DEEPER INSIGHT into ...

MGD - Pathophysiology & Vicious Circles

 

The pathophysiology of Meibomian Gland Dysfunction (MGD) - the main causative factor for the onset and progression of Dry eye Disease - is not yet completely elucidated although today we appear to have a valid working concept of this condition that has greatly improved our options in diagnostics and therapy of MGD.

Vicious circles certainly occur in MGD and contribute to the disease process. This concerns e.g.:

  • the influence of bacterial colonization and downstream lipid mediators on the maintenance of a chronic sub-clinical disease process
  • the role of internal influence factors such as age
  • the influence of pathogenetic factors from the conjunctiva through the tarsal plate onto the Meibomian gland
  • the integration of MGD as a pathological carousel (large vicious circle) into the full picture of the pathophysiology of Dry Eye Disease

 

The PATHOPHYSIOLOGY of MGD is complex ... but not complicated and influenced by many factors

The Summary Figure for the TFOS MGD Report was prepared by Members of the Ocular Surface Center Berlin (OSCB) and summarizes important pathogenetic factors in one diagram that is intuitively understandable. The main pathogenetic factors are Hyperkeratinization of the epithelium together with Increased Viscosity of the Secretum that can result, together or alone, in Meibomian Gland Obstruction. Further factors of importance, as well as their interaction ... are explained in the text to the left side of this diagram.

For the TFOS MGD Report, Members of the Ocular Surface Center Berlin (OSCB) have prepared the Summary Figure that aims to make all the factors that contribute to, and interfere in, MGD intuitively understandable in one diagram - this is widely known to everybody in the field, and was before published in another article on the Meibomian Glands in health and disease.

It becomes clear that the pathogenesis of MGD depends on Internal and External Influence Factors - such as in Dry Eye Disease in general (for details please see the section ´Overview on Dry Eye Disease´).

 

Pathogenetic Factors that influence MGD are, e.g.:

  • age and sex
  • endocrine hormones, in particular levels of sex hormones
  • systemic and topical medication
  • contact lens wear
  • bacterial colonization and downstream pathogenic factors
    • bacterial lipases
    • modification of the normal Meibomian lipids into
      • inflammatory mediators, such as inflammatory lipid species
      • lipids with increased melting point
      • potentially lipids with decreased melting point/ seborrhea

 

BACTERIAL COLONIZATION IS A FACTOR IN MGD AND CAN LEAD TO ONSET OF A VICIOUS CIRCLE

Of particular importance is apparently the influence of bacterial colonization on the lid margin and potentially inside the glands that has been investigated in detail by the group of James McCULLEY, Ward SHINE, Joel DOUGERTHY and colleagues. They have reported that:

Commensal Bacterial Species occur on the normal lid margin and have also been found inside freshly expressed Meibomian secretum. In pathological conditions of the Meibomian Gland the bacteria increase in number - which is termed increased ´colonization´ and does not represent an ´ínfection´. The bacteria produce enzymes that degrade the normal Meibomian lipids and induce formation of lipids that are irritant to the cells, with downstream activation of inflammatory mediators, and also to the tear film that becomes unstable. This leads to the onset of an inflammatory vicious circle that promotes important pathogenetic factors in MGD such as hyper-keratinization, obstruction and stasis of lipids inside the gland ... which again reinforces bacterial growth.

These bacteria produce lipid degrading enzymes such as bacterial lipase and esterase, that induce the production of

  • lipids with increased melting point
    • ... which explains the occurrence of inspissated secretum
    • that leads to orifice plugging
  • IRRITANT LIPID SPECIES such as free fatty acids (e.g. linoleic acid, oleic acid, arachidonid acid) -  these
    • irritate the tissue on lid margin and in the ductal system and they are one factor to explain the observed increased keratinization that contributes to the obstructive process
    • irritate the Tear Film and lead to Instability of the Tear Film
      • with all the described downstream events such as short Tear Film Break-Up Time (BUT)
      • Increased Evaporation, Hyper-Osmolarity, increased Mechanical Friction
      • eventually this leads, via another route, to epithelial irritation and activation and production of inflammatory mediators as a first step of the tissue for a protective and reparative response... etc. 
    • regulate and promote inflammatory reactions - the irritant fatty acid arachidonic acid is the substance from which the metabolism of potent pro-inflammatory molecules originates

Sub-clinical inflammatory processes conceivably play a role in the patho-physiology of MGD. However, according to the present histological evidence, MGD typically does not include inflammatory cells and overt inflammation. It may be assumed that in chronic MGD an inflammatory response is maintained by irritant lipid species and downstream inflammatory mediators as discussed by McCULLEY and SHINE, that form inflammatory cascades without the necessary involvement of leukocytic cells.

