Lens

• Transparent, biconvex structure
• Contributes 10-15 dioptres to visual system
• Anterior curvature greater than posterior
• 10mm diameter
• 4mm thickness (3mm at birth and 6mm at age 80)
• 35% water (normally)
• Lens proteins are mostly water soluble (except for MIP)
• Lens osmolality is greater than aqueous

Embryology

• Lens placode develops from surface ectoderm at 27 days
• Invaginates into optic cup to form lens vesicle at 33 days

• Central lens pit produces hollow lens cavity (temporarily in communication with the amniotic cavity via the lens pore)

• Detaches from surface ectoderm and sinks below optic cup

• Development of the neural retina provides signals to induce formation of primary lens fibres 

• These produce crystallins
• Fibres elongate towards the anterior lens epithelium and occupy lens cavity
• Nuclei migrate anteriorly to form lens bow with anterior convexity
• Secondary lens fibres develop at the equatorial zone of the anterior lens epithelium

• Embryonic and fetal nourishment is provided by the tunica vasculosa lentis: a vascular net which surrounds the lens from 9 weeks. Derived from anastomoses between:

• Hyaloid vessels posteriorly
• Pupillary membrane vessels from the long posterior ciliary arteries

Capsule

• Thickened, smooth basement membrane produced by lens epithelium
• Variable thickness: 
• Thinnest at the posterior poles (about 2 micrometers) 

• Thickest anteriorly (about 15 micrometers) as the anterior lens benefits from the active epithelium which secretes capsular material throughout life: this is limited at the posterior lens

• Type IV collagen, GAGs, fibrillin, heparin sulphate, fibronectin

• Elastic

• Permeable to water, ions and small molecules or proteins up to the size of albumin (68,000 kD).

Lens epithelium

• Only present anteriorly
• Simple cuboidal epithelium
• Mitosis produces new lens fibres: greatest activity at the equator
• Regulates the water and ion balance of the lens
• An Na/K ATPase pump removes sodium from the lens epithelium
• Highest concentration of the pump at the equator
• Cells elongate, sink below the superficial layer and nuclei migrate anteriorly (lens bow)

Lens fibres

• Innermost primary lens fibres comprise the embryological nucleus: no cells are lost during life

• Fetal nucleus surrounds that, followed by the adult nucleus and the cortex (newest fibres)

• Gap junctions allow cell communication (via connexins) including ion movement
• Deepest, oldest fibres are anucleate

• Superficial fibres are rich in cell components eg. ribosome, polysomes and rough ER, to produce crystallins and also express the lens-fibre-specific major intrinsic protein (MIP)

• Note: all crystallins in the lens are water soluble except for main intrinsic polypeptide (MIP)

• Within the fetal nucleus, the ends of neighbouring fibres form anterior and posterior sutures 

• Anterior is Y-shaped
• Posterior is inverted Y-shaped

• These most mature cells become terminally differentiated and the nuclei disintegrate as do other components including mitochondria (these organelles would scatter light and reduce visual acuity otherwise)

Lens proteins

• 33% of lens weight is protein
• Crystallins account for 90-95% of total protein (but aren’t specific to the lens)
• Crystallins contribute the refractive index of the lens
• Unique characteristics
• Highly stable structure
• Remain soluble at high protein concentration so opaque clumps don’t form
• Two main families
• Alpha
• Beta, gamma
• Protein synthesis occurs in peripheral lens cells and ceases as they become fibres
• Proteolysis is not a significant process since these proteins last for decades

• Calpains are ‘endopeptidases’: enzymes that degrade alpha and beta crystallins, actin and some membrane proteins. Calpain dysregulation has been implicated in cataract formation

• Ubiquitin binds to damaged proteins and facilitates their digestion (noted to be reduced in old lenses)

• Lens fibres are rich in microfilaments and microtubules: vimentin is the major intermediate filament in the lens cells

Alpha-crystallin

• Largest lens protein: 30-40 subunits (of types alphaA and alphaB)
• Encoded by chromosomes 21 and 11.
• Undergo extensive post-translational modification
• These large molecules scatter light so transparency relies on a specific configuration
• Member of the “heat shock protein” family: inducible by heat and stresses
• Alpha-crystallin is a ‘molecular chaperone’: 

• Protective of other proteins when they are vulnerable eg. prevents heat induced aggregation of proteins like beta-crystallin and prevents inactivation of glutathione reductase (hence why some proteins can survive for so long in the lens and it can remain transparent).

