of dry eye disease secondary to other hormonal imbalance (e.g. ACTH-triple A syndrome, multiple endocrine deficiency) [106, 110].

Some environmental factors (e.g. pollutions, visual display terminals, temperature, humidity) promotes dry eye disease, however the pathomechanism is still discussed [111, 112]. Contact lenses wear influences lipid layer, changes the dynamics of the whole tear film and is the reason of dry eye symptoms [113–115].

There are a lot of date on the influence of medications (both topical and systemic) on the tear film. Some samples: ß-blockers used for glaucoma therapy reduce test Shirmer I and break-up time values, long term general anesthesia decrease basal tear production, antihistamines block both goblet cells and lacrimal glands, topical glaucoma therapy reduces LLT, oral mucolytics modify mucous layer, systemic

**9**

**4. Conclusions**

**Table 4.**

*Tear Film – Physiology and Disturbances in Various Diseases and Disorders*

Insufficient protein intake (bariatric patients)

• Non- Sjőgren syndrome dry eye (nSSDE)

Incomplete blinking (inadequate lipid distribution)

Lipid layer MGD: atopic local changes, chronic blepharitis, generalized dysfunction of the sebaceous glands, chemical agents, tabacco smokers, diabetes mellitus

(primary, without other accompanying symptoms and secondary, with other

Mucus layer • Insufficiency of vitamin A: malnutrition or malabsorption (gastroenterological

Multilayer • Aging: decreased tear production, tantalic problems (eyelid incongruency as

• Environment (pollutions, ambient temperature, humidity)

(senile hyposecretion, lacrimal excision, lacrimal duct obstruction, immune lacrimal gland damage, sensor or motor reflex block, scarring condition of the conjunctiva, corneal hypoesthesia as a result of CL wearing, heretical keratitis or surgical procedures)

diseases, condition affecting liver, pancreas insufficiency, alcoholism, restrictive

• Destruction of the goblet cells (cicatricial conjunctival changes: e.g. pemphigoid, Stevens-Johnson syndrome, trachoma, GVHD, severe thermal and chemical burns)

• Hormonal changes (androgens, estrogens, prolactin, ACTH, thyroid hormone) • Neurological problems (both afferent and efferent part of the reflex loop)

entropion, ectropion, eyelid irregularities, exophthalmos, epitheliopathy; e.g. corneal

Androgen deficiency: aging, anti-androgen therapy, congenital impairment or absence of

**Causes of disturbances**

the androgen receptor

autoimmune diseases)

diets, low quality food)

• Visual display terminals

• Medicines (both topical and systemic)

antidepressants, anticholinergics or antihypertensives increase risk of dry eye problems [56, 103, 116–122]. A comprehensive review of this problem with the list of medicines and herbs has been prepared by Askeroglu et al. [123]. Analyzing influence of medicines on the ocular surface and dry eye disease we have to remember that topical used multidose artificial tears and lubricants contain preservatives. The most common Benzalkonium chloride – BAK disrupts tear stability, causes corneal and conjunctival epithelium damage and induces inflammatory changes that depends on dose and time of use. Alternative preservatives (e.g. Polyquaternium-I: Polyquad®, Polyhexamethylene biguanide: PHMB, Sodium perborate: GenAqua®, Deqest®, stabilized Oxychlorocomplex SOC: Purite®, OcuPure®, ionic-buffered solution containing zinc chloride, borate, propylate glucol and sorbitol:Sofzia) are used in some artificial tears, lubricants or glaucoma drops. Published date on the ocular performance of them generally show they induce significantly less disturbances of

The ocular surface contacts with the environment by the tear film as interface. Thus, tear production, composition, dynamics and function is so important to prevent it healthy. There are many diseases and conditions (both systemic and

the ocular surface than BAK [124, 125] (**Table 4**).

*DOI: http://dx.doi.org/10.5772/intechopen.94142*

Medicins Aqueous layer • Sjőgren syndrome dry eye (SSDE)

• Medicines

• Medicines

scars)

• Preservatives

*The main causes of tear film deficiency [7, 58–125].*

*Tear Film – Physiology and Disturbances in Various Diseases and Disorders DOI: http://dx.doi.org/10.5772/intechopen.94142*


#### **Table 4.**

*Ocular Surface Diseases - Some Current Date on Tear Film Problem and Keratoconic Diagnosis*

active goblet cells [8, 100–103].

