Part 5  The Lens

  

Basic Science of the Lens

Michael E. Boulton 5.1 
This structure is continuously synthesized, anteriorly by the lens epithe-
Definition:  A normally transparent intraocular structure whose lium and posteriorly by the fiber cells.
function is to alter the pathway of light that has entered the eye to focus
the image on the retina.
Epithelial Cells
The lens epithelium is a single layer of cuboidal cells approximately 10 µm
Key Features high and 15 µm wide beneath the anterior capsule that extends to the
equatorial lens bow. Their basal surface adheres to the capsule, whereas
• The lens comprises three parts: (1) the capsule, (2) the lens their anterior surface abuts the newly formed elongating lens cytoplasm
epithelium, and (3) the lens fibers.
(“fibers”). Lens epithelial cells have a large array of organelles and contain
• α-, β- and γ-crystallins constitute 90% of the total protein content of dense bodies and glycogen particles. Lateral attachment to adjacent cells
the lens.
occurs through both desmosomes and tight junctions.3,8–10
• Lens function is dependent on the metabolism of glucose to produce Lens epithelial cells contain three cytoskeletal elements: microfilaments
energy, protein synthesis, and a complex antioxidant system.
(actin), intermediate filaments (vimentin), and microtubules (tubulin).
• Lens transparency is dependent on the highly organized structure These elements form a network that provides structural support, control of
of the lens, the dense packing of crystallin, and the supply of
cell shape and volume, intracellular compartmentalization and movement
appropriate nutrients.
of organelles, cell movement, distribution of mechanical stress, and medi-
• The lens can change its focusing power through a process called ation of chromosome movement during cell division.
accommodation.
• The lens exhibits age-related changes in structure, light transmission,
metabolic capacity, and enzyme activity.
• Secondary cataract occurs when residual lens cells after cataract GROSS ANATOMY OF THE ADULT HUMAN LENS
extraction cause opacification of the visual axis.
proliferative capacity
increases
anterior
INTRODUCTION
pregerminative epithelial central pregerminative
The lens is a vital refractive element of the human eye. The World Health zone cells zone cortex zone
Organization estimates that lens pathology (cataract) is the most common germinative germinative
cause of blindness worldwide, affecting over 17 million people.1 Not sur- zone zone
prisingly, cataract surgery is the most common procedure performed in
the developed world.2 An understanding of the basic science of the lens
equator equator
provides valuable insight into the various pathologies involving the lens
and their treatment.

transitional transitional
ANATOMY OF THE LENS zone zone
The adult human lens is an asymmetric oblate spheroid that does not
possess nerves, blood vessels, or connective tissue.3 The lens is located embryonic nucleus capsule bow
behind the iris and pupil in the anterior compartment of the eye. The fetal nucleus posterior
anterior surface is in contact with the aqueous; the posterior surface is infantile nucleus
in contact with the vitreous. The anterior pole of the lens and the front adult nucleus
of the cornea are separated by approximately 3.5 mm.4 The lens is held
in place by the zonular fibers (suspensory ligaments), which run between
Fig. 5.1.1  Gross Anatomy of the Adult Human Lens. Note the different regions are
the lens and the ciliary body. These fibers, which originate in the region
not drawn to scale.
of the ciliary epithelium, are fibrillin rich and converge in a circular zone
on the lens. Both an anterior and a posterior sheet meet the capsule
Fig. 5.1.2  Changes
1–2 mm from the equator and are embedded into the outer part of the THICKNESS OF THE LENS CAPSULE in Thickness of
capsule (1–2 µm deep). It also is thought that a series of fibers meets the the Adult Lens
capsule at the equator.5,6 anterior pole Capsule With
Histologically the lens consists of three major components—capsule, 14m Location.
epithelium, and lens substance (Fig. 5.1.1). 21m 21m

Capsule 17m 17m

The lens is ensheathed by an elastic envelope composed of epithelial cells
and fibers that allows the passage of molecules both into and out of the
23m 23m
lens. Capsule thickness varies by location (Fig. 5.1.2) and, except for the
posterior capsule, increases with age.4–6 The capsule is composed of a
number of lamellae stacked on top of each other that are narrowest near 4m
the outside of the capsule and widest near the cell mass.7 Major structural posterior pole e1
proteins and a small amount of fibronectin are found within the lamellae.8

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 Epithelial cell density is greatest in the central zone, where cells nor-

5 mally do not proliferate. These cells are the largest epithelial cells found
in the lens. The proliferative capacity of epithelial cells is greatest at the
equator (see Fig. 5.1.1). Cells here are dividing constantly, with newly
LENS WEIGHT AND CELL NUMBERS WITH AGE

formed cells being forced into the transitional zone where they elongate
The Lens

and differentiate to form the fiber mass of the lens.3,11 weight 250
(mg) c. 761,184 epithelial cells
c. 3,045,100 fibers
Lens Substance
200 c. 1,009,312 epithelial cells
The lens substance, the bulk of the lens, is composed of densely packed c. 3,546,100 fibers
lens cells with very little extracellular space. The adult lens substance con-
sists of the nucleus and the cortex, which are often histologically indistinct.
150
Although the size of these two regions is age dependent, a study of lenses
with an average age of 61 years indicated that the nucleus accounted for
approximately 84% of the diameter and thickness of the lens and the cortex
for the remaining 16%.12 The nucleus is subdivided into embryonic, fetal, 100
infantile, and adult nuclei (see Fig. 5.1.1). The embryonic nucleus contains
the original primary lens fiber cells that are formed in the lens vesicle.
birth
The rest of the nuclei are composed of secondary fibers, which are added 50 c. 402,595 epithelial cells
concentrically at the different stages of growth by encircling the previously c. 1,662,010 fibers
formed nucleus. The cortex, which is located peripherally, is composed of
all the secondary fibers formed after sexual maturation.
0
Fibers are formed constantly throughout life by the elongation of lens 0 20 40 60 80
epithelial cells at the equator. Initially, transitional columnar cells are
age (years)
formed, but once long enough, the anterior end moves forward beneath
the anterior epithelial cell layer and the posterior end is pushed back-
ward along the posterior capsule. The ends of this U-shaped fiber run
Fig. 5.1.3  Increase in Lens Weight and Cell Numbers With Age. Note the
toward the poles of both capsular surfaces.3–6 Once fully matured, the fiber
correlation between these two parameters. (Lens weight data from Phelps Brown N,
detaches from the anterior epithelium and the posterior capsule. Each new Bron AJ. Lens growth. In: Phelps Brown N, Bron AJ, Phelps Brown NA, editors. Lens
layer of secondary fibers formed at the periphery of the lens constitutes a disorders. A clinical manual of cataract diagnosis. Oxford: Butterworth-Heinemann;
new growth shell. Lens fibers are bound by the interlocking of the lateral 1996. p. 17–31. Cell number data from Kuszak JR, Brown HG. Embryology and
plasma membranes of adjacent fibers. Both desmosomes and tight junc- anatomy of the lens. In: Albert DM, Jakobiec FA, editors. Principles and practices of
tions are absent from mature lens fibers, although desmosomes are found ophthalmology. Basic sciences. Philadelphia: WB Saunders; 1994. p. 82–96.)
between elongating fibers.3,8,9