Beta,gamma-crystallins

• No known function

• Gamma-crystallins are highly concentrated in old, hard lenses with no accommodative ability

• GammaD crystallin is the most abundant in the lens

Major intrinsic polypeptide (aka aquaporin-0)

• Water insoluble lens specific protein component of fibre cell membranes
• As an aquaporin, functions as a water channel
• Function reduces with age
• AQP0 gene on 12q

Lens biochemistry

• Sodium is low (~10mmol/L): removed by epithelial pump
• Sodium enters the lens from the vitreous, down a concentration gradient
• It is then pumped into the aqueous across the anterior epithelium
• Potassium is high (~120mmol/L)
• Potassium exits the lens down a concentration gradient into the vitreous

• When normal regulation of electrolytes fails:
• Potassium leaks out
• Sodium floods in
• Chloride follows the sodium
• And water follows the new osmotic gradient: entering the lens
• Entry of water disrupts transparency

• The Na/K ATPase maintains the normal balance of the lens by active transport

• Mainly at the anterior surface in epithelium and immature fibres with highest concentration at the equator

• ATP is generated in the anterior lens epithelial cells by anaerobic glycolysis
• Oxygen tension is low compared to other tissues
• Glucose is obtained from the aqueous and enters via GLUT1 (insulin-dependent)
• Anaerobic metabolism accounts for 80% of glucose consumption

• Only len epithelial cells possess mitochondria so this is the only place that aerobic metabolism (Kreb’s cycle) can occur happen

• The lactic acid diffuses into the aqueous
• A small proportion of glucose is metabolised via the pentose phosphate pathway
• In conditions of excess glucose the sorbitol pathway occurs

• Amino acids are actively transported into lens
• But note that glutathione is a polypeptide synthesised in the lens

Some causes of cataract

• Risk factors for age-related cataract
• African ethnicity
• Smoking
• Lower education level
• Female 
• Oxidative modifications of lens proteins accumulate with age and contribute to
• Crystallin crosslinking 
• Alterations in fluorescence
• Protein associated pigmentation
• Aggregations of lens proteins, light scattering and cataract

• Reduced glutathione levels (a scavenger of free radicals in the lens)

• Loss of alpha-A and gamma-S crystallins

• Specific causes:
• Statins

• Chlorpromazine and thioridazine (phenothiazines): pigment deposition on the anterior capsule

• PUVA/UV light: sun exposure is associated with cortical cataract
• Dehydration
• Alcohol
• Tobacco
• Poor nutrition
• Amiodarone and phenothiazines: anterior capsular, stellate cataracts
• Diabetes:

• Poorly controlled type 1 diabetes is associated with a snowflake cortical cataract and/or vacuolated cataract

• Adult-onset diabetes is associated with early onset age-related cataract

• Hyperglycaemia may be cause accumulation of sorbitol within cells (via aldose reductase), creating osmotic pressure and drawing water into the lens

• In younger patients associated with posterior subcapsular cataract especially in younger patients

• Galactosaemia: a deficiency in galactose-1-phosphate uridyltransferase (accumulation of galactitol in the lens): 

• Autosomal recessive
• Systemic features: failure to thrive, hepatomegaly/liver failure, hypoglycaemia

• Bilateral oil-droplet cataracts

• Treatment is galactose-free diet
• Chronic hyperbaric oxygen usage: nuclear sclerotic cataracts
• Trauma: stellate posterior cataracts

• Atopic dermatitis: anterior subcapsular cataracts more common than posterior

• Retinitis pigmentosa: PSCC
• Myotonic dystrophy: Christmas tree cataracts

• Wilson’s disease (and copper foreign bodies): green sunflower cataract

• Fuchs heterochromic cyclitis: unilateral cataract.

• Also associated with Amslers sign: bleeding from the angle after paracentesis due to fragile vessels crossing the angle

• Posterior polar cataract
• Associated with remnants of the vascular hyaloid system
• Autosomal dominant or sporadic
• Mapped to chromosome 16
• Increased risk of posterior capsule rupture