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Aqueous Humor Production and Dynamics

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Title: Aqueous Humor Production and Dynamics
Author: Janine Yang MSIV, Susan Chortkoff MD
Date: 10/4/2022
Keywords/Main Subject: Glaucoma, Aqueous Humor, Anatomy


Background

The aqueous humor is a water-like fluid that fills the anterior chamber of the eye with continual production, secretion, and reabsorption.1,2 The production, circulation and reabsorption of aqueous humor are vital processes maintaining homeostasis of the eye. Imbalances between the production and secretion of aqueous humor may lead to increased intraocular pressure and optic nerve damage such as in the setting of ocular hypertension or glaucoma. Therefore, understanding the physiology behind aqueous humor as well as changes observed in pathologic states is important in managing glaucomatous processes.

Chemistry and Function

Aqueous humor is produced by the ciliary body epithelium at a rate of 2-3 microliters per minute.1-3 It is composed of organic and inorganic ions, carbon dioxide, amino acids, carbohydrates, glutathione, and water.1,2,4 Important transport and enzymatic proteins involved in synthesis may be targeted in glaucoma drugs, discussed below.1,2,5

Aqueous humor functions as a physical component allowing clear optics and filling the anterior chamber of the eye.1-3 It is responsible for providing nourishment to the avascular components of the anterior chamber including the cornea and lens.1-3 In addition, aqueous humor is responsible for removing waste products, blood, macrophages and other debris from the anterior chamber, including the trabecular meshwork.1-3 The structure and function of the trabecular meshwork may become compromised by chronic oxidative stress from reactive oxygen species and insufficient antioxidant defense in the aqueous humor.1-3,6,7 Decreased levels of antioxidants in aqueous humor are present in glaucomatous eyes versus normal eyes, consistent with the presence of increased oxidative stress and low-grade inflammation.6,7

Production and Circulation

The primary anatomic structures vital to the homeostasis of aqueous humor include the ciliary body as the site of principle production, and the trabecular meshwork and uveoscleral pathway as the sites of primary outflow.1,8 Aqueous humor is produced by the ciliary body via a multistep process closely correlating with systemic vascular blood flow.1,9,10 Initially, blood enters the ciliary processes, which propels ultrafiltrate from the blood into the ciliary interstitial space via a pressure gradient.1,9,10 Next, the ciliary epithelium transports plasma components from the basal to the apical surface in order to synthesize aqueous humor and transport it into the posterior chamber.1,9,10 Passive diffusion and ultrafiltration are key in initial synthesis, and active secretion across a blood-aqueous barrier via aquaporins, Na-K-ATPase and carbonic anhydrase enzymes are necessary for final synthesis.1,4,9,10 These active transport enzymes necessary for final synthesis are common pharmacologic targets in decreasing aqueous humor production. Although systemic blood flow via the ciliary artery is required for the initial production of ultrafiltrate, the production of aqueous humor is independent from systemic blood pressure due to a fixed rate of 4% filtration of plasma.10 Therefore, there is minimal association between hypertension and elevated intraocular pressure. The estimated rate of aqueous humor production is approximately 2.4 microliters per minute, with diurnal variations leading to higher aqueous humor flow in the morning and lower flow in the evening.1,9 

While aqueous humor production is well documented, the mechanism of drainage is still poorly understood. There are two main drainage pathways – the conventional pathway (trabecular meshwork, Schlemm’s canal, collector channels, and the episcleral venous system), and the unconventional pathway (uveoscleral, uveovortex, uveolymphatic).1,5,9 

The conventional pathway involves passive drainage throughout the trabecular meshwork although the Schlemm’s canal has been documented with paracellular and intracellular pores.1,5,9 The trabecular meshwork is a triangular porous structure composed of a layer of connective tissue and endothelium with sympathetic innervation from superior sympathetic ganglion, and parasympathetic innervation from the ciliary ganglion.1,5,9  The meshwork may be divided into the uveal meshwork (iris root, ciliary body, peripheral cornea), corneoscleral meshwork (scleral spur), and juxtacanalicular meshwork (transition into Schlemm’s canal).1,5,9  Schlemm’s canal is a structure with composition similar to venous vasculature, with fenestrated thin endothelium surrounded by connective tissue.1,5,9 After drainage through the trabecular meshwork and the Schlemm’s canal, aqueous humor continues through collector channels into the episcleral venous system which deposits into the main venous system.1,5,9

Resistance to outflow through the trabecular meshwork and Schlemm’s canal has been documented although it is poorly understood, yet resistance remains an important factor in regulating intraocular pressure and the pathogenesis of glaucomatous processes. In humans, up to 75% of aqueous outflow resistance is contributed by the trabecular meshwork while the remaining 25% is due to resistance beyond Schlemm’s canal.1 The rate of outflow is directly influenced by iris and ciliary muscles which contract and relax based on cholinergic innervation and pharmacodynamics.1,5,8,9,11 In ciliary contraction, the trabecular meshwork and Schlemm’s canal dilate, decreasing resistance and increasing outflow.1,5,8,9,11 The rate of outflow is also influenced by intraocular pressure, with higher intraocular pressure altering the structure of endothelial lining in Schlemm’s canal to increase the number of porous vacuoles allowing increased outflow.1,5,8,9,11 However, it is still debated if this finding substantially contributes to increasing outflow in glaucomatous eyes.1,5,8,9,11*

The unconventional pathway involves drainage into the orbital vasculature, vortex veins and ciliary lymphatics, contributing up to 25-40% of total aqueous outflow in cynomolgus and vervet monkey models.2,5 The uveoscleral pathway involves diffusion into the sclera and episcleral through the orbital vasculature.2,5 The uveovortex pathway involves osmotic absorption of fluid through the choroid, passing into the vortex veins.2,5 Lastly, the uveolymphatic pathway involves drainage into lymphatic vessels within the ciliary body, although the extent of drainage under normal physiological conditions remains controversial.2,5 In addition, the unconventional pathway also includes corneal, iridial and retinal routes, albeit less clinically significant.12 Regardless of downflow pathway, all unconventional paths require drainage through the interstitial spaces of the ciliary muscle.2,5,12 Resistance also exists within the unconventional pathway likely due to ciliary muscle tone, as seen with changes in outflow in the setting of pilocarpine, increasing ciliary tone and decreasing flow, and atropine, decreasing ciliary tone and increasing flow.2,5,12 Therefore, the unconventional pathways are also clinically important in moderating intraocular pressure, and serve as a potential target in glaucoma therapy.

In the Setting of Glaucoma

Aqueous humor dynamics and circulation are vital in the pathogenesis of glaucomatous damage to the optic nerve.1,9,10 One of the primary risk factors and causative factors in glaucoma is an elevated intraocular pressure above the normal physiologic range of 12 to 21 mmHg.1,9,10 Extended periods of elevated intraocular pressure above 22 mmHg have been associated with development of glaucomatous damage.1,9,10  Elevated intraocular pressure from increased resistance and decreased outflow of aqueous humor and/or increased production leads to compression of the optic nerve which limits oxygen and nutrition supply to the nerve. There are two main categories of glaucoma, each involving aqueous humor circulation and production in relation to resulting optic neuropathy. 

Primary open angle glaucoma (POAG) causes optic neuropathy in the setting of an ‘open angle’, while primary angle closure glaucoma (PACG) in the setting of peripheral angle obstruction or narrowing.1,9,10 The ‘angle’ refers to the intersection of the peripheral iris with the cornea, a key anatomical player in conventional aqueous humor drainage.1,9,10* as this is where the trabecular, Sclemm’s canal are located. In POAG where the iris-cornea angle remains open for drainage, the mechanism for glaucomatous damage includes overall increased resistance to outflow despite maintaining an open angle, and increased aqueous humor production.1,9,10 In PACG, the iris-cornea angle is acutely or chronically obstructed which leads to significant decrease in aqueous humor outflow and an elevation in intraocular pressure.1,9,10