Sutures with age.16 The radius of curvature of the anterior surface decreases from
Sutures are found at both the anterior and the posterior poles. They are 16 mm at the age of 10 years to 8 mm by the age of 80 years. There is
formed by the overlap of ends of secondary fibers in each growth shell. No very little change in the radius of curvature of the posterior surface, which
sutures are found between the primary fibers in the embryonic nucleus. remains at approximately 8 mm.
Each growth shell of secondary fibers formed before birth has an anterior
suture shaped as an “erect Y” and a posterior suture shaped as an inverted
Y. The formation of sutures enables the shape of the lens to change from
PHYSIOLOGY OF THE LENS
spherical to a flattened biconvex sphere.3,9,13 Permeability, Diffusion, and Transport
After involution of the hyaloid blood supply to the lens, its metabolic needs
Growth are met by the aqueous and vitreous humor. The capsule is freely perme-
The lens continuously grows throughout life but at a reduced rate with able to water, ions, other small molecules, and proteins with a molecular
increased age.7 The number of both epithelial cells and fibers increases weight of up to 70 kDa. Epithelial cells and fibers possess a number of
by approximately 45%–50% during the first two decades of life (Fig. 5.1.3). channels, pumps, and transporters that enable transepithelial movement
After this, the increase in cell numbers is reduced, with the proportional to and from the extracellular milieu.
increase in fibers being very small.3 During an average lifespan, the surface
area of the lens capsule increases from 80 mm2 at birth to 180 mm2 by the Transport of Ions
seventh decade.5,7 Fiber cells contain large concentrations of negatively charged crystallins.
As a result, positively charged cations enter the lens cell to maintain electri-
Mass cal neutrality, and the osmolarity of the intracellular fluid becomes greater
than that of the extracellular fluid. Fluid flow and swelling are minimized
The weight of the lens increases rapidly from 65 mg at birth to 125 mg by the resting potential of the plasma membrane being set at a negative
by the end of the first year. It then increases at approximately 2.8 mg/ voltage through potassium (K+)-selective channels.
year until the end of the first decade, reaching 150 mg. Thereafter, the rate The Na+ ions that leak into the cells are exchanged actively for K+ ions,
slows to reach a weight of 260 mg by the age of 90 (see Fig. 5.1.3).14 The which diffuse through the lens down their concentration gradient and
average male lens weighs more than that of an age-matched female, with a leave through ion channels in both the epithelial cells and surface fibers.
mean difference of 7.9 ± 2.47 mg.15 There is a net movement of Na+ ions from posterior to anterior and of K+
ions from anterior to posterior.17
Although a pH gradient exists, which increases from the central nucleus
Dimensions to the periphery, the intracellular pH of the lens is approximately 7.0. Lens
The equatorial diameter of the human lens increases throughout life, cells need to continually extrude intracellular protons, which accumulate
slowing after the second decade. The diameter grows from approximately due to inward movement of positive ions from the extracellular space and
5 mm at birth to 9–10 mm in a 20-year-old. The thickness of the lens also lactic acid from anaerobic glycolysis. The pH is regulated by mechanisms
increases but at a much slower rate. The distance from the anterior to capable of increasing and decreasing intracellular acid levels. Molecules,
the posterior poles grows from 3.5–4 mm at birth, to 4.75–5 mm (unac- especially proteins, also act as buffers.
commodated).4,14 The thickness of the nucleus decreases with age due to
compaction, whereas cortical thickness increases as more fibers are added Amino Acid and Sugar Transport
e2 at the periphery. Because the increase in cortical thickness is greater than The majority of amino acids and glucose enter the lens from the aqueous
the decrease in size of the nucleus, the polar axis of the lens increases across its anterior surface. In addition, the lens can convert keto acids

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 TRANSMITTANCE OF THE LENS PRINCIPAL ABERRATIONS OF THE LENS
5.1
Spherical aberration
transmittance 100

Basic Science of the Lens

(%)

80
lens transmittance:
total, 4½ years
60 direct, 4½ years
direct, 53 years
direct, 75 years
40

20

0
300 400 500 600 800 1000 1200 1600 2000
wavelength (nm)

Fig. 5.1.4  Changes in Transmission (UV and Visible) of the Normal Aging Chromatic aberration
Human Lens. (From Boettner EA, Wolter JR. Transmission of the ocular media. Invest
Ophthalmol Vis Sci 1962;1:776–83.)

into amino acids. The lens acts as a pump–leak system: Amino acids are
“pumped” into the lens through the anterior capsule and passively “leak”
out through the posterior capsule.

BIOPHYSICS
Light Transmission
The lens acts as a spectral filter absorbing long ultraviolet B (UV-B,
300–315 nm) and most of the UV-A (315–400 nm) wavelengths. While
there is a transmission band centered around 320 nm of about 8% in
children under 10 years, it is reduced to 0.1% by age 22. By age 60, no
UV radiation transmits across the lens. The total transmittance of the
young lens begins increasing rapidly at about 310 nm and reaches 90%
at 450 nm, compared with the older lens, which begins transmitting at Fig. 5.1.5  Principal Aberrations of the Lens.
400 nm but does not reach 90% total transmittance until 540 nm (Fig.
5.1.4). The overall transmission of visible light decreases with increasing
age, a feature that arises largely from age-related changes and brunescence rates of transmission through the lens and some deviation. As a conse-
in the lens (see Fig. 5.1.4).18,19 quence, yellow light (570–595 nm) is normally focused on the retina;
light of shorter wavelengths, for example blue (440–500 nm), falls in front
because of its slower transmission and increased refraction compared with
Transparency yellow light. Light of longer wavelengths, for example red (620–770 nm),
The lens is opaque during the early stages of embryonic development. As falls behind because of the faster transmission and less refraction (Fig.
development continues and the hyaloid vascular supply is lost, the lens 5.1.5). Because the amount of dispersion between the red and the blue
becomes transparent. Transparency is due to the absence of chromophores images is approximately 1.50–2.00 diopters (D), very little reduction occurs
able to absorb visible light and the presence of a uniform structure that in the clarity of the image that is formed. As the lens accommodates,
scatters light minimally (less than 5% in the normal human lens). Light refraction increases as a result of the increasing power of the lens and,
scatter is minimized in fiber cells once the fibers have elongated and their therefore, the amount of chromatic aberration also increases.20,22–24
organelles have degenerated. Although the epithelial cells contain large
organelles that scatter light, the combined refractive index of this layer and Spherical Aberration
the capsule is no different from the refractive index of the aqueous, so
light scatter is very small. The lens of the human eye is designed to minimize spherical aberration
since: (1) refractive index increases from the periphery to the center of the
Refractive Indices lens; (2) curvature of both the anterior and the posterior capsule increases
towards the poles; and (3) curvature of the anterior capsule is greater than
The refractive index increases from 1.386 in the peripheral cortex to 1.41 in that of its posterior counterpart.
the central nucleus of the lens. Because both the curvature and refractive As a result of these structural features, the focal points of the peripheral
index of the lens increase from the periphery toward the center, each suc- and central rays are similar, which ensures that reduction in the quality of
cessive layer of fibers has more refractive power and therefore can bend the image is minimal (see Fig. 5.1.5). The pupil diameter also affects the
light rays to a greater extent.20 The anterior capsular surface of the lens has amount of spherical aberration, because light rays do not pass through the
a greater refractive index than the posterior capsular surface (1.364–1.381 periphery of the lens (unless the pupil is dilated). The optimal size of the
compared with 1.338–1.357). The increase in refractive index from the pupil needed to minimize this imperfection is 2–2.5 mm.20,22–24
surface to the center results from changes in protein concentration; the
higher the concentration, the greater the refractive power. This increase Accommodation
must occur as a result of both packing and hydration properties, because
protein synthesis in the nucleus is minimal.18,21 The lens is able to change its shape and thus the focusing power of the
eye. This process is known as accommodation, and it enables both distant
Chromatic Aberration and close objects to be brought into focus on the retina. At rest, the ciliary
muscle is relaxed and the zonules pull on the lens keeping the capsule
When visible light passes through the lens, it is split into all the colors of under tension and the lens flattened. Light rays from close objects are e3
the spectrum. The different wavelengths of these colors result in different divergent and are focused behind the retina in this configuration. The lens

