Smoking and Age-Related Macular Degeneration: Review and Update

8/18/2019 Smoking and Age-Related Macular Degeneration: Review and Update

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Journal o Ophthalmology

: Summary o the nonmodi able and the modi able risk actors or age-related macular degeneration∗ .

Nonmodi able risk actorsAgeGenderIris colorEthnicity HyperopiaNuclear sclerosisFamily history o AMDComplement actor H polymorphismH RA polymorphismCX CR polymorphismComplement actors , and B polymorphism

Modi able risk actorsSmokingBody mass indexHypertensionDiabetesCholesterolHDL-cholesterolAcute myocardial in arctionStrokeAnginaHigh alcohol intakeDietary antioxidants and omega- atty acidsChronic renal ailureHormone replacement therapy Chlamydia pneumonie in ectionPhysical activity Sunlight exposureCataract surgery

∗ AMD: age-related macular degeneration; H RA : HtrA serine peptidase ;CX CR : CX C chemokine receptor ; HDL: high-density lipoprotein.

AMD sign except or CNV). Neovascular AMD accounts orthe most cases o severe vision loss, although the atrophic

orm is the most requent presentation o the disease [ – ].A variety o risk actors or AMD have been described.

However, the evidence and strength o such associations arewidely variable, probably due to the difficulty o measuringsome o these actors in clinical practice [ , ]. Advancedage, Caucasian race, certain genetic polymorphisms, higherbody mass index, excessive alcohol consumption, and ahistory o smoking are provenrisk actors in thedevelopmento AMD and progression to late AMD [ – ].

Risk actorsmay be classi ed as modi ableandnonmod-i able ( able ). Tey can also be divided depending on thegrade o evidence showed in the literature. Age showed thehighest evidence, as the odds ratio (OR) increases rom at

– years to . – . at – years and . – . in agesbetween and years [ – ]. Smoking (OR range: . –

. ) is the second most consistent risk actor related withAMD [ , ]. Race and ethnicity may also play an important

role, as the whites are the racial group with a higher risk o AMD compared with the blacks or the Hispanic whites[ – ]. Other signi cant risk actors are amily history o AMD (OR range: . – . ), previous cataract surgery (OR:

. ), high body mass index (OR range: . – . ), andhypertension (OR range: . – . ) [, ].

Te purpose o this review is to analyze the current sci-enti c evidence o smoking as an independent risk actor inAMD and the relevance o advising patients to quit smoking

or their visual health.

2. Material and Methods

A systematic review o all o the peer-reviewed articlesindexed in PubMed about smoking and age-related maculardegeneration was per ormed. Te analyzed data were sum-marized classi ying them into our main headings: reportedepidemiological association between smoking and AMD;studied mechanisms or toxic damage to the retina and

choroid induced by smoking; smoking and biomarkers inAMD; and treatment considerations or AMD and smoking.

3. Results and Discussion. . Epidemiological Association between Smoking and AMD.

Smoking is a major modi able risk actor or AMD. Teassociation between smoking andAMDhasbeenconsistently demonstrated in many epidemiological studies carried outwithin different populations in the last decades con rmingprevious clinical impressions. Cross-sectional studies andprospective cohort studies have described the natural history o the disease and its associations with risk actors, wheresmoking has been the most consistent actor associated withgeographic atrophy and neovascular AMD.

. . . Cross-Sectional Studies. Cross-sectional studies exam-ining theassociation between smoking andAMD include twoAmerican, three European, and two large Australian popula-tions. Further studies also provided additional in ormationabout smoking as a risk actor or AMD in different ethnicgroups and geographic areas ( able ). Population-basedepidemiologic studies have provided estimates o prevalenceandincidence o advanced AMDamong various racial/ethnicgroups: geographic atrophy and neovascular AMD are rarebe ore years o age, becoming more prevalent in patientsaging over ; overall, the prevalence is higher in Caucasianand lower in A rican-American patients.