Ocular hypertension (OHTN) is defined as elevated intraocular pressure without any signs of vision loss or optic neuropathy otherwise classified as glaucomatous changes.2,3 Patients with OHTN have demonstrated reduced trabecular outflow and uveoscleral outflow with normal aqueous production which explains the mechanism for elevated intraocular pressure2,3 This is a similar mechanism to patients with POAG. However, the understanding of elevated intraocular pressure in the setting of OHTN or POAG is limited, such as in situations with OHTN without POAG or normal tension glaucoma.2,3

Current glaucoma pharmacologic and surgical therapies are targeted at decreasing aqueous humor production, such as carbonic anhydrase inhibitors or ciliary body ablative laser treatments, or increasing outflow, such as prostaglandin agonists, adrenergic agonists, and physical modifications to optimize or bypass the outflow pathways.1,9

Figures

Yang_126138_Figure_1

Taken from American Academy of Ophthalmology, Aqueous Humor Flow

Yang_126138_Figure_2

Taken from article: Waly et al, 2010 (System Dynamic Model for Normal Intraocular Pressure)

Yang_126138_Figure_3

Taken from: Toris CB, Koepsell SA, Yablonski ME, Camras CB. Aqueous humor dynamics in ocular hypertensive patients. J Glaucoma. Jun 2002;11(3):253-8. doi:10.1097/00061198-200206000-00015

References

  1. Goel M, Picciani RG, Lee RK, Bhattacharya SK. Aqueous humor dynamics: a review. Open Ophthalmol J. Sep 3 2010;4:52-9. doi:10.2174/1874364101004010052
  2. Sunderland DK SA. Physiology, Aqueous Humor Circulation. 
  3. Toris CB, Koepsell SA, Yablonski ME, Camras CB. Aqueous humor dynamics in ocular hypertensive patients. J Glaucoma. Jun 2002;11(3):253-8. doi:10.1097/00061198-200206000-00015
  4. Macknight AD, McLaughlin CW, Peart D, Purves RD, Carre DA, Civan MM. Formation of the aqueous humor. Clin Exp Pharmacol Physiol. Jan-Feb 2000;27(1-2):100-6. doi:10.1046/j.1440-1681.2000.03208.x
  5. Johnson M, McLaren JW, Overby DR. Unconventional aqueous humor outflow: A review. Exp Eye Res. May 2017;158:94-111. doi:10.1016/j.exer.2016.01.017
  6. Ferreira SM, Lerner SF, Brunzini R, Evelson PA, Llesuy SF. Oxidative stress markers in aqueous humor of glaucoma patients. Am J Ophthalmol. Jan 2004;137(1):62-9. doi:10.1016/s0002-9394(03)00788-8
  7. Kaeslin MA, Killer HE, Fuhrer CA, Zeleny N, Huber AR, Neutzner A. Changes to the Aqueous Humor Proteome during Glaucoma. PLoS One. 2016;11(10):e0165314. doi:10.1371/journal.pone.0165314
  8. Brubaker RF. The flow of aqueous humor in the human eye. Trans Am Ophthalmol Soc. 1982;80:391-474. 
  9. R TCYMT. Aqueous humor dynamics. In: DC CNL, ed. Atlas of Glaucoma. Second edition ed. Informa HK; 2007:13 – 28:chap 3.
  10. Kiel JW, Hollingsworth M, Rao R, Chen M, Reitsamer HA. Ciliary blood flow and aqueous humor production. Prog Retin Eye Res. Jan 2011;30(1):1-17. doi:10.1016/j.preteyeres.2010.08.001
  11. Roy Chowdhury U, Hann CR, Stamer WD, Fautsch MP. Aqueous humor outflow: dynamics and disease. Invest Ophthalmol Vis Sci. May 2015;56(5):2993-3003. doi:10.1167/iovs.15-16744
  12. Fautsch MP, Johnson DH. Aqueous humor outflow: what do we know? Where will it lead us? Invest Ophthalmol Vis Sci. Oct 2006;47(10):4181-7. doi:10.1167/iovs.06-0830

Faculty Approval by: Susan Chortkoff MD
Copyright Statement: Copyright Janine Yang, ©2022. For further information regarding the rights to this collection, please visit: http://morancore.utah.edu/terms-of-use/
Identifier: Moran_CORE_126138