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 Fig. 5.1.6  Change in Form of the Lens

5 on Accommodation in a Person of Age

29 Years. (A) Relaxed. (B) Accommodated.
(Grid squares 0.4 mm.) Note the change
in curvature of the anterior surface. (From
The Lens

Phelps Brown N, Bron AJ. Accommodation

and presbyopia. In: Phelps Brown N,
Bron AJ, Phelps Brown NA, editors.
Lens disorders. A clinical manual of
cataract diagnosis. Oxford: Butterworth-
Heinemann; 1996. p. 48–52.)

A B

accommodates these objects by contraction of the ciliary muscles, relax- reduced form of flavin adenine dinucleotide (FADH2). These donate their
ing the zonules, thus increasing the curvature of the anterior surface and electrons to oxygen, which releases large amounts of free energy that is
decreasing the radius of curvature from 10 mm to 6 mm. The increase subsequently used to generate ATP. This cycle, which is restricted to the
in curvature of the anterior surface increases the refractive power, so epithelial layer, also provides carbon skeleton intermediates for biosynthe-
that the light rays from close objects are refracted toward each other to a sis, such as amino acids and porphyrins.27,29
greater extent and, therefore, converge on the fovea. Because the front of The bulk of the pyruvate produced by the glycolytic pathway is reduced
the lens has moved forward, the depth of the anterior chamber decreases to lactate by lactate dehydrogenase (see Fig. 5.1.7), which is concentrated
from 3.5 mm to 3.2–3.3 mm. Very little change occurs in the curvature of in the cortex. The formation of lactate results in the reoxidation of NADH
the posterior capsule, which remains at approximately 6 mm (Fig. 5.1.6). to NAD+. Glyceraldehyde-3-phosphate dehydrogenase regulates the activ-
Accommodation is accompanied by a decrease in pupil size and conver- ity of lactate dehydrogenase by controlling the rate of conversion of
gence of the two eyes. glyceraldehyde-3-phosphate into 1,3-diphosphoglycerate and, therefore, the
Accommodation can be divided into both physical and physiological availability of NADH.27–29
processes. Physical accommodation, a measure of the change in shape of The 5%–10% of glucose that is not phosphorylated into G6P either
the lens, is measured in terms of the amplitude of accommodation using enters the sorbitol pathway or is converted into gluconic acid (see Fig.
the unit diopter. It represents a measure of the extent to which objects 5.1.7). Glucose is converted into sorbitol by aldose reductase, an enzyme
close to the eye can be brought into focus. Physiological accommodation, localized to the epithelial layer. Sorbitol is converted by polyol dehydroge-
a measure of the force of ciliary muscle contraction per diopter, is mea- nase into fructose, a less optimal substrate for glycolysis. Both sorbitol and
sured with the unit myodiopter. The myodiopter increases during the act fructose have the potential to increase osmotic pressure and may help to
of accommodation.25,26 regulate the volume of the lens.27–29

BIOCHEMISTRY Protein Metabolism

The lens requires energy to drive thermodynamically unfavorable reac- The protein concentration within the lens is the highest in the body.
tions. Adenosine triphosphate (ATP) is the principal source of this energy, The majority of ongoing synthesis creates crystallins and major intrinsic
the majority of which comes from the anaerobic metabolism of glucose. protein 26 (MIP26). It is thought that this occurs in the epithelial cells and
Nicotinamide adenine dinucleotide phosphate (NADPH), which is pro- cortical fibers, which contain the organelles needed.30
duced principally via the pentose phosphate pathway, is used as a reducing Lens proteins remain stable for long periods because the majority of
agent in the biosynthesis of many essential cellular components, such as the degradative enzymes normally are inhibited. This is coordinated by
fatty acids and glutathione. marking those to be degraded with a small 8.5 kDa protein called ubiqui-
tin. This system, which is ATP dependent, is most active in the epithelial
Sugar Metabolism layer. Lens proteins are broken down into peptides by endopeptidases and
then into amino acids by exopeptidases. Neutral endopeptidase is activated
Approximately 90%–95% of the glucose that enters the normal lens is by both calcium and magnesium and is optimal at pH 7.5 (the pH of the
phosphorylated into glucose-6-phosphate (G6P) in a reaction catalyzed by lens is approximately 7.0–7.2). The principal substrate of this enzyme is
hexokinase. Although this enzyme exists as three different isoforms, only α-crystallin. The calpains (I and II) are localized mainly in the epithelial
types I and II have been found in the lens. Type I has a greater affinity for cells and cortex and function to degrade crystallins and cytoskeletal pro-
glucose and is concentrated in the nucleus, where glucose levels are low. teins. They are cysteine endopeptidases, the activities of which are regu-
Type II, which accounts for 70% of the hexokinase, has a lower affinity for lated by calcium. These enzymes are inhibited by calpastatin, a natural
glucose and is found predominantly in the epithelium and cortex, where inhibitor found at higher concentrations than the calpains. The lens also
glucose levels are higher. G6P is used either in the glycolytic pathway (80% contains a serine proteinase and a membrane-bound proteinase.28,29,31 The
of total glucose) or in the pentose phosphate pathway (hexose monophos- main exopeptidase is leucine aminopeptidase, an enzyme optimal at pH
phate shunt; 10% of total glucose) (Fig. 5.1.7). Hexokinase is saturated by 8.5–9.0, which catalyzes the removal of amino acids from the N-terminal
physiological concentrations of glucose found in the lens and limits the of peptides. Aminopeptidase III has an optimal pH of 6.0 and as a
rate of both glycolysis and the pentose phosphate pathway. Glycolysis also result has a greater activity than leucine aminopeptidase in the normal
is regulated by phosphofructokinase and pyruvate kinase.27,28 lens.28,29,31
The lens lacks vascularity and thus exists in a hypoxic environment,
which results in at least 70% of lens ATP being derived from anaerobic Glutathione
glycolysis. Approximately 3% of lens glucose passes into the more efficient
tricarboxylic acid cycle (see Fig. 5.1.7), generating 25% of lens ATP. Glycol- Glutathione is found at high concentrations in the lens (3.5–5.5 mmol/g
e4 ysis and the tricarboxylic acid cycle generate two energy-rich molecules; wet weight), especially in the epithelial layer. Glutathione has many import-
the reduced form of nicotinamide adenine dinucleotide (NADH) and the ant roles in the lens, including28,29,32:

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 Fig. 5.1.7  Overview of the Major
MAJOR PATHWAYS OF GLUCOSE METABOLISM IN THE LENS Pathways of Glucose Metabolism in the
Lens. Percentages represent the estimated 5.1
amount of glucose used in the different
pathways.

