Importance of Vitreous Liquefaction in
Age-Related Cataract
George J. Harocopos,1,2 Ying-Bo Shui,1,2 Megan McKinnon,1 Nancy M. Holekamp,1
Mae O. Gordon,1 and David C. Beebe1
PURPOSE. Vitrectomy is associated with the rapid progression of
nuclear cataracts. This study was conducted to test the hypoth-
esis that age-related liquefaction of the vitreous gel may also be
associated with lens opacification.
METHODS. Lenses from eye bank eyes were graded for nuclear,
cortical, and posterior subcapsular opacities, and the amount
of liquid vitreous was measured.
RESULTS. Nuclear sclerosis (NS) grade, percent liquefaction, and
age all correlated highly (P 0.0001). After adjustment was
made for age, the correlation between NS and percent lique-
faction was 0.37 (P 0.0001), and the correlation between
age and NS after adjustment for liquefaction was 0.57 (P
0.0001). After the eyes were stratified into age groups, the
correlation between NS and percent liquefaction was found to
be highest in eyes from donors aged 51 to 70. Cortical and
posterior subcapsular opacities increased with age, but scores
for these cataract types did not significantly correlate with
vitreous liquefaction.
CONCLUSIONS. Loss of vitreous gel during aging increases the
risk of nuclear cataracts. Preservation or replacement of the
vitreous gel may protect patients from nuclear cataract. (Invest
Ophthalmol Vis Sci. 2004;45:77 85) DOI:10.1167/iovs.03-
0820
T he mechanisms responsible for the formation of age-re-
lated cataracts in humans are poorly understood. Epidemi-
ologic studies have identified cigarette smoking and high my-
opia as risk factors for nuclear cataracts1 4; high levels of
sunlight exposure, female sex, and dark iris color, for cortical
cataracts3,57; and steroid use or radiation exposure for poste-
rior subcapsular cataracts.7,8 The mechanisms that link these
risk factors to cataract have not been identified.
Numerous studies have shown that nuclear cataracts are
associated with increased oxidative damage to the proteins and
lipids of the oldest cells in the lens.9 13 Recent studies have
shown that diffusion decreases within the lens with age, per-
From the 1Department of Ophthalmology and Visual Sciences,
Washington University School of Medicine, St. Louis, Missouri.
2
Contributed equally to the work and therefore should be consid-
ered equivalent senior authors.
Supported by a Research to Prevent Blindness Jules and Doris
Stein Professorship (DCB), NIH Grant EY04853 (DCB), a Core Grant for
Vision Research EY02687 to the Department of Ophthalmology and
Visual Sciences (DOVS), and an unrestricted grant to the DOVS from
Research to Prevent Blindness, Inc.
Submitted for publication August 1, 2003; accepted August 28,
2003.
Disclosure: G.J. Harocopos, None; Y.-B. Shui, None; M. Mc-
Kinnon, None; N.M. Holekamp, None; M.O. Gordon, None; D.C.
Beebe, None
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked advertise-
ment in accordance with 18 U.S.C. 1734 solely to indicate this fact.
Corresponding author: David C. Beebe, Department of Ophthal-
mology and Visual Sciences, Campus Box 8096, 660 S. Euclid Avenue,
Washington University, St. Louis, MO 63110; beebe@vision.wustl.edu.
Investigative Ophthalmology & Visual Science, January 2004, Vol. 45, No. 1
Copyright Association for Research in Vision and Ophthalmology
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haps making the lens nucleus more susceptible to oxidative
damage.14 16 However, these studies have not identified a
mechanism that would explain why nuclear cataracts develop
in some individuals, but not in others, or why nuclear cataracts
develop in some persons at age 50 and in others after age 90.
The possibility of a relationship between the state of the
vitreous body and nuclear cataract formation is suggested by
several observations. Vitrectomy replaces the gel vitreous with
liquid. Most patients who have undergone vitrectomy exhibit
changes in the lens that cause a myopic shift and nuclear
cataracts within 2 years.1725 In contrast, when retinal surgery
is performed in a manner that preserves the structure of the
vitreous body, the formation of cataract and the accompanying
changes in the refractive power of the lens are not accelerat-
ed.26,27 High myopia is associated with increased liquefaction
of the vitreous body,28 30 and preexisting high myopia has
been identified as a risk factor for nuclear cataract.31 Finally,
Stickler syndrome, a hereditary disorder in which the vitreous
body liquefies prematurely, is associated with the premature
onset of cataract, including nuclear cataract.32,33 These studies
suggest a correlation between loss of gel vitreous and the
occurrence of nuclear cataract.