Te Beaver Dam Eye Study recruited patients romBeaver Dam (WI, USA) rom . Afer controlling subjects

or age and passive smoking, higher rates o neovascularAMD in current-smokers compared to those who had neversmoked independently o gender were evidenced [ ].

More recently, the study on the large Beaver Dam Off-spring Study (BOSS) cohort ound a prevalence o AMD o

. %. Afer controlling subjects or age and gender, a his-tory o current-smoking and greater numbers o pack-yearssmoked were associated with early AMD [ ].

Te Rotterdam Study is a single-center prospectivestudy o the population aging over years in Rotterdam


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: Cross-sectional and prospective cohort studies examining the association between smoking and AMD: current-smokers versusnever-smokers ∗ .

Studies AMD types Odds ratio ( % CI)∗

Beaver Dam Eye Study

Early AMD

Neovascular AMD

Ever-smokers versus never-smokers:M . ( . – . )F . ( . – . )

Ever-smokers versus never-smokers:M . ( . – . )F . ( . – . )

Current-smokers versus never-smokersor exsmokers:

M . ( . – . )F . ( . – . )

Rotterdam Study Atrophic AMD

Neovascular AMD

RR . ( . – . ), RR ∗∗ . ( . – . )RR . ( . – . ), RR ∗∗ . ( . – . )

RR ∼ . ( . – . )

Blue Mountains Eye Study

Early AMDAll late AMDAtrophic AMDNeovascular AMD

. ( . – . )

. ( . – . )

. ( . – . )

. ( . – . )Visual Impairment Project AMD . ( . – . ), = 0.11Beaver Dam Offspring Study Early AMD . ( . – . )

Age-Related Eye Disease Study (AREDS) Early AMDAtrophic AMDNeovascular AMD

Ever-smokers versus never-smokers:. ( . – . ), < 0.01. ( . – . ), < 0.05. ( . – . ), < 0.01

EUREYE Study Atrophic AMDNeovascular AMD

Smoking in previous years. ( . – . ). ( . – . )

Eye Disease Case-Control Study Group Neovascular AMD . ( . – . ), = 0.002POLA Study Late AMD . ( . – . )Moon BG, Early AMD . ( . – . ), = 0.02

Cacket P, PCV

Neovascular AMD. ( . – . ), = 0.002. ( . – . ), < 0.001

Prospective Cohort Study AMD types Relative risk ( % CI)∗

Physicians’ Health Study Neovascular AMD . ( . – . ), < 0.001

Nurses’ Health Study All AMD

Current smokers . ( . - . ),Women who smoked or morecigarettes per day . ( . - . ),

< 0.04

Beaver Dam Eye Study, yearsEarly AMD

Progression o AMD

M . ( . – . )F . ( . – . )M . ( . – . )F . ( . – . )

Beaver Dam Eye Study, yearsEarly AMDLate AMD

Progression o AMD

. ( . – . )

. ( . – . )

. ( . – . )

Blue Mountains Eye Study, yearsGeographic atrophy Neovascular AMDAny late AMD

. ( . – . )

. ( . – . )

. ( . – . )

Blue Mountains Eye Study, yearsGeographic atrophy Neovascular AMDAny late AMD

. ( . – . ). ( . – . ). ( . – . )

AREDS ollowup Geographic atrophy . ( . – . )

. ( . – . )

Coleman AL, Early AMDLate AMDOR . ( . – . )OR . ( . – . )

∗

AMD: age-related macular degeneration; ∗

age and sex adjusted; ∗∗

less than years; ∼

more than years; CI: con dence interval; M: male; F: emale; RR:relative risk; POLA: Pathologies Oculaires Liées à l’Age; PCV: polypoidal choroidal vasculopathy; OR: odds ratio.


