~Cataracts, Part 2 - Anatomy and Physiology
ANATOMY AND PHYSIOLOGY (STRUCTURE AND FUNCTION)
- The Lens
- Refractive Properties of the Lens
A lens is formed from specialized epithelial cells during embryonic development. The epithelium is a sheet of cube-shaped cells covering the anterior surface of the lens near the cornea. The major part of the lens consists of concentric layers of elongated fiber cells. The outermost shells of fiber cells extend from beneath the epithelium to the posterior lens surface near the vitreous body. The lens is one centimeter from front to back, surrounded by the capsule--an elastic matrix of cells produced during embryonic development by secretions from epithelial and fiber cells on the lens surface.40
In an adult lens, only a few epithelial cells replicate, proliferating slowly, producing new fiber cells that elongate and accumulate crystallins (lens proteins). Crystallins give the lens its refractive power to focus light on the retina.41 During maturation layers of fiber cells build up.42
After the elongation process, a differentiation begins that degrades all intracellular, membrane-bound organelles.43 Mature fiber cells are buried deeper within the lens as generations of fiber cells go this process. The lens increases in size and cell numbers throughout life.44 Because protein synthesis stops with organelle degradation, mature fiber cells are more stable than cells having other functions in the body.45
The lens is suspended by inelastic microfibrils called zonules located above and below the lens in the anterior part of the lens and extending into the lens capsule. Zonules are inelastic compared to other fibrils in the body (e.g., in the skin and arterial walls), but stretch enough to create the tension responsible for altering lens curvature. This is required for focusing on objects at different distances, a process known as accommodation.46
Refractive Properties of the Lens
The refractive properties of the lens result from the high concentration of crystallins in the cytoplasm of lens fiber cells and the curvature of the lens. Lens crystallins are water-soluble proteins in lens fibers that provide a high refractive index. The lens is able to focus light on photoreceptors in the retina.47 In a healthy lens, refractive error is caused by abnormalities in corneal curvature or length of the ocular globe, but rarely from defects in the curvature or refractive index of the lens itself.20
An essential component of lens transparency is a high concentration of lens crystallins and minimization of light scattering and absorption. Light passes through the lens because of the regular structure of lens fibers, an absence of membrane-bound organelles, and small, uniform spaces between the cells. This reduced light scattering is due to short-range interactions among densely packed crystalline molecules.48
Nuclear Cataract Formation
- Nuclear Cataract Formation
- Cortical Cataract Formation
- Posterior Subcapsular Cataract Formation
Cataract formation, especially in nuclear cataracts, is caused by oxidative stress that occurs in all biological systems and particularly the lens. Oxidative stress and generation of free radicals results from normal activity of mitochondria and other metabolic processes.49 Oxidation is controlled by an environment of reducing agents. Reducing agents produced in the mitochondria neutralize free radicals.
Production of reducing agents requires energy output, a challenge for the deeper lens fiber cells that lack mitochondria. The enzyme systems in deeper cells are less active because they were synthesized decades earlier.20 These central lens fiber cells are delicate balanced between being damaged by oxidation of membrane lipids and cytoplasmic protein, and being protected by reducing agents transported from epithelial cells and immature lens fiber cells near the surface. Transport of reducing agents is difficult because there is little space between lens fiber cells. Movement is by diffusion.50
Another challenge is maintenance of protein stability for many decades. Once a lens is formed, proteins are synthesized in outer fiber cells close to the surface. Proteins deeper in the lens generated during embryogenesis have to last a hundred years or more. Accumulated damage to these proteins reduces enzymatic activity and increases protein aggregation, a component of cataract formation.29
Cortical Cataract Formation
Unlike nuclear cataracts, cortical cataracts show disorganization of fiber cell structure. Causes of cortical cataracts include loss of calcium balance, protein breakdown and aggregation, and diminished antioxidant protection (from glutathione). There is evidence for a genetic cause of cataract formation.51 There is no overall explanation why initial damage is restricted to the center of affected cells or why the preferred location of cortical cataracts is the lower half of the lens.52
Posterior Subcapsular Cataract Formation
Posterior subcapsular cataracts are less common and occur with the other two types. A "pure" posterior subcapsular cataract is uncommon, occurring in only 10% of cases.16,53
An important risk factor in posterior subcapsular cataract development (and cortical cataracts) is exposure to excessive X-ray or gamma-radiation.54 Mechanisms that initiate cellular or molecular dysfunction are poorly understood.20
ENDOCRINOLOGY AND BIOCHEMISTRY (REGULATION AND METABOLISM)
- Energy Sources
- Oxidative Damage: Protective Biomechanisms
The lens' oxygen concentration is lower than most parts of the body because it has no direct blood supply.55 The lens depends on glycolytic metabolism to produce much of the adenosine triphosphate (ATP) and reducing agents for metabolism.56