Because surgical or hereditary loss of vitreous structure
increases the risk of nuclear cataract, it is reasonable to hy-
pothesize that age-related vitreous liquefaction would also be
associated with cataract. In humans, the vitreous body gradu-
ally liquefies with age.34 The collagen fibrils of the vitreous
core aggregate into thick cables, instead of the random orien-
tation of fine fibrils found in the gel network earlier in life.3537
This age-related redistribution of the fibrillar components of
the vitreous body leaves the spaces between the collagen
cables filled with liquid, a process that has been termed vitre-
ous syneresis, synchysis senilis, or vitreous liquefaction. The
process of liquefaction begins as early as age 4, and by age 90
the vitreous may be more than 50% liquefied.36,38,39 During the
later stages of vitreous liquefaction, the vitreous cortex may
separate from the inner limiting membrane of the retina, caus-
ing posterior vitreous detachment (PVD). The factors respon-
sible for age-related vitreous liquefaction and PVD have not
been established, although light exposure, oxidation, and in-
creased proteolytic activity have been postulated to be
causes.28,40 43
The present study was designed to determine whether an
association exists between vitreous liquefaction and the occur-
rence of age-related cataracts. We graded the degree of nu-
clear, cortical, and posterior subcapsular opacities and mea-
sured the extent of vitreous liquefaction in donor eyes. The
possible relationship between lens opacification and liquefac-
tion of the vitreous body was then assessed.
METHODS
Acquisition and Dissection of Donor Eyes
All procedures conformed to the provisions of the Declaration of
Helsinki for the use of human tissue in research and were approved by
the Washington University Humans Subjects Institutional Review
77
 78 Harocopos et al.
FIGURE 1. (A) A pair of human lenses mounted in cuvettes in the
orientation in which they were viewed by slit lamp. (B) One lens
observed from the side showing the glass coverslip bracing the lens in
the anterior forward position.
Board. Donor eyes, including whole globes and posterior poles pro-
vided after removal of the cornea, were obtained from Mid-America
Transplant Services (St. Louis, MO), the Lions Eye Bank (Portland, OR),
and the National Disease Research Interchange (Philadelphia, PA).
Preliminary experiments showed that eyes obtained more than 72
hours after death were sometimes dehydrated. To provide at least a
12-hour cushion against possible dehydration, we restricted the globes
used in the present study to eyes received 60 hours or less after death.
In a few cases, eyes that were initially received and dissected were later
excluded from statistical analysis when it was realized that more than
60 hours had elapsed since death. The prior medical and ocular
histories of most donors were not available.
Two hundred ten eyes were dissected. Of these, 16 were excluded
on account of pseudophakia; 16 because of greater than 60 hours time
elapsed since death; 5 because of poor condition noted during dissec-
tion, including damage to the lens; and 2 because the age of the donor
was unknown. The remaining 171 eyes were included in the statistical
analysis. These eyes represented 95 donors, with 76 donors contrib-
uting two eyes, and 19 donors contributing one. Of the 19 donors who
contributed one eye, in 9 cases the fellow eyes were not received, and
in 4 cases the eyes are excluded because of obvious damage that
occurred before shipping, in 2 cases because of poor condition noted
during dissection, and in 4 cases because of pseudophakia.
Before dissection, the circumference of each eye was measured so
that the amount of liquid vitreous could be corrected for globe size. A
string was used to encircle the globe at it largest circumference
perpendicular to the optic axis, and the length of the string was
measured. From whole globes, the cornea was removed, with a scalpel
used to make the initial incision at the limbus and iris scissors used to
extend the incision to 360. The iris was removed by grasping it with
forceps and gently tearing it away from its insertion. A spatula was used
for blunt dissection of the lens from the zonules and anterior vitreous
face, being careful not to disturb the anterior face of the vitreous body
excessively. The lens was lifted out of the eye and placed in a cuvette
filled with Leibowitz L-15 medium (Life Technologies, Rockville, MD).
