Physiology, Aqueous Humor Circulation

Issues of Concern

Dysfunction in the balance between aqueous humor secretion and reabsorption can lead to increased intraocular pressure (IOP). Intraocular pathologies of increased pressure, such as ocular hypertension or glaucoma, may mandate treatment with medications or surgical repair.

Cellular Level

Active transport at the site of the non-pigmented epithelial cells is thought to be the major contributor to aqueous humor formation. The energy required for active transport is generated via the hydrolysis of ATP to ADP, mediated by the enzyme Na-K-ATPase, which is found on both pigmented and non-pigmented ciliary epithelia. Na-K-ATPase is of specific pharmacological interest as it can be inhibited by many different molecules, including cardiac glycosides, dinitrophenol, and acetazolamide. Carbonic anhydrase, an enzyme also found in pigmented and non-pigmented ciliary epithelia, mediates bicarbonate transport across ciliary epithelium via hydration of CO, forming HCO and protons.

The formation of bicarbonate regulates pH for optimal active ion transport, which influences fluid transport by affecting Na. Chloride (Cl) is the major anion transported across the epithelium through Cl channels. Other molecules actively transported include ascorbic acid and certain amino acids. Active transport produces an osmotic gradient across the ciliary epithelium, promoting the movement of other plasma components via ultrafiltration and diffusion.[2]

Development

In prenatal development, neural ectoderm forms the optic vesicle, which later forms the optic cup. The anterior rim of the optic cup forms the ciliary body epithelium, which secretes aqueous humor. The drainage of aqueous humor is a poorly understood mechanism; the structures currently implicated in this process include the trabecular meshwork, Schlemm’s canal, and the ciliary muscle. These three structures derive from the periocular mesenchyme, a subpopulation of the cranial neural crest.[3]

Organ Systems Involved

As an integral component of eye function, aqueous humor circulation is involved in the visual system as a subdivision of the central nervous system. Ongoing research has demonstrated that aqueous humor plays a role in the lymphatic system by inducing ocular lymphatic regression. This finding may lead to promising therapeutic strategies for treating lymphatic disease inside and outside the eye.[4] The cardiovascular system is also involved in the circulation of aqueous humor via pulsatile ocular blood flow in the choroid, termed ocular pulse. Research is ongoing to determine a correlation between ocular pulse and ocular diseases such as ocular hypertension and glaucoma.[5]

Function

Aqueous humor is a slightly alkaline ocular fluid formed by epithelial cells of the ciliary body at a rate of 2 to 3 microliters/minute. The formation and chemical composition of aqueous humor is accomplished via three processes - diffusion, ultrafiltration, and active secretion by the ciliary processes - linear folds projecting from the ciliary body into the space behind the iris where the lens ligaments and ciliary muscle attach to the eyeball. 

Aqueous humor is composed of organic and inorganic ions, glutathione, carbohydrates, amino acids, carbon dioxide, oxygen, and water. A major function of aqueous humor is to supply nutrients and oxygen to the avascular tissues of the eye, the cornea, and the lens. Aqueous humor also functions to remove waste products, blood, macrophages, and other debris from the posterior cornea and anterior lens and maintain the shape and IOP of the eyeball.[2]

Mechanism

Aqueous humor is synthesized by the cells of the ciliary body in a three-step process. First, blood flows into the ciliary processes. Second, the pressure gradient between blood flow and the ciliary interstitium propels the ultrafiltration of plasma into the interstitium. Finally, the ciliary epithelium actively and selectively transports plasma components from the basal to the apical surface, thereby synthesizing aqueous humor and pumping it into the posterior chamber of the eye.

Though the first step in this process depends on blood flow, it is essential to note that systemic blood pressure has been demonstrated to have no significant effect on IOP. This fact is explainable physiologically in that the percentage of plasma filtered is meager at approximately 4%. The consistency of aqueous humor synthesis is the basis for IOP generation, though IOP also varies with the outflow facility. The resistance inherent in the aqueous humor drainage system determines the outflow facility.[6]

The exact mechanism of aqueous humor drainage from the eye is poorly understood, with conventional and unconventional drainage pathways being proposed. Both pathways begin with the synthesis of aqueous humor, as described above. The humor then flows from the posterior chamber to the anterior chamber by passing through the pupil, which is the point of divergence between the conventional and unconventional pathways.[7]

The conventional pathway continues with the humor draining through the following sequence of structures within the angle of the eye: the trabecular meshwork, Schlemm’s canal, collector channels, and the episcleral venous system. Flow through the trabecular meshwork is entirely passive. The flow through Schlemm’s canal has been demonstrated via paracellular and intracellular pores. Resistance to outflow has been documented in the trabecular meshwork and Schlemm’s canal, though the exact mechanisms are under debate. Flow resistance through these structures has the greatest effect on the outflow facility compared to all known structures of both the conventional and unconventional pathways.[8] Aqueous humor continues through collector channels until it reaches the episcleral venous system, where it gets deposited into the systemic cardiovascular circulation.