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CI: . – . ) [, ]. Te Physicians’ Health Study and theNurses’ Health Study nd signi cant - old higher risk o AMD in persons who had smoked more than cigarettesper day [ , ]. Te VIP Study results reveal that only theduration, notthe amount o smoking, isassociatedwith AMD[ ]. Inthe -year ollow-up results romtheBeaver Dam Eye

Study the relative risk o early AMD and progression o early AMDincreasedas theamount smoked increased [ ];the -year ollow-up results were inconsistent with earlier ndings

rom this and other studies, as no association o the amountsmoked or the incidence o late AMD was evidenced [ ].However, the Beaver Dam Offspring Study con rmed thatsmoking or more pack-years was associated with early AMD [ ]. Other studies in Korea and Japan also evidencedthat the level o smoking was associated with early and lateAMD [ , ].

. . . Te Effect o Quitting Smoking. Exsmokers still havean increased risk o developing AMD compared with never-smokers. Te Rotterdam Study was the rst to reveal thatthe increased risk o neovascular AMD remained present upto years afer cessation o smoking [ ], which was alsocon rmed in the POLA Study [ ]. Te Nurses’ Health Study reported that past-smoker women who previously smokedormorecigarettesperday had a - old increased risk o AMDeven years afer cessation o smoking [ ]. Other prospec-tive studies ound that ormer-smokers compared with thosewho never smoked had a modest increased risk o AMD [ ].

. . Mechanisms or oxic Damage to the Retina and Choroid Induced by Smoking. Cigarette smoke is known to containan abundant number o toxic compounds. Some o them areknown to be either toxic or mutagenic [ ]. Its pathologicaleffects through differentbiochemical pathwaysandan ocularexposure to cigarette smoke may cause oxidative damage, vascular changes, and in ammation within the pathogeniccascade o AMD. Smoke is responsible or cellular changesat the level o the RPE in AMD patients [ ].

. . . Angiogenesis and Neovascularization. Cigarette smokepromotes pathophysiological processes that contribute toatherosclerosis, including thrombosis, vascular in amma-tion, and endothelial dysregulation [ ]. Nicotine itsel promotes angiogenesis in experimental models due to its vasculogenic properties [ – ] and may also induce cate-cholamine release increasing platelet aggregability. Plateletscontribute to the growth o plaque through the accretion o thrombus, as well as through the release o growth actors(such as platelet-derived growth actor (PDGF)) that induce vascular smooth muscle cell proli eration. Te effect o nico-tine also enhances physiological angiogenesis, as observedin wound healing [ , ] where smoking is known to be arisk actor to delay the wound healing process. In a murinemodel o CNV, areas that underwent laser-induced ruptureo Bruch’s membrane are larger in mice afer nicotine expo-sure [ ]. Human choroidal and retinal arterial endothelialcells express nicotinic acetylcholine receptors (nAChR), andnicotine enhances their proli eration, migration, and tube-

orming ability. Nicotine also exerts a vasoconstrictive action

via -adrenergic stimulation which may impair blood ow through the choroid [ ].

Nornicotine, a metabolite o nicotine catalyses, can leadto the accumulation o lipo uscin and, there ore, also con-tribute to the ormation o drusen in RPE. Nornicotine cancatalyze the alkene isomerization o key retinal intermediates

through iminium-ion ormation and disrupt proper retinoidhomeostasis, revealing an underlying molecular mechanismor tobacco-dependent pathologies, particularly AMD [ ].

Cigarette smoke also contains dioxins that are presentprimarily in the gaseous phase. Most o the toxic effects o dioxins are mediated by the cytosolic dioxin receptor knownas aryl hydrocarbon receptor (AhR) [ , ]. Dioxin acts onocular tissues through the AhR pathway, promotes vascularendothelial growth actor (VEGF) production in mouseretinal tissues and human RPE cells, and exacerbates thedevelopment o laser-induced CNV in mice [ ].

