CATARACTS
PATHOPHYSIOLOGY
Nuclear 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
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.
PHARMACOLOGY
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
Conventional Therapy
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
NUTRITIONAL THERAPY
Protection from Free Radical Damage
The benefits of dietary supplements for of cataracts are widely documented.
Free-radical action is directly linked to cataracts and is a major cause
of damage to eyes and cataract formation.64
Numerous studies have documented the effects of supplements, including
their ability to reduce free-radical damage and reverse the damage in
some cases.65,66
Maintaining Glutathione Levels
A healthy eye contains glutathione in very high concentrations, whereas
low levels adversely effect the eye.67
Glutathione maintains the water balance in the lens. It is synthesized
in the lens (and elsewhere) and is essential to normal metabolism. Glutathione
can benefit lens function by:40,57
- Preserving the physicochemical integrity of proteins in the lens33
- Maintaining action of the sodium-potassium transport pump and molecular
integrity of lens fibers (protein)33
- Maintaining molecular integrity of lens fiber membranes and acting
as a free radical scavenger to protect membranes and enzymes from
oxidation66
- Preventing free-radical-induced photochemical generation of harmful
by-products61
- Reactivating oxidized vitamin C, which improves antioxidant capability
in the lens68
A suggested glutathione dose is 500 mg daily.
Vitamin C
Vitamin C (ascorbic acid) is essential for normal ocular metabolism
and occurs in the lens at a concentration 30-50 times higher than blood.
This concentration is second only to the central nervous system and
adrenal cortex. Vitamin C is found in high concentrations in eyes of
animals active during daylight hours; low concentrations are found in
nocturnal animals.69 Prior
to cataract formation, vitamin C concentrations significantly drop.
Vitamin C provides protective benefits for the lens by:70,71
- Protecting the lens from photochemical oxidation72
- Helping increase levels of glutathione57
- Supporting delicate membranes regulating transport of nutrients
and ions (minerals and electrolytes) into the lens60
- Protecting against damaging UV radiation and visible light73
- Protecting against superoxide radical, O2- (known to be extremely
destructive in every cell)74
A suggested dose of vitamin C is 500 mg daily.
Vitamin B2
Vitamin B2 (riboflavin) is a required precursor to the cofactor, reduced
flavin adenine dinucleotide (FADH) used by glutathione reductase, which
in the lens enzymatically reduces, and thereby, activates glutathione;
and makes that glutathione available for the enzyme glutathione-selenium
peroxidase, which chemically reduces peroxide free radicals to harmless
water. Deficiency of glutathione creates a faulty antioxidant defense
system in the lens.75
Light, especially ultraviolet (UV) light, destroys riboflavin and
FADH. Most B vitamins are not stored so they must be replaced daily.
Riboflavin deficiency is a prime cause of photosensitivity making the
eye more sensitive to UV damage. A daily dose of 50 to 150 mg of riboflavin
reduces this photosensitivity.76
Selenium and Vitamin E
Low plasma levels of vitamin E increase the risk of lens opacities.77
Selenium works with alpha-lipoic acid to increase cellular concentrations
of glutathione, which protects the eye lens from free radical damage.74
Taking 400–800 IU daily of vitamin E and 200–400 mcg daily
of selenium is prudent to protect the lens from cataract formation and
maintain overall good health.
Note: See
Appendix for Cautions and Contraindications
Alpha-Lipoic Acid
Supplementation of animals with alpha-lipoic acid prevents cataract
formation resulting from inhibition of glutathione synthesis. Alpha-lipoic
acid reduced cataract formation by 40% and protected the lens from losing
vitamins C, E, and glutathione. Unsupplemented animals lose these nutrients.78
A suggested dose of lipoic acid is 150-300 mg daily.
N-Acetyl-Cysteine and Garlic
A combination of diallyl disulfide (a major organosulfide in garlic
oil) and N-acetyl-cysteine (NAC) completely prevented cataract development
in animals.79 NAC assists
in glutathione production because it is a source of cysteine, one of
the three amino acids in this tripeptide.80
A suggested dose of NAC is 600 mg daily.
Note: See
Appendix for Cautions and Contraindications
Melatonin
Melatonin is an antioxidant that could impede cataract development.
In animals,81 melatonin potently
inhibited cataract formation, due to free-radical scavenging or through
stimulation of glutathione production. Melatonin production slows after
age 40, but by age 60 virtually no melatonin is produced at a time when
most cataracts develop. A suggested dose of melatonin is 500 mcg to
3 mg at bedtime.
Note: See
Appendix for Cautions and Contraindications
Lens Protein Protection
Vitamin B6
Vitamin B6 (pyridoxine) is essential for amino acid and protein metabolism,
absorption of vitamin B12, and proper synthesis of nucleic acids. Its
coenzyme is required for many reactions of amino acids and related metabolic
functions. Vitamin B6 is suggested for nutritional support for cataract
patients.82 A suggested dose
of vitamin B6 is 50-250 mg daily.
Acetyl-L-Carnitine
Acetyl-L-carnitine is an amino acid that maintains cellular metabolism
of fatty acids. During aging, mitochondria (energy-producing organelles
within the cell) begin to deteriorate, resulting in accumulation of
cellular debris and eventual cell death. Acetyl-L-carnitine can diminish
advanced glycation end product (AGE) damage that leads to cataract formation.83
Acetyl-L-carnitine can acetylate (deactivate) potential glycation sites
on crystallins and protect them from glycation-mediated protein damage.84
A suggested dose of acetyl-L-carnitine arginate is 3-4 capsules daily.
Note: See
Appendix for Cautions and Contraindications
Aminoguanidine
Aminoguanidine inhibits advanced glycation end products (AGEs) and
may treat diabetic cataracts. In moderately and severely diabetic rats,
aminoguanidine inhibited cataracts only in moderately diabetic rats.85
It is importance to maintain control over blood sugar levels, so that
antiglycating agents such as aminoguanidine can protect against cataract.
A suggested dose of aminoguanidine is 300 mg daily.
Note: Although
aminoguanidine has been safely used throughout the world for decades,
clinical experience is limited in the United States. Aminoguanidine
has not been approved by the U.S. Food and Drug Administration. Aminoguanidine
should be taken under the supervision of a physician. It can inhibit
vitamin B6 uptake so co-administration of B6 is suggested.
Note: The
Alteon Corporation (USA) has aminoguanidine (Pimagidine®) in stage
III trials for diabetes.
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