Glycolysis is the process by which sugars (like glucose) are metabolized to produce the energy currency of the body, adenosine triphosphate (ATP). When glycolysis occurs in differentiated lens fiber cells deep within the lens, the absence of oxygen (anaerobic glycolysis) only allows 10% of the energy available to be conserved. The glucose comes from the aqueous humor, the fluid sac between the lens and cornea. Energy from glucose is derived from (aerobic) oxidative pathways in superficial lens fiber cells and epithelial cells containing mitochondria. In animal studies, 50% of the ATP produced by epithelial cells came from oxidative metabolism and glycolysis accounted for almost all ATP produced in most lens fiber cells.56
Oxidative Damage: Protective Biomechanisms
Glutathione. Although the oxygen level within the lens is very low, the lens still derives a substantial proportion of ATP from mitochrondrial (aerobic) oxidative phosphorylation, which creates free radicals as an unwanted by-product. Glutathione provides the most important protection against damage from free radical and other oxidants.57 Glutathione is a very small specialized protein (a tripeptide) consisting of three amino acids: glutamic acid, cysteine, and glycine. Glutathione is concentrated within the lens and is readily oxidized by damaging oxidants. Those oxidants are chemically reduced (neutralized) as glutathione is chemically oxidized in cytoplasm of cells within the lens. When glutathione levels decline in the epithelial cells (or the entire lens), cell damage and cataract formation can occur unabated.58
Lens epithelial cells and superficial lens fiber cells synthesize glutathione. Additional glutathione is transported into the lens from the aqueous humor.59 Oxidized glutathione can be regenerated (i.e., reduced) by the enzyme glutathione reductase that uses the coenzyme called reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is the cofactor derived from the dietary or supplemental B vitamin: niacin or niacinamide, also known as vitamin B3.57 Regeneration of reduced glutathione from oxidized glutathione is especially important because it is the chemically reduced form of glutathione that is effective in neutralizing (chemically reducing) free radicals. Glutathione is unique in its ability to regenerate its chemically reduced state by simply finding an electron donor. This cycle allows one molecule of glutathione to continually act as a free radical scavenger.
Reduced glutathione diffuses into the lens fiber cells, moving toward the lens center, while oxidized glutathione moves toward the lens surface.33 Impediment of diffusion in an older lens is a possible cause of nuclear cataract.33 The rate of diffusion between superficial and deeper layers of the lens decreases with age. Consequently, proteins and lipids in nuclei of older lens are more affected by oxidative stress.
Vitamin C. Ascorbic acid (vitamin C) protects the lens from oxidative damage. In the aqueous humor, ascorbic acid reaches concentrations that are 30 to 50 times the levels in blood. Ascorbic acid is in the lens and surrounding ocular tissues in substantial quantities.60 Dehydroascorbate (the oxidized form of ascorbic acid) can enter the lens through a glucose transporter. It is then reduced by glutathione-dependent processes.61 Ascorbic acid reacts readily with free radicals and other oxidants in the aqueous humor and lens, preventing damage to lens proteins, lipids, and nucleic acids.
No successful anti-cataract drug is available. Research continues on possible anti-cataract agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) such as salicylic acid and ibuprofen. Animal trials have tested the effects of aldose reductase inhibitors. High levels of aldose reductase (an enzyme) are associated with diabetic cataracts. No clinical trials have demonstrated that these substances have any convincing anti-cataract effect.62
Surgical Removal and Intraocular Lens Implantation. The most common treatment is surgical removal of the cataract and replacement with an artificial lens. Widely used surgical procedures are phacoemulsification and extracapsular extraction. In phacoemulsification, a small incision is made in the cornea. A probe vibrating with ultrasound waves is then used to emulsify the cataract and the fragments are removed by suction. The lens capsule is left in place to provide support for a lens implant.63
If a cataract has advanced to an extent that phacoemulsification cannot effectively break up the lens, the preferred alternative is extracapsular extraction, requiring a larger incision so the lens nucleus is removed in one piece through the open lens capsule. The softer lens cortex is vacuumed out, leaving the shell in one piece.63
After the cataract is removed, an artificial lens is implanted into the empty lens capsule. This implant, an intraocular lens (IOL), is made of plastic, acrylic, or silicone. An IOL requires no care and becomes a permanent part of the eye. Early IOLs were rigid plastic and the incision required several sutures. IOLs currently used are flexible, allowing a smaller incision requiring no sutures. Flexible IOLs are folded by a surgeon and inserted into the capsule. Reading glasses will be required after surgery.63
Secondary Cataracts. A common complication of extracapsular cataract extraction is formation of secondary cataracts. Secondary cataracts occur because lens epithelial cells migrate under the IOL to the posterior capsule that has been denuded of cells by surgery. These cells are then abnormally transformed into a mass of fiber-like cells (globular clusters) or fibrotic plaques, which scatter light, degrade visual images, and cause secondary cataract formation.20 Secondary cataracts develop postoperatively in one out of two cases.63
A common, effective method for secondary cataract removal uses a laser procedure called YAG capsulotomy. A YAG (yttrium aluminum garnet) laser delivers tiny, rapid bursts of energy that pass through the front of the eye and the IOL. When the laser beam reaches the posterior capsule, it makes a tiny opening. Light can then pass into the vitreous body and reach the retina. Enough of the posterior capsule is left to hold the IOL in place.63
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