uv and the eye timothy sullivan professor of ophthalmology glen gole professor of ophthalmology...
TRANSCRIPT
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UV and the Eye
Timothy Sullivan
Professor of Ophthalmology
Glen Gole
Professor of Ophthalmology
University of Queensland
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Case Summary
• Jack – 83 yo retired farmer– Past history precancerous lesions, NMSC,
cataracts– Wants a driver’s licence check
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Ophthalmology
• The branch of medicine that deals with the anatomy, functions, pathology, and treatment of the eye
• Opthalmology 55%
• Optalmology 40%
• Rhinoceros 2%
• Ophthalmology3%
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Subspecialties
• Anterior Segment
• Glaucoma
• Uveitis
• Neuroophthalmology
• Paediatric Ophthalmology/Strabismus
• Vitreo-Retinal
• Ocular Adnexal
• Ocular Pathology
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Don’t wait for the planets to be aligned
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Opportunities
• Interested Clinicians
• Basic Science Researchers
• Clinician Scientists
• Clinical Research
• Poor beaten wretches at the coal face of clinical practice
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Worldwide Significance
• 45 million people are blind – 76 million by 2020
• 269 million have low vision– 145 million restored with glasses
• 90% of blind people live in low-income countries– Global economic impact $US42 Billion/year
– Restoration of sight, and blindness prevention strategies are among the most cost-effective interventions in health care
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Causes of Blindness
60%
10%
15%
15%
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Australian Significance
• 50 000 people are blind – 100000 by 2020
• 500 000 have low vision– 1 million by 2020– 60% refractive– 10% cataract– 10% ARMD
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Ophthalmohelioses
• Ocular Adnexae
• Ocular Surface
• Lens
• Uveal Tract
• Vitreous
• Retina
• Ocular Alignment
• Systemic
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Ocular Adnexae
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Ocular Surface
• Keratitis– Snow blindness
• Pterygium
• Ocular Surface Squamous Neoplasia
• Reactivation Herpes
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Crystalline Lens
• Early Presbyopia
• Cataract
• Pseudoexfoliation
• Dysphotopsia
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Uveal Tract
• Melanoma
• Pigment Dispersion
• Uveitis
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Vitreoretinal
• Liquefaction
• Solar maculopathy
• Macular Degeneration
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Systemic
• Melanoma
• NMSC
• Xeroderma Pigmentosa
• Basal cell nevus syndrome
• Photosensitivity
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Ophthalmic History
• Most ophthalmic conditions can be diagnosed from history alone
• Life or sight threatening systemic diseases can have ocular symptoms and signs
• Ophthalmic history taking and diagnosis require knowledge of anatomy of eye, orbit and visual pathways, pupillary responses, as well as innervation of EOM’s
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History
• Specific Complaints– Pain– Foreign body sensation, ache, photophobia,
referred pain– Redness– Eye, eyelid, unilateral, bilateral , other
symptoms.
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Visual Symptoms
• REMEMBER RED EYE + PAIN IS NOT CONJUNCTIVITIS
• Beware of discharge, pus,watery eyes
• Itch
• Burning stinging dryness
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Visual Symptoms
• Loss of vision
• Gradual, sudden, uni -or bilateral , other symptoms “flashes, floaters” transient, permanent
• Diplopia/ Turned eyes
• Unilateral (not muscle palsy) bilateral, intermittent, directional
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Visual Symptoms
• Night blindness
• Colour Vision
• Visual Phenomena
• Spots, scotomata, flashes floaters, halos
• Visual distortion
• Micropsia, macropsia, metamorphopsia
• Ptosis
• Gradual, sudden
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Background
• Incidence of skin cancer in Queensland is the highest in the world– BCC 1700/year/100,000– SCC 600/year/100,000– Melanoma 56/year/100,000
• United States– 800,000 BCC/year– 200,000 SCC/year– 53,000 Melanoma/year
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Layers of the skin
• Thinnest skin on body
• Epidermis– BCC basal layer– SCC more superficial– MM usually basal
• Dermis
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Normal Skin Maturation (26-42Days)
• Keratinocytic Stem cells
• Basal Layer/Hair Follicles
• Divide into identical stem cells and transit amplifying cells
• Transit cells proliferate, differentiate, move upwards and are shed as squames
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Skin Cancer
Disease characterised by genomic instabilityInherited mutations are termed germlineAcquired mutations are termed somatic
Rarely tumours are hereditaryMost tumours are due to
Altered DNA replicationCarcinogensDefects in DNA repair
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Skin Cancer
• Two broad classes of genes contribute to cancer
• Oncogenes
• Tumour suppressor genes
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Skin Cancer
• Oncogenes– Growth signaling molecules that become
activated and are perpetually turned on– Genetically dominant – Mutation of one copy of the proto-oncogene
will produce the phenotype– RAS cutaneous melanoma
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Skin Cancer