. . . Oxidative Damage. Te oxidative damage to the RPE

contributesto thedevelopmentandprogressiono AMD, andthe alterations in the metabolic support o the RPE causeapoptosis o the photoreceptors [ , ]. Cigarette smokecontains a large number o prooxidant compounds. Nicotinepromotes nitric oxide (NO) production, and the effect o other proangiogenic growth actors [ ]. Cadmium accumu-lates pre erentially in the RPEandchoroid [ ] and may con-tribute to the development o AMD through an increase inreactive oxygenspecies (ROS). However, hydroquinone (HQ)is the most abundant oxidant and is not only in cigarettesmoke but also in processed oods, plastic containers, andatmospheric pollutants as well as its widespread occurrencein nature [ , ].

Te RPE cells provide support or the structure andunction o the outer retina by secreting several cytokines

including monocyte chemoattractant protein- (MCP- ) [ ,]. RPE cells afer exposure to HQ can secrete MCP-

during in ammatory responses promoting macrophagedys unction. MCP- expression is markedly decreased in RPEcells in smoker AMD patients and mightplaya key role in thepathogenesis o AMD [ , ]. Both in vitro and in vivo nd-ings suggest that HQ-induced oxidative damage is unequiv-ocally associated with an imbalance between VEGF andPEDF [ ] leading to pathological angiogenesis or the devel-opment o CNV [ ]. RPE cells rom smoker AMD patientsexhibit VEGF expression increase and PEDF expressiondecrease [ – ].

Te exposure to cigarette smoke and HQ results inRPE membrane blebbing and sub-RPE deposits in mice.In cultured RPE cells, HQ-induced oxidative injury resultsin reorganization o actin cytoskeleton and blebs ormationimportant or accumulation o deposits [ – ]. Afer expo-sure to HQ, phosphorylate heat shock protein (Hsp )expression increases, and there is an F-actin reorganizationrequired or RPE-derived bleb ormation [ ]. Tere ore,phosphorylated Hsp might be a key mediator in AMD.

Cigarette smoke extract (CSE) is widely used or in vitromodels [ – ]. CSE causes oxidative damage to humanRPE cells in vitro, cell death, signi cantly reduces viability in both ARPE- cells and primary RPE cells, via alterations


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in mitochondrial integrity, and increases lipid peroxidation[ ]. Lower concentrations o CSE may induce ROS releaseand thus cause oxidative stress in primary human RPEcells. reatment o primary human RPE cultures with CSEcould signi cantly increase the proportion o -galactosidase(SA- -Gal) cells [ ]. Sublethal concentrations o hydrogen

peroxide have been shown to induce senescence associatedto SA- -Gal activity in primary cultured RPE cells [ ] andin vivo in RPE cells o old primate eyes [ ].

Other molecules are involved in oxidative damage. Expo-sure o primary human RPE cells to CSE may also leadto signi cant elevations o Apo J, C GF, and bronectinexpression, which are senescence-associatedbiomarkers [ ].All three biomarkers are inducible by oxidative stress [ , ]and have been previously detected in the RPE o AMDdonor eyes, although its role and unction in the RPE remainunclear.

Oxidative stress is thought to be essential in lipo uscinand drusen ormation [ , ]. Acrolein, an unsaturatedaldehyde ound in the gas phase o cigarette smoke, exerts anoxidant-mediated damage by inducingproteinmodi cations.RPE cells exposed to acrolein show a decrease in viability andmitochondrial membrane potential due to oxidative stress[ ]. In theacrolein RPEmodel, there is a signi cant decreasein mitochondrial membrane potential, oxygen consumption,and activity o mitochondrial complexes, and it increasedsigni cantly the calcium-ion level [ ].

. . . oxicity. Polycyclic aromatic hydrocarbons (PAHs) areone o the most toxic compounds in cigarette smoke [ ].Tey orm DNA adducts. Benzo(a)pyrene (B(a)P) is a PAHwith toxic effects on cultured RPE and RPE/choroid rombovine exposedto chroniccigarettesmoke. Itcauses extensivemitochondrialDNA damage andincreases lysosomal activity,

ormation o a reactive epoxide [ ], and caspase-mediatedcell apoptosis o human RPE cells [ ] perhaps through thegeneration o epoxides.Tese altered cell biological processesin the RPE may contribute to the ormation o drusen in indi- viduals who are cigarette smokers and underlie susceptibility to genetic mutations associated with AMD.