Basic Science of the Lens

5% 5%
Sorbitol Glucose Gluconic acid
Aldose reductase

Polyol dehydrogenase Sorbitol

Hexokinase 90%
pathway

10%
Fructose Glucose-6-phosphate 6-phosphogluconate
Pentose phosphate
Phospho- pathway
Glycolysis Ribulose-5-phosphate
fructokinase
80%

Glyceraldehyde-3-phosphate

Glycercaldehyde-
C6
3-phosphate
dehydrogenase
Tricarboxylic
Pyruvate kinase C4 acid cycle C5
Lactate
dehydrogenase 3%
Lactate Pyruvate Acetyl CoA
C4

• Maintaining protein thiols in the reduced state, which helps to main- ROS have the capacity to damage the lens in many ways29,35:
tain lens transparency by preventing the formation of high molecular
weight crystallin aggregates.
• Peroxidizing membrane lipids results in the formation of aldehydes,
which in turn can form cross-links between membrane lipids and
• Protection of thiol groups involved in cation transport and permeability; proteins.
for example, oxidation of the -SH groups of the Na+,K+-ATPase pump,
which results in an increased permeability to these ions.
• Introducing damage into the bases of the DNA (e.g., base modifica-
tions) and reducing DNA repair efficiency.
• Protection against oxidative damage (see later in this chapter). • Polymerizing and crosslinking proteins result in crystallin aggregation
• Removal of xenobiotics; glutathione-S-transferase catalyzes the conju- and inactivation of many essential enzymes, including those with an
gation of glutathione to hydrophobic compounds with an electrophilic
antioxidant role (e.g., catalase and glutathione reductase).
center.
Protection against damage induced by ROS is achieved in a number
Amino Acid Transport of ways. The superoxide anion undergoes dismutation by superoxide dis-
Glutathione has a half-life of 1–2 days and is recycled constantly by the mutase or by interaction with ascorbate (see below), which results in the
γ-glutamyl cycle; its synthesis and degradation occur at approximately formation of H2O2. This, along with the high levels of exogenous H2O2, is
the same rate (Fig. 5.1.8). Glutathione is synthesized from L-glutamate, detoxified by the enzyme catalase or glutathione peroxidase or both (Fig.
L-cysteine, and glycine in a two-step process that uses 11%–12% of lens 5.1.9).36 Catalase is present in epithelial cells at higher levels than in fibers.
ATP.28,29,32 Reduced glutathione also can be taken into the lens from the Glutathione peroxidase, however, is found in significant amounts in both
aqueous. A reduced glutathione transporter that allows the uptake of glu- epithelial cells and fibers. The glutathione system is thought to provide
tathione by the lens epithelium has been characterized.33 The breakdown the most protection against H2O2, but it also protects against the lipid-free
of glutathione releases its amino acids, which are recycled. radical chain reaction by the neutralization of lipid peroxides.29,32,34,35
Ascorbic acid (vitamin C) plays a major role in the antioxidant system,
Antioxidant Mechanisms although this may be species dependent, because the human lens is rich
in ascorbate (1.9 mg/kg wet weight or 1.1 mmol/kg). Ascorbate is present
The term reactive oxygen species (ROS) refers to highly reactive oxygen at high levels in the outer layers of the lens but virtually absent from
radicals that have the potential to damage lipids, proteins, carbohydrates, the nucleus. It reacts rapidly with superoxide anions, peroxide radicals,
and nucleic acids. These include the superoxide anion, the hydroxyl free and hydroxyl radicals to give dehydroascorbate. It also scavenges singlet
radical, hydroperoxyl radicals, lipid peroxyl radicals, singlet oxygen, and oxygen, reduces thiol radicals, and is important in the prevention of lipid
hydrogen peroxide (H2O2). ROS generally arise from cell metabolism or peroxidation. The ascorbic acid and glutathione systems are coupled, as
photochemical reactions. Photochemical damage occurs when light is dehydroascorbate reacts with the reduced form of glutathione to generate
absorbed by a photosensitizer that, upon photoexcitation, forms a tran- ascorbate and GSSG (oxidized glutathione).31,34,37,38
sient excited triplet state that is long lived, allowing for interaction with This system, however, is not 100% efficient, and a low level of cumula-
other molecules producing free radicals or singlet oxygen. The continu- tive damage occurs throughout life.
ous entry of optical radiation into the lens, in particular the absorption
of shorter wavelengths (295–400 nm), makes lens tissue particularly sus-
ceptible to photochemical reactions. The major ultraviolet (UV) absorb-
LENS CRYSTALLINS
ers in the lens are free or bound aromatic amino acids (e.g., tryptophan), Crystallin Structure
numerous pigments (e.g., 3-hydroxykynurenine), and fluorophores. Reac-
tive oxygen species also can enter the lens from the surrounding milieu Up to 60% of the wet weight of the human lens is composed of proteins.
(e.g., H2O2 is present at high levels in the aqueous humor, 30 mmol/L These lens proteins can be subdivided into water-soluble (cytoplasmic pro- e5
in humans).29,34 teins) and water-insoluble (cytoskeletal and plasma membrane) fractions.

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 Fig. 5.1.8  The γ-Glutamyl Cycle. (From

5 Enzymes
THE -GLUTAMYL CYCLE Harding JJ, Crabbe MJC. The lens:
development, proteins, metabolism and
cataract. In: Davson H, editor. The eye.
3rd ed. London: Academic Press; 1984. p.
The Lens

1. Membrane-bound Amino acid 207–492.)

-glutamyltransferase
2. -glutamylcyclotransferase
-Glutamyl
3. 5-oxoprolinase 5-Oxoproline ATP
amino acid
4. -glutamylcysteine 2
3
synthetase
5. Glutathione synthetase ADP + Pi
6. Dipeptidase 6
Cysteinylglycine Glutamate

Amino 1 ATP
Glycine Cysteine
acid
4
Glutathione ADP + Pi

5
-Glutamyl
cysteine

extracellular intracellular ADP + Pi ATP

Fig. 5.1.9  Coupling of the Ascorbic Acid

COUPLING OF THE ASCORBIC ACID AND GLUTATHIONE SYSTEMS and Glutathione Systems.

– +
2O2 + 2H Ascorbate GSSG NAD(P)H2

Nonenzymatic Glutathione reductase

H2O2 + O2 Dehydroascorbate GSH NAD(P)

Catalase Glutathione peroxidase

H2O + 1/2O2 2H2O + GSSG

The water-soluble crystallins constitute approximately 90% of the total is maintained, with the result that the α-crystallins are found in both lens
protein content of the lens.39,40 epithelial cells and fibers, whereas the β- and γ-crystallins are found only
The crystallins found in all vertebrate species can be divided into the in the lens fibers. α-Crystallin synthesis is far greater in the lens epithe-
α-crystallin family and the β/γ-crystallin superfamily. The properties of lium than in the fibers. The α-crystallins are found in both dividing and
these crystallins are summarized in Table 5.1.1. The α-crystallins are the nondividing lens cells, whereas the β- and γ-crystallins are found only in
largest. nondividing lens cells. Differentiation of a lens epithelial cell into a fiber,
The β-crystallins are composed of light (βL) (c. 52 kDa) and heavy (βH) therefore, may be one of the factors that triggers a decrease in transla-
(150–210 kDa) fractions. The light fraction can be further subdivided into tion of the α-crystallin gene and stimulates the synthesis of the β- and
two fractions, βL1 and βL2.39–43 γ-crystallins.45
The smallest of the crystallins are the γ-crystallins. Six members of this
family, known as γA–γF, have a molecular weight of 20 kDa. Crystallin Function
The high concentration of crystallins and the gradient of refractive index are
Crystallin Gene Expression During Lens Growth responsible for the refractive properties of the lens. The short-range order
The α-, β-, and γ-crystallins are synthesized in the human lens during of these proteins ensures that the lens remains transparent. α-Crystallins
gestation, and the absolute quantities of these crystallin families increases may be involved in the assembly and disassembly of the lens cytoskeleton.
during development. The first crystallin to be synthesized is α-crystallin, Similarities in structure between the small heat shock proteins (sHSPs)
which is found in all lens cells. The β- and γ-crystallins are first detected and αβ-crystallin suggest that this crystallin family may provide the lens
e6 in the elongated cells that emerge from the posterior capsule to fill the with stress-resistant properties.40,41,46 α-Crystallins have chaperone-like
center of the lens vesicle.44 Throughout life the same pattern of synthesis functions that enable them to prevent the heat-denatured proteins from

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 ant
TABLE 5.1.1  Properties of Different Crystallins
α β γ γs
5.1
Subunits αA, αAI, αB, αB1, Basic: βB1, βB2, γA–γF γs

Basic Science of the Lens

up to nine βB3
minor subunits Acidic: βA1, βA2,
βA3, βA4
Subunit 20 kDa Basic: 26–32 kDa 20 kDa 24 kDa
molecular Acidic:
weight 23–25 kDa
Native molecular 600–900 kDa βH: 150–200 kDa 20 kDa 24 kDa
weight βL: c. 50 kDa
eq
Number of 30–45 βH: 0–8 1 1
subunits βL: 2
Thiol content Low High High High
N-Terminal Masked Masked Glycine or Masked nu
amino acid alanine
Secondary Predominantly β-pleated sheet β-pleated β-pleated
structure β-pleated sheet sheet sheet
Three- Unknown Two domains Two domains Two domains
dimensional with four with four with four
structure “Greek key” “Greek key” “Greek key”
motifs motifs motifs Fig. 5.1.10  Scanning Electron Micrograph of Equatorial Region of Cortical Fiber
Chromosome αA: 21 βB1–βB4: 22 2 3 Plasma Membranes. Note the circular shade with the fracture of fibers in the deep
αB: 11 βA1/βA3: 17 equatorial cortex (eq) (arrows) and folding fibers in the anterior deep cortex (ant)
βA2: 2 (arrowheads). (nu, lens nucleus). (From Vrensen GFJM. Aging of the human eye lens –
a morphological point of view. Comp Biochem Physiol A Physiol 1995;111:519–32.)

becoming insoluble and facilitate the renaturation of proteins that have Furthermore, the changes in structure of the plasma membrane and the
been denatured chemically.47 They also act as chaperones under conditions degradation of cytoskeletal components may contribute to the increase in
of oxidative stress and therefore may help to maintain lens transparency.48 the number of furrowed membranes and microvilli found on the fiber
Although the function of the β-crystallins is unknown, their structural surface.49 From the fourth decade onward, ruptures are found in the equa-
similarities with the osmotic stress proteins suggest that they also may torial region of cortical fiber plasma membranes (Fig. 5.1.10). Reparation of
act as stress proteins in the lens.46 The γ-crystallins (with the exception these ruptures often prevents the formation of opacities. Any opacities that
of γs-crystallin) are found in the regions of low water content and high do develop become surrounded by deviated membranes and are therefore
protein concentration, such as the lens nucleus. The presence of this isolated from the remainder of the lens.
family of crystallins correlates with the hardness of the lens. Concentra- The lens capsule thickens throughout life. It also increases in surface
tions are higher in those lenses that do not change shape during accom- area as a result of the growth of the lens. Ultrastructural changes include
modation, as in fish, than in those that do, as in the human.40 the loss of laminations and an increase in the number of linear densities.
Although the young lens capsule is known to contain collagen type IV and
the aged capsule collagen types I, III, and IV, the presence of types I and
AGE CHANGES III collagen in the young capsule has yet to be confirmed, but their synthe-
Morphology sis may be age related.53

Continued increases in both the mass and dimensions of the lens are
greatest during the first two decades of life. This results from the prolifer-
Physiological Changes
ation of lens epithelial cells and their differentiation into lens fibers. The Changes to the cellular junctions and alterations in cation permeability
oldest epithelial cells are found in the middle of the central zone under occur with age. The major gap junction protein MIP26 loses some of
the anterior pole. Because cells are added to the periphery of this zone its amino acids to form new variants, which include polypeptides with
throughout life, the age of the cells decreases from the pole toward the molecular weights of 15, 20, and 22 kDa.51,52 The membrane potential of
outer units of this region, so that the newest cells always are found near an isolated, perfused human lens may be −50 mV at the age of 20 years,
the pregerminative zone. Because newly formed fibers are internalized as but only −20 mV at the age of 80 years. Potassium (K+) levels remain con-
more are added at the periphery of the lens, the oldest fibers are found in stant at approximately 150 mmol/L, but the sodium (Na+) content of the
the center of the nucleus and the newest fibers in the outer cortex. Each lens increases from 25 mmol/L at the age of 20 years to 40 mmol/L by
growth shell, therefore, represents a layer of fibers that are younger than the age of 70 years. Thus, the Na+:K+ permeability ratio increases approx-
those in the shell immediately preceding it.49 imately sixfold, which results in a proportionately greater increase in the
As the lens ages, epithelial cells become flatter, flatten their nuclei, sodium content of the lens.54 The change in the ratio of these two ions
develop end-organ failure bodies and vacuoles, and exhibit a dramatic correlates with the increase in optical density of the lens.55 The change
increase in the density of their surface projections and cytoskeletal com- in ion permeability with increasing fiber age is thought to occur due to
ponents. The basal surface area of the cell increases; thus the number of a decrease in membrane fluidity as a result of the age-related increase in
cells needed to cover a region of the growing anterior capsule is less than the cholesterol-to-phospholipid ratio. The lens, therefore, becomes more
that needed to cover a region of the same size in a younger lens. This, in dependent on the Na+,K+-ATPase in the epithelial cells. The decrease in
combination with the decrease in proliferative capacity, means that epithe- membrane potential also results from changes in the free Ca2+ levels,
lial cell density decreases as the lens ages.49,50 which increase from 10 mmol/L at the age of 20 years to approximately
Lens fibers show partial degradation or a total loss of a number of 15 mmol/L by the age of 60 years. It is thought that the Ca2+-ATPase may
plasma membrane and cytoskeletal proteins with age. The most significant be inhibited by the decrease in membrane fluidity, which decreases the
degradation is that of MIP26. Early in life spectrin, vimentin, and actin are rate at which Ca2+ is pumped out of the cell. It also is possible that the
present in both the outer cortical fibers and the epithelial layer, but they increase in Na+ and Ca2+ permeability may result from the increased activ-
are degraded as the fibers age and are further internalized. By 80 years of ity of nonspecific cation channels.54
age, expression of these cytoskeletal proteins is restricted to the epithelial
cells. The cholesterol-to-phospholipid ratio of fiber cell plasma membranes Biophysical Changes
increases throughout life, and consequently membrane fluidity decreases
and structural order increases. These changes, which are known to occur The absorption of both UV and visible light by the lens increases with age.
from the second decade, are greatest in the nucleus and are therefore Free and bound aromatic amino acids (tryptophan, tyrosine, and phenylal- e7
partially responsible for the increase in nuclear sclerosis (hardening).51,52 anine), fluorophores, yellow pigments, and some endogenous compounds

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 5 MAIN SPECIES IN THE HUMAN LENS
WHICH ABSORB LIGHT TRANSMITTAL BY THE CORNEA
PRESBYOPIC CHANGES IN AMPLITUDE
OF ACCOMMODATION WITH AGE
The Lens

amplitude of 14
relative 1.2
accommodation (D)
absorbance 12

10
0.8
8

6
0.4
4

0.0 0
295 345 395 445 495
10 20 30 40 50 60 70
yellow, aged proteins wavelength (nm)
age (years)
o--glucoside of 3-hydroxykynurenine
protein-bound tryptophan

Fig. 5.1.11  Main Species in the Human Lens That Absorb Light Transmitted Fig. 5.1.12  Presbyopic Changes in the Amplitude of Accommodation With
by the Cornea. (From Dillon J. The photophysics and photobiology of the eye. J Age. The different colored symbols represent the data obtained from different
Photochem Photobiol B 1991;10:23–40.) publications. (From Fisher RF. Presbyopia and the changes with age in human
crystalline lens. J Physiol 1973;223:765–79.)

(such as riboflavin) are responsible for the absorption properties of the

lens.51 Tryptophan is cleaved in the presence of sunlight and air to form • Stiffness of the lens substance increases, which renders the lens less
N-formylkynurenine and a series of other metabolic products, including deformable.
3-hydroxykynurenineglucoside (3-HKG). Because more than 90% of the • Although the cortex increases in thickness throughout life, very little
UV radiation that reaches the lens is UV-A (315–400 nm), and 3-HKG change occurs in the thickness of the nucleus. The effect of the round-
absorbs light between 295 and 445 nm whereas tryptophan only absorbs ing of the nucleus on the change in curvature of the anterior surface
light between 295 and 340 nm, this glucoside has a relative absorbance during accommodation, therefore, is reduced with age.
that is greater than that of tryptophan in the young human lens (95% com- • The radius of curvature of the anterior capsule decreases, which renders
pared with 5%) (Fig. 5.1.11). the lens rounder. Contraction of the ciliary muscle, therefore, does not
As the lens ages, it changes from colorless or pale yellow to darker greatly alter the shape of the lens.
yellow in adulthood, and brown or black in old age.55 The autofluores- • The distance between the anterior surface of the lens and the cornea
cent properties of the lens also change with age. These changes in col- decreases.
oration, which are limited to the nucleus, are thought to result from the • The internal apical region of the ciliary body moves forward and inward
attachment of 3-HKG and its metabolic derivatives to proteins to produce with age. The zonules, therefore, no longer put the lens under as much
yellow-pigmented proteins that also absorb light. As the concentration of tension in the unaccommodated state.
these yellow pigments increases, they compete with 3-HKG and become
the major absorbing species of the lens.56,57 Because these yellow proteins The increases in curvature and thickness of the lens suggest that the
are fluorescent species, the wavelength absorbed increases to approximately refractive power should increase with age, resulting in myopia. This,
500 nm (see Fig. 5.1.11). A blue fluorophore, which absorbs between 330 however, does not happen because these changes are accompanied by
and 390 nm and fluoresces between 440 and 466 nm, increases as the lens small alterations to the gradient of refractive index. This gradient becomes
ages. Oxygen-dependent photolysis of the blue fluorophore contributes to flatter near the center of the lens and steeper near the surface and, there-
the formation of a green fluorophore, which is excited between 441 and fore, the refractive power of the eye is lowered.63
470 nm and emits between 512 and 528 nm.58 The increased capacity of
the lens to absorb visible light, in combination with the increased scat- Biochemical Changes
tering properties of the lens (because of the aggregation of lens proteins
and possibly the release of bound water), results in a decrease in transpar- The overall metabolic activity of the lens decreases with increasing age,
ency.50 The increase in the total number of photons absorbed is accompa- partially due to decreasing enzyme activities in the cortex and nucleus.
nied by an age-related loss in antioxidant levels, increasing the amount of Many of the enzymes involved in the metabolism of glucose decrease with
photo-oxidative stress. age, including glyceraldehyde-3-phosphate dehydrogenase, G6P dehydro-
Nonenzymatic glycation of proteins by the Maillard reaction results in genase, aldolase, enolase, phosphoglycerate kinase, and phosphoglycerate
the formation of advanced glycation end products, which also increase the mutase. Although overall metabolic activity decreases, the lens still main-
yellowing of the lens. This reaction is initiated by the attachment of a sugar tains the capacity to synthesize proteins, fatty acids, and cholesterol at sub-
molecule (e.g., glucose) to an amino acid, normally valine or lysine. In stantial rates. Decreased metabolic activity, therefore, does not serve as a
young lenses, 1.3% of lysine residues of human crystallins are glycated, significant limiting factor for the production of new lens fibers.51,52
but by the age of 50 this increases to 2.7% and to approximately 4.2% in A reduction in the activity or levels or both of many antioxidants occurs
older lenses.51 Yellow fluorescent photoproducts also are formed in the with increasing age. Because this decrease is greatest in the nucleus, fibers
presence of ascorbic acid, which is present at high levels in the lens.59 in this region of the lens are more susceptible to oxidative damage and
lipid peroxidation. As a result, they rely on the overlying cortical fibers
Accommodation Changes and epithelial layer to protect them. The activity of both catalase and
superoxide dismutase decreases with age, as do levels of ascorbate and
The amplitude of accommodation decreases throughout life from glutathione.50 The reduced activity of both glutathione synthetase and
13.00–14.00 D at the age of 10 years to 6.00 D at 40 years and almost 0.00 D γ-glutamylcysteine synthetase, accompanied by a decrease in the uptake of
by the age of 60 years (Fig. 5.1.12). This manifests clinically as presbyopia. L-cysteine (an amino acid needed for glutathione synthesis), decreases the
The change in accommodative power is attributable to a number of factors, rate of synthesis of reduced glutathione (Fig. 5.1.13).64 This is partly due to
including60–62: reduced activity of glutathione reductase, which converts oxidized glutathi-
one into reduced glutathione. Glutathione peroxidase (which is involved in
e8 • Young’s modulus of capsular elasticity decreases from 700 N/cm2 at the breakdown of lipid peroxides and hydrogen peroxide) levels increase
birth to 150 N/cm2 by the age of 80 years. from birth until approximately 15 years of age and then slowly decrease