• Tumour suppressor genes– Negatively regulate cell growth– Promote cell death– Both copies must be inactivated for complete loss of function
• Gatekeeper genes– Restrict cellular growth– The patched (PTC) gene– Inactivated in sporadic and hereditary BCCs
• Caretaker genes – maintain integrity of the genome– Impaired function > mutations in gatekeepers leading to
tumourigenesis (Xeroderma Pigmentosa)
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Photomutagenesis
• Carcinogenic wavelengths of UV correspond to absorbtion spectrum of DNA
• UV photon absorption causes an excited state to produce dipyrimidine “photoproducts”– Predominately Cyclobutane
pyrimidine Dimer (CBD)
• Specific UV fingerprint mutations– UVB (290 – 320 nm)
• Cytosine > Thymine C > T CC > TT
– UVA (320 – 400 nm)• Thymine > Guanine T > G
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Local Immunosuppression
• UV induces an environment of local immunosuppression
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Langerhans Cells
Normal Epidermis
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UV
Interferes with AG presentation with Langerhans Cells being the prime target
Depletes Langerhan’s Cells
Alters their dendritic morphological features
Decreases expression of Class II MHC molecules (ICAM1)
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UV
Non Langerhans Inflammatory Cells
trans-Urocanic acid
cis-Urocanic acid
Abundant in stratum corneum
Converts to cis isomer with UV
Induces TNF α from keratinocytes
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UV
Non Langerhans Inflammatory Cells
TNF α
Further negative effect on LC
Alters morphology
Increases depletion from the epidermis
Inhibit Contact Hypersensitivity Reaction (CHS)
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UV
Non Langerhans Inflammatory Cells
TNF α IL-10
UV stimulates IL-10 production from keratinocytes Main source is from macrophages
Inhibits presentation of tumour Ag’s by APC
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UV
Non Langerhans Inflammatory Cells
TNF α IL-10
Th1
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UV
Non Langerhans Inflammatory Cells
TNF α IL-10
IL-12, IFN γ
IL-4, IL-10
Th1 Th2
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UV alters APC function and cytokine production to sway immunosuppression from helper to suppressor pathways
UV impairs certain cell mediated immune responses and may lead to a long lived state of antigen specific tolerance and immunosuppression, predisposing to further tumours
This immunosuppression may be as important as the UV carcinogenesis in developing NMSC
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BCC Aetiology
• Arise from pluripotential immature cells of the epidermis (interfollicular basal cells)
• Resemble cells of the epidermal basal layer
• Arise de novo, not from precursor lesions
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BCC Aetiology
• No “promotion stage”• Involves mutations of the PATCHED gene
– Human homologue of a Drosophila gene
• UV B is the major carcinogen
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Hedgehog/patched/smoothened/Gli pathway
• Mutations in PTCH causes Gorlin’s syndrome and sporadic BCC’s
• 9q22.3
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Multistage Model of Carcinogenesis
• SCC conforms to this model
• Precursor lesions acquire successive genetic lesions– p53 clones– Actinic keratosis– Intraepidermal
carcinmoma– Invasive SCC
• Metastasis
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Melanoma Aetiology
• Intermittent intense sun exposure– Blond/red hair, freckles and a tendency to
burn and tan poorly– > 2 episodes of painful/blistering sunburn
• Nevi– Large congenital nevi, dysplastic nevi– >50 common nevi
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Melanoma Aetiology
• Arise from epidermal melanocytes– Limited capacity to proliferate– UV induces minor damage – High content of anti-apoptotic protein Bcl-2– These cells are retained possibly to
maintain then protective function of melanin– Harbour mutations and are at risk of further
mutations and malignant transformation
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Genetic changes in Melanoma
• UV signature mutations rare in melanoma– P53 unlikely to play a major role in
melanoma
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Genetics changes in Melanoma
• Multiple genetic alterations– Somatic activating BRAF mutation is common– Also seen in nevi, present early in progression– Activating ras mutations also seen
• Growth suppressing pathways– INK4a– PTEN (phosphatase and tensin homologue)
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Melanoma Linear Tumour Progression Model
NormalNevus
VGPDysplastic RGP
Metastasis
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Histological progression in melanoma
Atypical Melanocytic hyperplasia Lentigo maligna
Level 1 melanoma RGP Melanoma VGP
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Sebaceous Carcinoma
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Skin Lesions Management
• Is the lesion benign or malignant
• Signs of benign lesions– Well circumscribed, regular borders, slow
growth
• Signs of malignancy– Tissue destruction, irregular borders, loss of
normal anatomy– Around eye look for loss of lashes
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Skin Lesions Management
• 5FU
• Imiquimod – immune response modifier – toll-like receptor 7 (TLR7) to stimulate
cytokines (IFN-α, TNF, IL-6)
• Surgical excision with margin control
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What about Jack
• Type 1 Fitzpatrick skin type
• Melanoma (+ve family history)
• Possible metastatic SCC
• Fitness to drive
• Cataracts
• UV effects on the eye