The lens rested on a diagonally oriented piece of coverslip inside the
cuvette (Fig. 1) and was viewed by placing the cuvette on a specially
designed housing mounted on a slit lamp (model SL-7; Kowa, Tokyo,
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IOVS, January 2004, Vol. 45, No. 1
Japan). With the anterior face of the lens facing the observer, the
examination of the donor lens simulated that of a live patient.
Cataracts were graded using the reference photographs and seven-
decade scale originally designed for the Lens Opacification Classifica-
tion System (LOCS) III for in vivo grading.44 The lenses in our sample
had similar degrees of nuclear opalescence and brunescence. There-
fore, these scores were combined, and a single number from 0.1 to 6.9
was assigned to quantify both opalescence and brunescence. For
cortical and posterior subcapsular cataracts, instead of grading from a
range of 0.1 to 1.0 for the first reference interval, we classified lenses
that had grades of less than 1.0 as 0, because minor postmortem
changes could not be differentiated from trace cortical or subcapsular
opacities. Grading of the lens was always performed before assessing
the extent of vitreous liquefaction to ensure masking of subjective lens
opacification grading.
After lens extraction, the eye was placed in a Petri dish and
weighed. The eye was then oriented superior-side up in a second,
preweighed Petri dish, using the posterior long ciliary arteries and
extraocular muscles to establish orientation. A method similar to that
of OMalley39 and Roth and Foos,45 was used to slice the eye trans-
versely approximately 1 mm superior to the optic nerve with a rect-
angular scalpel, with iris scissors used when necessary to complete the
incision. This incision divided the eye into two calottes, and allowed
the liquid vitreous to be readily expressed into the Petri dish. The
calottes were transferred to the original Petri dish, and both dishes
were reweighed to determine the amount of liquid vitreous. The
weight lost from the first dish and the weight gained by the second
dish (generally within 0.1 g of each other) were averaged to yield the
weight of liquid vitreous.
Data and Statistical Analysis
To control for globe size as a possible confounding factor in measure-
ments of liquid vitreous weight, percent liquefaction instead of abso-
lute liquid weight was used for data analyses. Percent liquefaction was
calculated as follows: The volume of the eye was calculated from the
measured circumference, assuming that the eye is a sphere. Vitreous
volume was estimated by multiplying the eye volume by 0.8, because
the vitreous occupies approximately 80% of the eye volume.46 The
measured liquid weight was then divided by the vitreous volume to
obtain percent liquid vitreous. We could not use methods for estimat-
ing vitreous volume that account for variations in axial length because
the corneas had been removed from many of the eyes.
The Spearman rank correlation coefficient was used to analyze the
relationship between lens opacity grade, percent liquefaction, and
weight of liquid vitreous. Because the values of these variables were
highly correlated in right and left eyes (all correlations greater than
0.90), one eye was selected at random from each of the 76 donors who
had contributed two eyes. Randomization was performed as follows:
(1) A list of random numbers was generated from a uniform distribu-
tion. (2) Half of the numbers were assigned to the right eyes and half
to left eyes to ensure an equal probability of selection. (3) This list was
sorted in ascending order to produce an ordered list. (4) The list of
donors with two eyes in the sample was sorted in ascending order by
identification number. (5) The ordered lists of eyes and donors were
merged. Therefore, the 95 eyes that were analyzed included 76 eyes
randomized as described, plus 19 eyes of donors who contributed only
one eye.
NS grade and percent liquefaction correlated highly with age,
possibly obscuring any potential relationship between NS grade and
percent liquefaction. The partial Spearman coefficient was used to
analyze the relationship between NS grade and percent liquefaction
after adjusting for age and between age and NS grade after adjusting for
liquefaction. Because of the large number of 0 grades for cortical or
posterior subcapsular opacities, Kendalls correlation was used to eval-
uate the relationships between vitreous liquefaction and grade in these
cataracts.
The susceptibility of the lens to nuclear cataract is known to be low
before age 50.14 16,18 Examination of our data showed that NS grade
 IOVS, January 2004, Vol. 45, No. 1 Vitreous Liquefaction and Cataract 79

FIGURE 2. Scatterplots showing the relationship between (A) NS grade (opacification) and percent liquefaction, (B) NS grade and age, and (C)
percent liquefaction and age. The lines show the best linear fit to the data. The table shows the correlations between age, NS grade, and percent
liquefaction.

was high in most eyes older than 70. The relationship between NS and
percent liquefaction was therefore reanalyzed after the eyes were
stratified into age groups: 1 to 50, 51 to 70, and 71 to 90. Spearman
coefficients were calculated for NS opacity grade versus percent liq-
uefaction, opacity grade versus age, and percent liquefaction versus
age for each age group. The relationships between time from donor
death to dissection and percent liquefactions, nuclear opacity and
donor age were also evaluated to determine whether time since death
affects the cataract grade or extent of vitreous liquefaction.
RESULTS
One hundred seventy-one eyes of 95 donors were included in
the study. Mean age was 60 15 years and mean percent
liquefaction of the vitreous body was 19% 13%.
Because the extent of vitreous body liquefaction and lens
opacification grades correlated highly in fellow eyes (0.90;
P 0.0001), data from one eye of each pair were selected at
random for statistical analysis. For the total data set, 52% were
left and 48% right eyes (n 95). Plots of cataract severity,
donor age, or percent liquefaction versus time from donor
death to dissection did not demonstrate significant correlations
(data not shown).
Although percent liquefaction was used in preference to
absolute liquid vitreous weight in our analyses, to avoid possi-
ble confounding introduced by globe size, plots were also
made of absolute liquid vitreous weight. These were essentially
indistinguishable from those made of percent liquefaction
(data not shown).
Because nuclear sclerotic cataracts are the most common
type of cataract to occur after vitrectomy, we first analyzed the
relationship between age, NS grade, and vitreous body lique-
faction. The data presented in Figure 2 show that higher NS
grade and greater liquefaction were associated with increased
age and that higher NS grade was associated with increased
liquefaction. Spearman rank correlation coefficients showed
that all three relationships were highly significant (P
0.0001). The partial Spearman correlation between NS grade

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 80 Harocopos et al. IOVS, January 2004, Vol. 45, No. 1

FIGURE 3. Scatterplots showing the relationship between NS grade (opacification) and percent liquefaction in different age groups. (A) All
subjects, (B) 50, (C) 51 to 70, (D) and more than 70 years. The table shows the correlations between percent liquefaction and NS grade for eyes
in the different age groups.

and percent liquefaction after adjusting for age was 0.37 (P
0.0001), indicating that liquefaction of the vitreous body was
significantly associated with nuclear opacification, indepen-
dent of age. Similarly, the partial Spearman correlation coeffi-
cient for nuclear sclerosis grade and age was 0.57 (P
0.0001), showing that age was significantly associated with
opacification of the lens nucleus, independent of liquefaction
of the vitreous body.
Previous studies suggested that younger eyes are less sus-
ceptible to nuclear cataract, even after vitrectomy.16,18 Data in
Figure 2 suggest that the oldest eyes have the highest NS
grades, even when vitreous liquefaction was in the lower range
for this age group. Therefore, the relationship between vitre-
ous liquefaction, lens opacification grade, and age was ana-
lyzed by age groups (50, 5170, and 70 years). The distri-
bution of the sample by age group was: 50, 22%; 51 to 70,
51%; and older than 70, 27%. The correlation between NS
grade and percent liquefaction was highest in the 51 to 70 age
group (Fig. 3). In this group, the association between NS grade
and percent liquefaction was greater than between age and NS
grade and between age and percent liquefaction (Fig. 4). In the
51 to 70 age group, the partial Spearman correlation between

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 IOVS, January 2004, Vol. 45, No. 1
FIGURE 4. Scatterplot showing the relationships between NS grade
(opacification), age, and percent liquefaction in eyes in the 51 to 70
age group. The table shows the correlations between NS grade, age,
and percent liquefaction in these eyes and the statistical evaluation of
each association.
NS grade and percent liquefaction, after adjusting for age, was
0.45 (P 0.0015).
As expected, the number of eyes with cortical or posterior
subcapsular (PS) cataracts increased with age (Fig. 5). How-
ever, there was no appreciable correlation between the extent
of liquefaction of the vitreous body and the grades for these
types of cataracts after adjusting for age, suggesting that lique-
faction of the vitreous body does not significantly contribute to
their etiology.
DISCUSSION
To date, the vitreous body has been most often studied with
regard to its involvement in retinal disease, especially prolifer-
ative diabetic retinopathy and macular hole.28,47 49 The possi-
ble role of vitreous body degeneration in the etiology of age-
related lens opacification has received little attention, even
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Vitreous Liquefaction and Cataract 81
though nuclear cataracts are a frequent consequence of vitrec-
tomy.18 25
It is unlikely that the cause of postvitrectomy cataracts is the
underlying retinal disease that was the impetus for vitrectomy.
Patients who undergo vitrectomy during the removal of pre-
retinal membranes often experience development of nuclear
cataracts, as do patients who have a vitrectomy during other
types of retinal surgery. However, individuals who undergo
surgery for preretinal membranes who do not undergo vitrec-
tomy do not have nuclear cataracts or the myopic shift that
typically precedes nuclear cataracts.26,27 Furthermore, retinal
diseases that often require vitrectomy, like macular hole, reti-
nal detachment, and diabetic retinopathy, are not themselves
associated with rapid-onset nuclear cataracts. It is only when
treatment of these conditions involves vitrectomy that rapidly
developing nuclear cataracts occur. One cannot rule out the
possibility that the infusion fluids or drugs used during vitrec-
tomy contribute to postvitrectomy cataracts. However, we
believe it significant that the attribute shared by both postvit-
rectomy and age-related nuclear cataracts is the destruction of
the vitreous gel.
Previous studies suggested a link between degeneration of
the vitreous body and nuclear sclerotic cataract. In a study of
patterns of vitreous liquefaction in donor eyes, OMalley ob-
served a larger than expected extent of vitreous body liquefac-
tion in both eyes of seven donors in which one eye was
aphakic (presumably as a result of cataract surgery) and the
other phakic.39 Because the amount of liquefaction was similar
in the phakic and aphakic eyes, the cataract surgery was not
the cause of the increased loss of gel vitreous. Rosen50 ob-
served that 94 of 100 patients with nuclear sclerosis also had
posterior vitreous detachment, a higher rate than would be
expected for the age of the patients in his series.38 He also
commented that the degree of nuclear sclerosis appeared to be
proportional to the extent of vitreous detachment. Given that
vitreous detachment is highly correlated with, and likely the
result of, vitreous liquefaction,28,51 an association might be
inferred between vitreous liquefaction and the formation of
nuclear sclerotic cataract.
To our knowledge, the present study is the first to examine
the association between vitreous liquefaction and age-related
lens opacification. In eyes of 95 donors, the correlation be-
tween the extent of nuclear opacification and percent lique-
faction was highly significant after adjusting for age. Age was
also significantly associated with nuclear opacification, inde-
pendent of the extent of vitreous liquefaction. Liquefaction of
the vitreous body was not significantly associated with the
presence of cortical or posterior subcapsular cataracts. This
result is consistent with other reports showing that different
risk factors contribute to the etiology of the three major types
of age-related cataracts.13
The magnitude of the correlation between vitreous lique-
faction and nuclear opacification was greatest in the 51 to 70
age group, suggesting that it is in this age group that the lens
may be most susceptible to the consequences of vitreous body
liquefaction. It was also within the 51 to 70 age group that we
found the greatest variability in the extent of vitreous liquefac-
tion (Fig. 2C), a result that is similar to the observations of
OMalley in his study of the extent of vitreous body degener-
ation in 800 donor eyes.39
The Link between Vitreous Liquefaction and
Nuclear Opacification
If liquefaction of the vitreous body is a significant risk factor for
nuclear cataract, it is important to identify the changes that
follow the destruction of the vitreous gel, either during aging
or after vitrectomy, that contribute to the opacification of the
lens nucleus. Several possibilities can be considered.
 82 Harocopos et al. IOVS, January 2004, Vol. 45, No. 1

FIGURE 5. Scatterplots showing the relationships between cortical cataract grade and age (A) or percent liquefaction (B) and between posterior
subcapsular (PS) cataract grade and age (C) or percent liquefaction (D). Both types of cataracts increased in older individuals (A, C), but showed
little relationship to the degree of liquefaction of the vitreous body (B, D). The table shows the partial correlations between percent liquefaction
and cortical or posterior subcapsular cataract grade after adjusting for age.

It is possible that one or more essential metabolites may be
lost after vitreous degeneration and the absence of this material
may contribute to the formation of nuclear cataracts. Although
this possibility cannot be ruled out at this time because the
composition of the vitreous body is complex, examination of
gel and liquid vitreous has found that they have similar com-
position.28
It is also possible that the factors responsible for the lique-
faction of the vitreous body independently cause nuclear
opacification or that opacification and hardening of the lens
nucleus somehow lead to degeneration of the vitreous body.
The causes of age-related vitreous liquefaction are not known,
although it has been suggested that light, oxidative damage, or
increased proteolytic activity may be responsible.28,40 43 Sev-
eral studies have shown that increased sunlight exposure is not
associated with increased risk of nuclear cataracts.5,6,52 There-
fore, sunlight exposure is not likely to explain the relationship
between vitreous liquefaction and opacification of the lens
nucleus. Oxidative damage to lens proteins and lipids is a
hallmark of nuclear cataracts. Therefore, increased oxidative
stress in the eye may contribute to vitreous degeneration and
formation of nuclear cataract. It is not apparent how elevated
levels of proteases could lead to selective damage to the lens
nucleus without damaging the outer cells of the lens, or how
opacification and hardening of the lens nucleus might alter the
properties of the vitreous, although these possibilities cannot
be ruled out.
Nuclear opacities occur frequently in the first 2 years after
vitrectomy, as well as being more prevalent in eyes with
liquefaction of the vitreous body. Therefore, it seems possible

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 IOVS, January 2004, Vol. 45, No. 1 Vitreous Liquefaction and Cataract 83

FIGURE 6. Diagrams showing the known or proposed distribution of oxygen in the posterior segment of the eye. (A) Oxygen distribution in the
intact vitreous body of a normal eye, as measured with oxygen electrodes in previous studies.5355,56,57 Most of the gel vitreous is blue, representing
the low oxygen tension found there. Areas with high oxygen concentration are red (retinal arterioles and the gel vitreous adjacent to these vessels).
It is likely that retinal metabolism maintains low oxygen levels in the cortical vitreous that is not adjacent to an arteriole. The lens nucleus is pale
yellow, indicative of minimal opacification. (B) Proposed distribution of oxygen in the eye after vitrectomy. The remaining gel vitreous is shown
at the posterior of the lens. The oxygen in the liquid and gel vitreous is red. The lens nucleus is brown, indicative of increased opacification. (C)
Proposed distribution of oxygen (red) in the eye after degeneration (liquefaction) of the vitreous body and partial posterior vitreous detachment.
The lens nucleus is brown, indicative of increased opacification.

that it is the loss of the gel state of the vitreous body that
increases the risk of nuclear cataract. In an eye with an intact
vitreous gel, soluble substances, such as growth factors, ions,
and metabolites, are redistributed by the relatively slow pro-
cess of diffusion. The concentration of these molecules should
be highest near the tissues that produce them or transport
them into the eye and lowest near tissues that consume them
or transport them out of the eye. Liquefaction or removal of the
vitreous body, which permits the fluid in different regions of
the eye to intermix rapidly, would prevent the formation of
these gradients and rapidly distribute solutes throughout the
posterior segment of the eye.
One solute that should be significantly altered in its distri-
bution in the eye after loss of the vitreous gel is oxygen.
Oxygen diffuses from the retinal arterioles into the vitreous
body and the cells of the inner retina consume oxygen, remov-
ing it from the vitreous body.53 These competing processes
result in a steep, standing oxygen gradient within the narrow
band of vitreous gel that is closest to the retinal arteries and
arterioles (Fig. 6A).5355
Consistent with these studies, the oxygen concentration
measured around the lens is remarkably low in the intact
human eye. Throughout the central and anterior vitreous body
the partial pressure of oxygen is approximately 16 mm Hg
(2% O2).56,57 Comparably low oxygen levels (1.8%) have
been measured in the anterior chamber near the surface of the
lens capsule.58 Most tissues show signs of hypoxia when oxy-
gen levels fall below 5%. Thus, the lens is normally exposed to
especially low levels of oxygen.
When the retina is not bounded by the vitreous gel, as
occurs after vitrectomy or posterior vitreous detachment, ox-
ygen from the retinal vessels would be carried away from the
surface of the retina by fluid movement and distributed
throughout the liquefied portion of the vitreous (Figs. 6B,
6C).59 Fluid movement over the unbounded inner surface of
the retina should occur frequently (for example, after most
movements of the head or eyes). Redistribution of oxygen from
well oxygenated (perfused) to hypoxic (nonperfused) areas of
the retina has been demonstrated after vitrectomy or posterior
vitreous detachment and is believed to explain the beneficial
effects of these conditions in diabetic retinopathy and branch
retinal vein occlusion.59 61 In a similar manner, circulation of
the vitreous fluid after vitrectomy or degeneration of the vit-
reous gel could expose the lens to higher concentrations of
oxygen than in an eye with an intact vitreous gel (Figs. 6B, 6C).
In agreement with these predictions, our recent studies dem-
onstrate that, in human eyes, vitrectomy leads to loss of the
normal gradient of oxygen in the eye and increases the level of
oxygen close to the lens (Shui Y-B, et al. IOVS 2003;44:ARVO
E-Abstract 3022). An increase in oxygen around and within the
lens is also found in rabbits after vitrectomy (Dillon J, et al.
IOVS 2003;44:ARVO E-Abstract 3501).
Exposure of the lens to elevated levels of oxygen can cause
cataracts. Patients treated with hyperbaric oxygen therapy for
1 hour each day for a year or more showed frank nuclear
cataract or early signs of nuclear opacification, including a
myopic shift.62 Studies of shorter duration have also shown
that hyperbaric oxygen treatments cause a shift toward myo-
pia.63,64 Precataractous changes are also seen in the lenses of
experimental animals if they are regularly exposed to hyper-
baric oxygen.65 68
Based on these observations, we suggest the intact vitreous
gel normally helps to maintain the low level of oxygen around
the lens by preventing bulk flow of the vitreous fluid. Degen-
eration or destruction of the vitreous gel would allow more
oxygen to reach the lens, and increased exposure of the lens to
oxygen causes nuclear cataract (Fig. 6C).
Association between Age, Vitreous Liquefaction,
and Opacification of the Lens Nucleus
Many studies, including the present one, have shown that age
is an important risk factor for lens opacification. Data from the
present study also show that liquefaction of the vitreous body
is a risk factor for nuclear opacification when eyes of all ages
were considered together. However, when eyes were divided
into age groups, the relationship between liquefaction of the
vitreous body and nuclear opacification grade in subjects
younger than 50 years was low and statistically not significant
in this study. This suggests that, in younger individuals, the lens
may be less susceptible to oxygen or other harmful conse-
quences of vitreous body liquefaction. A similar result was
found for cataract risk after vitrectomy: patients older than 50

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 84 Harocopos et al.
were 10 times more likely to have nuclear cataract within 2
years after surgery than those younger than 50.18
Laboratory studies have suggested that between ages 30 and
50 a barrier to the diffusion of small molecules forms between
the lens cortex and nucleus.14 16 Reduced glutathione, a me-
tabolite that normally protects the proteins and lipids of the
lens from oxidative damage,11,69 is produced in the lens cortex
and reaches the lens nucleus by diffusion.14,70 The formation
of a diffusion barrier in the lenses of older individuals would be
expected to decrease the amount of reduced glutathione avail-
able to the lens nucleus, thereby increasing its susceptibility to
oxidative damage. Consistent with this view, glutathione levels
are low and an increased proportion of this glutathione is
found in the oxidized state in nuclear cataract.10,11,14,71,72
Therefore, oxygen or other oxidants have greater potential to
cause damage to the lens nucleus of older individuals. These
observations provide a possible explanation for the contribu-
tion of age to the risk of nuclear cataract.
In the oldest age group studied (70 years), opacification of
the lens nucleus was high, no matter what the extent of
vitreous liquefaction. This may indicate that the age-related
increase in the susceptibility of the lens to oxidative injury is
the most important determinant of opacification in this age
group. However, cataract surgery is also more frequent in this
age group. Because pseudophakic eyes were excluded from
our study, it is possible that we preferentially excluded indi-
viduals with higher levels of vitreous liquefaction because
these individuals had already had cataract surgery. Although
we measured the extent of vitreous liquefaction in the pseu-
dophakic eyes (data not shown), we could not relate these
measurements to nuclear opacification, because we did not
have information about the types of cataracts that led to lens
removal. Additional studies would be needed to explore more
fully the contribution of vitreous body liquefaction to nuclear
cataracts in this age group.
Acknowledgments
The authors thank Kathryn Trinkaus for assistance with the statistical
analysis, Russell Van Gelder for the use of the slit lamp, and the staff of
Mid-America Transplant Services, the National Disease Research Inter-
change, and the Lions Eye Bank of Portland, Oregon, for their support
of this work.
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