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 EFFECT OF AGE ON THE CAPACITY
TO SYNTHESIZE REDUCED GLUTATHIONE 5.1

Basic Science of the Lens

GSHg–1 lens 3000
(cpm 10000–1)

2000

1000

0
0 20 40 60 80 100
age (years)
data from one lens
overlapping data from two lenses Fig. 5.1.14  Fibrosis of the Posterior Capsule. This opacification developed in a
5-year-old child 20 days after extraction of a traumatic cataract (perforation with
a knife). No intraocular lens was implanted. (From Rohrbach JM, Knorr M, Weidle
Fig. 5.1.13  Effect of Age on the Capacity to Synthesize Reduced Glutathione. EG, et al. Nachstar: klinik, therapie, morphologic, and prophylaxe. Akt Augenheilkd
(From Rathbun WB, Murray DL. Age-related cysteine uptake as rate-limiting in 1995;20:16–23.)
glutathione synthesis and glutathione half-life in the cultured human lens. Exp Eye
Res 1991;53:205–12.)
It is thought that many of the HMW aggregates act as precursors for
the accumulation of insoluble proteins. Below the age of 50 years, approx-
TABLE 5.1.2  Levels of Degraded Polypeptides in Water-Soluble High- imately 4% of lens proteins are insoluble, but by the age of 80 years, this
Molecular-Weight Proteins of Human Lenses increases to 40%–50%.67 The increase in insolubility is approximately the
same in the cortex and nucleus before age 30 years, but with increasing
HMW Protein-Associated HMW Protein age, insolubility increases to a greater extent in the lens nucleus. Up to
Donor’s HMW Protein/ Degraded Polypeptides/ as Degraded
Age (years) Lens (mg) Lens (mg) Polypeptides (%) 80% of the nuclear proteins of an aged lens may be insoluble, and most
of the nuclear α-crystallin is insoluble by the age of 45 years.51,52 This con-
16–19 0.16 0.009 5.6
tributes to the loss of lens transparency and the development of senile
38–39 0.93 0.17 18.2
cataract.
49–51 2.17 0.255 11.75 Tryptophan residues in the crystallins are photooxidized to produce pho-
55–56 2.2 0.42 19.1 tosensitizers. This results in a decrease in tryptophan fluorescence and an
60–80 2.3 0.62 26.9 increase in nontryptophan fluorescence throughout life. The oxidation of
HMW, High-molecular-weight. sulfhydryl groups results in the formation of disulfides, which may be one
Adapted from Srivastava OP, Srivastava K, Silney C. Levels of crystallin fragments and of the factors responsible for the age-related decrease in solubility of lens
identification of their origin in water soluble high molecular weight (HMW) proteins of human
lenses. Curr Eye Res. 1996;15:511–20. proteins. Because the γ-crystallins have sulfhydryl groups that are more
exposed, they are more susceptible to this oxidation than are the α- and
β-crystallins.52 Increases in the glycation of crystallins in the presence of
throughout adulthood.51,52 This decreased antioxidant activity coupled with glucose or ascorbic acid results in protein cross-linking and the resultant
increased photon absorption with increasing age promotes photo-oxidative formation of HMW proteins. The α- and βH-crystallins rapidly cross-link;
damage in the lens. βL-crystallins are slower, and no γ-crystallin cross-linking occurs. One of
the modifications that occurs most frequently to aging crystallins is deam-
Crystallins idation of asparagine residues, which results in the formation of aspartic
acid residues, thus altering the structure, destabilizing the protein, and
With increasing age an increase in both the complexity and the increasing its susceptibility to proteolytic degradation.
number of crystallin fractions occurs, which includes accumulation of
high-molecular-weight (HMW) aggregates, partial degradation of crystal-
lin polypeptides, increased crystallin insolubility, photooxidation of tryp-
SECONDARY CATARACT
tophan, the production of photosensitizers, loss of sulfhydryl groups, and A major complication of extracapsular cataract extraction (ECCE) is sec-
nonenzymatic glycation. These changes can alter the short-range spatial ondary cataract (also known as after cataract). Posterior capsule opacifica-
order of the crystallins and thus decrease transparency.50–52,56 tion (PCO) is the most clinically significant type of secondary cataract and
Levels of soluble HMW aggregates (greater than 15×103 kDa) increase develops in up to 50% of patients between 2 months and 5 years after the
from approximately 0.16 mg in the lenses of donors between the ages of 16 initial surgery. The frequency of PCO is age related; almost all children
and 19 years to 2.3 mg by the age of 60 years (Table 5.1.2).65 This increase develop PCO after ECCE, but in adults the incidence is much lower. This
occurs as the result of many factors, including reduced proteolytic enzyme is thought to be because of the higher proliferative capacity of lens epithe-
activity. Most of these aggregates are localized to the lens nucleus and are, lial cells in the young compared with the old.68,69
in the majority of the young, principally composed of α-crystallin.50 As the After ECCE, the lens is composed of the remaining capsule and the
lens ages, these aggregates increase in complexity and become composed residual epithelial cells and cortical fibers that were not removed at the
of a mixture of crystallins. The major subunits thought to be involved are time of surgery. The lens epithelial cells still possess the capacity to pro-
αA-, αB-, and γs-crystallins. Many of these polypeptides undergo posttrans- liferate, differentiate, and undergo fibrous metaplasia. Migration of these
lational modifications, such as the formation of an intramolecular disul- cells toward the center of the posterior capsule, together with the synthesis
fide bond within αA-crystallin, glycation of lysine residues, cross-linking, of matrix components, results in light scatter that reduces visual acuity.
deamidation of αA- and γs-crystallins, and loss of the C-terminal end of In a minority of cases, PCO results from the deposition of fibrin and
αA-crystallin. Such modifications to α-crystallin result in a decrease in other cell types onto the posterior capsule either at the time of surgery or
the capacity of this crystallin to act as a chaperone protein.50,66 Below the postoperatively.69
age of 20 years, approximately 6% of the HMW protein is composed of The two morphologically distinct types of PCO are fibrosis and Elschnig’s
degraded polypeptides, but by the age of 60 years this increases to 27% (see pearls, which occur concurrently. In addition, ECCE procedures may result e9
Table 5.1.2).65 in the formation of a Soemmerring’s ring (Figs. 5.1.14–5.1.16).69,70

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 extracellular matrix produced in the fibrosis type of PCO is composed of

5 types I and III fibrillar collagen, collagen type IV, and a number of asso-
ciated proteoglycans (dermatan sulfate, heparin sulfate, and chondroitin
sulfate).72
In cases in which the cut edge of the anterior capsule rests on the intra-
The Lens

ocular lens (IOL) optic, residual anterior capsular cells may proliferate and
extend from this cut edge onto the surface of the IOL, which may result in
the formation of a membranous outgrowth within 1 week postoperatively.73
Detailed studies using polymethylmethacrylate IOLs have shown that cells
do not appear to cover the central part of the optic, and migration onto this
optic decreases as the cells in the region of the anterior capsule in contact
with the optic undergo fibrous metaplasia and begin to opacify. The cells
on the IOL completely disappear within 3 months. It is also possible that
cells may migrate around onto the posterior surface of the IOL implant
and therefore contribute to the formation of PCO.
Growth factors present in both the aqueous and the vitreous have been
implicated in the development of fibrosis-type PCO. These include acidic
and basic fibroblast growth factors, insulin-like growth factor-I, epidermal
growth factor, platelet-derived growth factor, hepatocyte growth factor, and
transforming growth factor-β.