 

SUB-CLINICAL INFLAMMATION IS AN IMPORTANT PATHOGENETIC MECHANISM IN MGD

Sub-Clinical Inflammation is a pathogenetic mechanism that interrelates several other pathogenetic factors, and thereby acts as an amplifying mechanism as in Dry Eye Disease in general. As shown in the MGD-Report Summary Figure (see above) Inflammation in MGD, prominently related to Bacteria, is located in the middle of a network of pathogenetic factors and related to e.g.:

  • stasis of secretum inside the glands that promotes
  • increased growth of and colonization by Bacteria, that produce lipases and toxic pro-inflammatory mediators
  • increased stasis with irritation and activation of epithelial cells with downstream inflammation as similarly occurs in Dry Eye
  • inflammatory reactions due to the latter two factors conceivably stimulates Hyperkeratinization
    • which is a simple response mechanism of epithelial cells and also occurs in squamous metaplasia of the bulbar conjunctiva as shown by Scheffer TSENG 1984 in his studies on Dry Eye Disease. 
    • for the obstruction of the hair-associated sebaceous skin glands it is shown, that inflammation results in Hyperkeratinization

This is in contrast to chronic inflammatory Dry Eye Disease that tends to develop overt clinical inflammation with an amplification into an immune-mediated inflammatory process with involvement of many activated lymphocytes and accessory leukocytes population.

 

The events in Meibomian gland Obstruction constitute a Vicious Circle of Gland Dysregulation in the Patho-Physiology of Dry Eye Disease

Meibomian Gland Dysfunction (MGD) is typically integrated into the full picture of Dry Eye Disease - for more Details please see the sections on `Vicious Circles in Dry Eye Disease´ and the ´Holistic Dynamic Concept of Dry Eye Disease´.

THE MEIBOMIAN GLANDS ARE IMMEDIATELY ADJACENT TO THE TARSAL CONJUNCTIVA and exposed to conjunctival Pathology

The tarsal plate with the included Meibomian Glands is in immediate vicinity of the conjunctiva - directly underneath the narrow connective tissue of the conjunctival lamina propria and only about 0,1mm from the lumen of the conjunctival sac.

The Meibomian Glands are located in the tarsal plates ... which may seem far away from the mucosal ocular surface. However, the tarsal plates are lying immediately underneath the narrow layer of the loose connective tissue of the conjunctival lamina propria.

The Meibomian glands fill almost the complete width of the tarsal plates and therefore also the gland tissue starts very closely underneath the conjunctiva.

Practically, the Glands are often only separated by about 0,1 mm of tissue from the lumen of the conjunctival sac.

 

 

TYPICAL PATHOGENETIC FACTORS IN DRY EYE DISEASE CAN INDUCE MEIBOMIAN GLAND PATHOLOGY

Negative Influence factors such as Contact Lenses and Inflammatory Conjunctival Disease (Allergic Conjunctivitis) lead to a destruction of the Meibomian Glands. This is detectable as visible Drop-Out of Gland Tissue in Meibography (bottom right, schematic representation) that constitute MGD, and by clinical Tear Film Deficiency that constitutes Dry Eye Disease. (Slit lamp Photo: Courtesy of Uwe Pleyer).

Due to the immediate vicinity of the tarsal plates with the Meibomian Glands to the tarsal conjunctiva, it can be assumed that many events that occur in and to the tarsal conjunctiva may also influenced the Meibomian glands.

This is in fact true, because studies from Reiko ARITA and colleagues with the technique of Meibography, have shown that in contact lens wear as well as in allergic conjunctivitis a Dysfunction of the Meibomian Glands (MGDoccurs with a (1) Deficiency of Tear Film Parameters and (2) with a loss of gland tissue as ´drop-out´ in Meibography.

It is presently unclear which negative influence factors may reach the Meibomian glands and lead to their optical drop-out and clinical dysfunction that is conceivably due to atrophy of the functional tissue.

 

 

MECHANICAL FRICTION AND INFLAMMATION OF THE TARSAL CONJUNCTIVA LEAD TO MGD

The most likely negative pathogenetic factors that can occur due to contact lens wear and have negative impact on the Meibomian Glands are:

  • (1) chronic mechanical irritation due tofriction by the contact lens and particularly its margin
  • (2) inflammatory mediators that occur in allergic conjunctivitis
    • Since chronic mechanical irritation leads to wounding and activation of the ocular surface epithelium with a response in the form of production of inflammatory cytokines - the mechanical irritation due to the contact lens may also act via inflammatory mediators in addition or instead of mechanical impact

Both, mechanical as well as chemical inflammatory influences, can conceivably reach the Meibomian glands via the narrow separating tissue layer underneath the tarsal conjunctiva.

 

MEIBOMIAN GLANDS AND MUCOSAL OCULAR SURFACE INFLUENCE EACH OTHER - IN HEALTH AND DISEASE

This verifies, that

  • typical pathogenetic factors that are present in ongoing Dry Eye Disease can influence the Meibomian Glands and induce MGD.
  • on the other hand, ongoingMGD is the main causative primary factor for Dry Eye Disease via lipid deficiency and downstream hyper-evaporative ... and thus leads to Dry Eye Disease.

Therefore, the pathology in MGD leads to the onset or the worsening of Tear Film Instability, which is a Primary Pathology of Dry Eye Disease, and downstream Surface Tissue Damage with the release of inflammatory mediators will REINFORCE the Pathology of the Meibomian Glands

Thus:  The pathology of the Meibomian Gland (MGD) is integrated as a large PATHOLOGICAL CAROUSEL - a large vicious circle - into the Pathology of Dry Eye Disease ... and LINKS the Pathology of the "flat surface"  (cornea and conjunctiva) to the pathology of the Gland Tissue.   - This is a main component of the HOLISTIC DYNAMIC CONCEPT of Dry Eye Disease: