What is the pathophysiology of cataracts?

Pathophysiology of Cataracts

Cataracts develop through age-related biochemical changes in lens proteins that cause light scattering, with distinct pathophysiologic mechanisms for nuclear, cortical, and posterior subcapsular types. 1

Core Molecular Mechanisms

Age-Related Protein Changes

• Lens proteins undergo non-enzymatic, post-translational modifications with aging, leading to accumulation of fluorescent chromophores that increase susceptibility to oxidation and cross-linking, ultimately causing increased light scatter. 1
• Water-soluble crystallin proteins denature and form high molecular weight (HMW) aggregates bound by α-crystallin, which scatter light without necessarily destroying the lens microarchitecture in age-related cataracts. 2
• The steady accumulation of chromophores and complex, insoluble crystallin aggregates in the lens nucleus leads to brown nuclear cataract formation in susceptible individuals, with the process being homogeneous while affected lens fibers retain their gross morphology. 1

Critical Age-Related Barrier Formation

• A barrier to glutathione transport forms around the lens nucleus beginning in the fourth decade of life, dramatically increasing the risk of oxidative damage to the lens core. 1
• Because the human lens grows throughout life, the lens core experiences prolonged exposure to oxidative influences, making it increasingly vulnerable to damage over time. 1

Type-Specific Pathophysiology

Nuclear Cataracts

• Nuclear cataracts result from homogeneous accumulation of protein aggregates in the lens nucleus, causing central opacification or discoloration that progresses slowly over many years and primarily affects distance vision. 3, 4
• The nucleus becomes progressively more rigid with age, resisting the shape changes necessary for accommodation, which forms the basis of presbyopia before frank cataract develops. 1

Cortical Cataracts

• Cortical cataracts develop through mechanical shear stress between the hardening nucleus and softer cortex during accommodation, causing cortical ruptures that appear as opaque spokes or oil droplets. 5
• These mechanical stresses become significant after age 45 when lens nuclear hardening accelerates, creating sharp limited fluid clefts in radial directions according to zonular traction. 5
• In pure cortical cataracts, the ion pump (K+ > Na+) and metabolic parameters remain largely intact, which explains why subcapsular opacities do not occur in this type. 5
• When water-soluble crystalline proteins contact free fluids in areas of mechanical cortical ruptures, grey opalescence and light scattering result. 5

Posterior Subcapsular Cataracts (PSC)

• PSCs are caused by ion pump damage (Na+ > K+) and metabolic alterations, allowing passive fluid entry from the vitreous and anterior chamber through the lens capsule. 5
• This passive fluid entry initially forms numerous free clear subcapsular fluid vacuoles that become secondarily grey and opaque. 5
• PSCs progress significantly faster than nuclear and cortical cataracts, developing and progressing over months to a few years rather than decades. 6
• Multiple causative factors damage the metabolic barrier, including aging, diabetes, corticosteroids (particularly posterior subcapsular location), iridocyclitis, and ionizing radiation. 6, 5

Genetic vs. Age-Related Pathways

Congenital Cataracts

• Severe genetic mutations cause major damage to lens proteins, inducing the unfolded protein response (UPR) and apoptosis that destroy the lens microarchitecture. 2
• Altered solubility and stability of crystallin proteins from mutations lead to decreased protective function, aggregate formation, and mislocalization to mitochondria with decreased mitochondrial function. 7

Age-Related Cataracts

• Genetic variants merely destabilize proteins, increasing susceptibility to cumulative environmental insults over decades rather than causing immediate damage. 2
• The lens loses transparency progressively with no chance of spontaneous reversal once visual acuity declines. 6

Environmental Acceleration Factors

• UV-B radiation causes cumulative oxidative damage over decades, with cortical cataracts showing the strongest dose-response relationship to lifetime UV exposure. 6
• Smoking accelerates cataract progression through dose-dependent oxidative stress, particularly affecting nuclear sclerosis. 6
• Ionizing radiation causes cataracts even at relatively low exposures, with effects manifesting years to decades after exposure depending on dose. 6

Clinical Progression Without Intervention

• For full-thickness cataracts, 60% of eyes lose 2 or more lines of vision over 5 years without surgery. 6
• After 3-5 years of untreated disease, 70-80% of eyes will have 20/200 or worse visual acuity. 6
• Currently there is no medical treatment for age-related cataract; surgical removal remains the only effective intervention when vision is sufficiently impaired. 8