Pearl-Type Posterior Capsule Opacification

The pearls formed in this type of PCO are identical in appearance to Wedl
(bladder) cells involved in the formation of posterior subcapsular cataracts
Fig. 5.1.15  Elschnig’s Pearls. This opacification developed within 3 years of
(see Fig. 5.1.16). Because Wedl cells are known to originate from equatorial
an extracapsular cataract extraction with implantation of a posterior chamber
intraocular lens. (From Rohrbach JM, Knorr M, Weidle EG, et al. Nachstar: klinik,
lens epithelial cells, it is believed that residual cells in this region of the
therapie, morphologic, and prophylaxe. Akt Augenheilkd 1995;20:16–23.) capsule are the predominant cells involved in the formation of pearls. Clin-
ically, cases of pearl formation occur somewhat later than those of fibrosis
(up to 5 years postoperatively).69
Pearls were first observed by Hirschberg74 in 1901 and then by Elschnig75
in 1911; they now are referred to as Elschnig’s pearls. After ECCE, the fiber
mass of the lens is no longer present, and as a result, no internal pres-
sure exists. Newly formed lens fibers, therefore, are no longer forced in
the anterior and posterior directions, which results in the formation of a
mass of cells loosely connected and piled on top of each other. Each pearl
represents the aberrant attempt of one epithelial cell to differentiate into a
new lens fiber, possessing characteristics of both epithelial cells and fibers,
and may be embedded in an extracellular matrix. Visual acuity is affected
only if the pearls protrude into the center of the posterior capsule.76–78

Soemmerring’s Ring
Soemmerring first noticed PCO in humans in 1828.79 After ECCE, the cut
edge of the remaining anterior capsular flap may attach itself to the poste-
rior capsule within approximately 4 weeks postoperatively through the pro-
duction of fibrous tissue. Any residual cortical fibers and epithelial cells,
therefore, are trapped within this sealed structure. The equatorial cells
still retain the capacity to proliferate and differentiate into lens fibers. The
increase in the volume of this lenticular material fills the space between
the anterior and the posterior capsule (see Fig. 5.1.16). Proliferating epi-
thelial cells remain attached to the anterior capsule but also are found to
a lesser extent on the posterior capsule, where they form small isolated
Fig. 5.1.16  Soemmerring’s Ring. Taken from behind the lens of a human eye groups. In some cases the epithelial cells escape from the ring and migrate
obtained postmortem. A three-piece, modified J, polypropylene loop posterior onto the anterior surface of the anterior capsule. Because the ring forms at
chamber intraocular lens is present. (From Apple DJ, Solomon KD, Tetz MR, et al. the periphery of the lens, vision is not affected.76,80,81
Posterior capsule opacification. Surv Ophthalmol 1992;37:73–116.)

Fibrosis-Type Posterior Capsule Opacification Prevention and Treatment of Posterior

Residual lens epithelial cells that are still attached to the anterior capsule
Capsule Opacification
after ECCE are thought to be the predominant cells involved in the forma- Currently there is no reliable treatment to prevent PCO. Posterior cap-
tion of fibrous membranes that can appear within 2–6 months of ECCE.69 sulectomy is the treatment of choice when PCO does affect the visual field.
Remnant epithelial cells left on the anterior capsule differentiate A posterior capsulectomy removes the central part of the posterior capsule
into spindle-shaped, fibroblast-like cells (myofibroblasts), which express and thereby instantly improves vision. Removal is achieved using a neo-
α-smooth muscle actin and become highly contractile. These fibroblastic dymium:yttrium–aluminum–garnet (Nd:YAG) laser (Fig. 5.1.17). In some
cells proliferate and migrate onto the posterior capsule to form a cellular patients with posterior segment problems, proliferation of lens epithelial
layer that secretes extracellular matrix components and a basal lamina-like remnants has been observed within months of the capsulectomy. As a
material. Cellular contraction results in the formation of numerous fine result, the size of the capsulectomy decreases, which may in turn reduce
folds and wrinkles in the posterior capsule. At this stage the capsule is visual acuity. It has been postulated that this occurs because of “activation”
only mildly opacified. No significant visual loss occurs until the cells of the cells, the release of growth factors from the vitreous, the direct stim-
migrate into the visual axis.68,71 More advanced stages of PCO result from ulation of proliferation, or a combination of these factors.82 Removal of the
further proliferation and multilayering of cells on the posterior capsule barrier between the posterior chamber and the vitreous cavity increases the
e10 and are associated with additional extracellular matrix production and the risk of complications such as cystoid macular edema, retinal detachment,
appearance of white fibrotic opacities (see Fig. 5.1.14). The majority of the uveitis, and secondary glaucoma.69

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For personal use only. No other uses without permission. Copyright ©2019. Elsevier Inc. All rights reserved.
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FA, editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB
Saunders; 1994. p. 82–96.
4. Saude T. The internal ocular media. In: Ocular anatomy and physiology. Oxford: Black-
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well Scientific; 1993. p. 36–52.
5. Snell RS, Lemp MA. The eyeball. Clinical anatomy of the eye. Oxford: Blackwell Scien-

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tific; 1989. p. 119–94.
6. Forrester J, Dick A, McMenamin P, et al. Anatomy of the eye and orbit. In: Forrester JV,
Dick AD, McMenamin P, et al, editors. The eye: basic sciences in practice. London: WB
Saunders; 1996. p. 1–86.
7. Seland JH. The lens capsule and zonulae. Acta Ophthalmol 1992;70:7–12.
8. Phelps Brown N, Bron AJ. Lens structure. In: Phelps Brown N, Bron AJ, Phelps
Brown NA, editors. Lens disorders: a clinical manual of cataract diagnosis. Oxford:
Butterworth-Heinemann; 1996. p. 32–47.
9. Kuszak JR. The ultrastructure of epithelial and fiber cells in the crystalline lens. Int Rev
Cytol 1995;163:305–50.
10. Lo W, Harding CV. Tight junctions in the lens epithelia of human and frog: freeze-fracture
and protein tracer studies. Invest Ophthalmol Vis Sci 1983;24:396–402.
11. Olivero DK, Furcht LT. Type IV collagen, laminin, and fibronectin promote the adhesion
and migration of rabbit lens epithelial cells. Invest Ophthalmol Vis Sci 1996;34:2825–34.
12. Taylor VL, Al-Ghoul KJ, Lane CW, et al. Morphology of the normal human lens. Invest
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