The unconventional pathway drains into the ciliary muscle interstitium via the uveal meshwork instead of the trabecular meshwork. This pathway subdivides into proposed uveoscleral, uveovortex, and uveolymphatic pathways, named for their respective vascular endpoints: orbital vasculature, vortex veins, and ciliary lymphatics, respectively. Each of these leads to the systemic cardiovascular circulation. The source of resistance in the unconventional pathway is likely ciliary muscle tone, as demonstrated in experiments involving pilocarpine, which increases tone and decreases unconventional flow, and atropine, which decreases tone and increases unconventional outflow. Further delineation of this pathway remains controversial.[9]

Related Testing

Aqueous humor production and drainage are not directly tested due to a lack of clinical utility. IOP acts as a surrogate measurement due to its association with glaucoma and the availability of cost-effective measuring devices. A clinician may measure IOP indirectly via ambulatory applanation tonometry, whereby air is used to flatten (applanate) an area of the cornea, and the pressure needed to do so is calculated.[10] The accuracy of this measurement depends on the practitioner's skill and the thickness of the patient's cornea. It is also possible to measure IOP by indentation tonometry, though this is not common in developed nations due to the availability of applanation tonometry. However, this method can be a cost-effective means of bringing IOP measurement to rural areas that may not have access to ophthalmic specialty services. Indentation tonometry tends to underestimate IOP when compared to the applanation gold standard.[11] Direct cannulation of the eye is also possible but is not done clinically due to the availability of less invasive methods.

Pathophysiology

Dysfunction in aqueous humor circulation, leading to high IOP, is a significant risk factor for glaucoma. Glaucoma is a progressive, irreversible disease of the eye in which IOP becomes pathologically high, which can ultimately lead to visual field loss and blindness. The normal IOP is 12 to 20 mmHg, with pressures maintained above 25 to 30 mmHg for long periods leading to vision loss. In most cases of glaucoma, the high IOP results from increased resistance to fluid outflow, though an increased production of aqueous humor is also a factor. 

Glaucoma is a set of optic neuropathies associated with, but not exclusively caused by, high IOP. As pressure within the eye rises, optic nerve axons become compressed at the optic disc. Compression of the optic nerve blocks the flow of cytoplasm down the axon into the optic nerve fibers. Lacking the oxygen and nutrients needed from the cytoplasm, the optic nerve becomes ischemic, ultimately leading to visual field loss and blindness of the individual. It is important to note that high IOP alone does not cause glaucoma. When the IOP is above normal, but the individual does not show signs of glaucoma, this is termed ocular hypertension.[12]

The two most common forms of glaucoma are primary open-angle glaucoma and primary angle-closure glaucoma. The term "angle" refers to the angle between the iris and cornea, the location of aqueous humor drainage. 

Primary open-angle glaucoma (POAG) is characterized by progressive loss of peripheral visual fields, followed by central field loss. In many but not all instances, POAG may be present in the presence of elevated IOP. Two possible mechanisms explaining POAG include decreased aqueous humor outflow and increased aqueous humor production. Findings on ophthalmoscopic examination include "cupping" of the optic nerve.

Primary angle-closure glaucoma (PACG) occurs when the peripheral aspect of the iris obstructs aqueous outflow, leading to increased IOP and damage to the optic nerve. Patients typically experience sudden and painful vision loss due to acute elevation of IOP.[13]

Clinical Significance

Aqueous humor circulation plays a significant role in IOP and, therefore, glaucoma. Glaucoma is a leading cause of irreversible blindness worldwide, with a global burden of 70 million people, 3 million of whom reside within the United States.[14] 

Screening patients for glaucoma via IOP measurement has been a controversial topic throughout the last decade. In 2013, the United States Preventative Services Task Force (USPSTF) updated its screening recommendation, citing a systematic review showing insufficient evidence to recommend glaucoma screening of primary care patients with normal vision.[15] In contrast, in 2016, the American Academy of Ophthalmology (AAO) guidelines promoted a comprehensive medical eye evaluation, including IOP measurement by applanation tonometry, every 5 to 10 years for adults under 40 years old with no risk factors. The suggested evaluation frequency increases with age, with screening recommended every 2 to 4 years in patients between 40 and 50 years old, every 1 to 3 years in those between 55 and 64 years old, and every 1 to 2 years in those 65 years of age and older.

The AAO made further recommendations for patients with diabetes mellitus or other risk factors for glaucoma. A yearly examination was recommended for patients with type 1 diabetes, beginning five years after disease onset. The annual examination was also recommended for patients with type 2 diabetes, beginning at diagnosis. Lastly, a biennial examination was recommended for any patient with risk factors for glaucoma, regardless of age. Risk factors for glaucoma include but are not limited to:

• High IOP
• Age over 60 years old
• Black, Hispanic, or Asian ethnicity
• Family history[16]

Familial history of glaucoma is a known risk factor, but most cases are sporadic and likely multifactorial.[17]

Current therapies for lowering IOP include increasing aqueous humor outflow and suppression of aqueous humor production, both of which may be achieved through various medications and surgical techniques.