**3.4 Multilayer disturbances**

via recurrent inflammation destroy goblet cells and promote subepithelial fibrosis, resulting in changes ranging from xerophthalmia to conjunctival keratinization and blindness [95–99]. Stevens-Johnson Syndrome, trachoma and severe burns (both thermal and chemical) impair mucin production by decreasing the number of

Moreover, some medications (e.g. mucolytics, antihistamines) and preservatives

Although three layers of the tear film are investigated, all of them remain in strict dependence of each other and many conditions cause disturbances of the tear film as a whole. The most common problem impairing ocular surface is progression with age; decreased tear production, tantalic problems, hormonal changes, medications and other diseases affect tear production, its' ingredients and spreading over the ocular surface [8, 57, 105, 106]. Tantalic dry eye seems to be one of the most important conditions influencing all three layers: eyelid incongruency (entropion, ectropion, lid margin irregularities, exophthalmos), epitheliopathy (e.g. corneal scars) and evaporation are the reason of tear loss. Neurological problems (both afferent and efferent part of the reflex loop) directly affect tear secretion [8, 57, 105].

Hormonal changes (androgens, estrogens, prolactin, thyroid hormone, insulin resistance/deprivation, ACTH resistance, adrenal insufficiency, multiple endocrine deficiency) influence tear stability as well [105, 106]. Meanwhile, the newest metaanalysis revealed no correlation between hormonal replacement therapy or oral contraceptives and tear film – it seems to be speculative [107, 108]. Dry eye disease due to hormonal disorders often connect both aqueous tear deficient and evaporative mechanism. Thyroid associated diseases result usually in autoimmune condition (impaired thyroid hormone activity, autoantibodies against THS receptors present in lacrimal glands, autoantibodies against thyroid hormone and/or their receptors) but the final effect of dry eye is connected also with ocular surface disturbances due to enhanced environment exposure, lid mechanical impairment (reduced lipids secretion, eyelid retraction, eye globe proptosis, impaired blinking) and therapy (thyroid hormone replacement, iodine suppression, immunomodulators specific for orbit and ocular disease, local radiotherapy and surgical procedures) [106]. In patients with diabetes mellitus the frequency of dryness varies from 15.4 to 82%. The mechanism of dry eye disease in diabetic patients is multifactorial: insulin resistance or deprivation is responsible for lacrimal gland size reduction, histological and molecular changes of it, polyneuropathy and nerve-conduction abnormalities that reduce secretion. Peripheral microvascular disease and insulin reduced input in target tissues are the other reasons of lacrimal gland and ocular surface disorders. Tear film instability and higher osmolarity are probably the result of higher glucose

and protein levels in the tears and changes in the protein profile [106, 109].

of the whole tear film and is the reason of dry eye symptoms [113–115].

In literature there are examples of dry eye disease secondary to other hormonal imbalance (e.g. ACTH-triple A syndrome, multiple endocrine deficiency) [106, 110]. Some environmental factors (e.g. pollutions, visual display terminals, temperature, humidity) promotes dry eye disease, however the pathomechanism is still discussed [111, 112]. Contact lenses wear influences lipid layer, changes the dynamics

There are a lot of date on the influence of medications (both topical and systemic)

on the tear film. Some samples: ß-blockers used for glaucoma therapy reduce test Shirmer I and break-up time values, long term general anesthesia decrease basal tear production, antihistamines block both goblet cells and lacrimal glands, topical glaucoma therapy reduces LLT, oral mucolytics modify mucous layer, systemic

influence the ocular surface and modify mucous layer [8, 57, 104].

**8**

*The main causes of tear film deficiency [7, 58–125].*

antidepressants, anticholinergics or antihypertensives increase risk of dry eye problems [56, 103, 116–122]. A comprehensive review of this problem with the list of medicines and herbs has been prepared by Askeroglu et al. [123]. Analyzing influence of medicines on the ocular surface and dry eye disease we have to remember that topical used multidose artificial tears and lubricants contain preservatives. The most common Benzalkonium chloride – BAK disrupts tear stability, causes corneal and conjunctival epithelium damage and induces inflammatory changes that depends on dose and time of use. Alternative preservatives (e.g. Polyquaternium-I: Polyquad®, Polyhexamethylene biguanide: PHMB, Sodium perborate: GenAqua®, Deqest®, stabilized Oxychlorocomplex SOC: Purite®, OcuPure®, ionic-buffered solution containing zinc chloride, borate, propylate glucol and sorbitol:Sofzia) are used in some artificial tears, lubricants or glaucoma drops. Published date on the ocular performance of them generally show they induce significantly less disturbances of the ocular surface than BAK [124, 125] (**Table 4**).

### **4. Conclusions**

The ocular surface contacts with the environment by the tear film as interface. Thus, tear production, composition, dynamics and function is so important to prevent it healthy. There are many diseases and conditions (both systemic and

### *Ocular Surface Diseases - Some Current Date on Tear Film Problem and Keratoconic Diagnosis*

local) that may affect each layer of the tear film separately or all of them together. Moreover, tear film disorders can manifest systemic diseases and, sometimes, be necessary or even be the only clue to diagnosis. The commonness of tear film problems and wide spectrum of its different background seem to require to be considered in everyday medical, not only ophthalmological, practice. Those problems should be analyzed to plan and undertake proper therapy, especially in patients with eye dryness symptoms.