. . . Experimental Models. ARPE- cells, a spontaneously arising human RPE cell line [ ], are widely used or in vitrostudies o cigarette smoke effect in RPE cells. Tese cells aretreated with different toxic substances derived rom cigarettesmoke such as HQ [ ], acrolein [ , ], CSE [ , ], B(a)P[ ], cadmium [ ], and , , , -tetrachlorodibenzo- p-dioxin( CDD) [ ]. Recently, the effect o the HQ has been studiedin a combination o three cellular lines: ARPE- cells, ratretinal neurosensory cells (R- ), and human microvascularcells (HMVEC), to demonstrate that nonapoptotic cell deathcan occurin many ormsaferthedamage[ ]. Humandonoreyes obtained rom the eye bank are processed to obtainhuman RPE cells. Tese cellular lines are exposed to HQ [ ]and CSE [ ] to demonstrate a decrease in the viability aferdamage. On the other hand, bovine RPE cells also are usedin in vitro experiments to study the effect o exogenous B(a)P[ ]. Other types o experiments include RPE/choroids rommice to analyze the treatment o HQ [ , ].

. . . In Vivo Animal Models. As in in vitro models, the sametoxic compounds are used in animals to investigate the effecto cigarette smoke in the retina. C BL/ -pigmented miceare the most widely used in the literature. Hence, these micereceive HQ orally in drinking water or a period o time[ ] and are injected intraperitoneally with CDD [ ]. On

the other hand, mice are placed into a smoking chamberor a period o time to analyze the effect o the CSE. Tischamber containsa smoking machine in differentmodelsthatburns some cigarettes. Control mice are kept in a ltered-air environment [ , , ]. Cigarette smoke has been alsostudied in RPE sheets rom rats exposed to nicotine indrinking water [ ].

. . . Histopathological Changes. Te RPE constitutes a cellmonolayer that is crucial to maintain a normalphotoreceptor

unction. RPE cell apoptosis and basal deposits, or accumu-lations o heterogeneous debris in Bruch’s membrane, are twocritical histopathologic changes that are well recognized to

occur during the development o early AMD [ ]. Fujiharaet al. observed these changes in mice afer chronic exposureto cigarette smoke [ ], and Espinosa-Heidmann showedthat shorter duration and higher concentration o cigarettesmoke in old mice induce ultrastructural changes to Bruch’smembrane and the choriocapillaris endothelium that arecompatible with early AMD [ ].

In summary, the most important alterations observedare Bruch’s membrane thickening, mild basal deposits andenlargement, and loss o basolateral in oldings, which are anestablished marker o epithelial cell injury. Te ormation o vacuoles is a second sign o RPE damage.

4. Biomarkers and Smoking in AMDIn order to look or the most appropriate therapies and toindividualize li estyle recommendations, it is ideally neces-sary to integrate the different clinical eatures, the habits, and,i available, the biomarkers o a certain disease. A biomarkeris a characteristic objectivelymeasured andevaluatedas indi-cator o physiologic/pathologic processes or pharmacologicresponses.

Different biomarkers have been studied in AMD patients[ – ]. However, very limited in ormation exists aboutbiomarkers in smokers and type, stage, and progressiono AMD or clinical response to treatment. Seddon et al.evaluated the association o serum C-reactive protein (CRP)levels and the risk o AMD, showing that in the smokingpopulation this risk was increased more than . - old in thelower PCR levels (CRP < . mg/L). Tere was no associationbetween smoking and AMD in the highest level o CRP(CRP > . mg/L). However, the CRPlevelswere signi cantly higher among participants with advanced AMD (casepatients) than among those with no AMD (controls; median values: . versus . mg/L; = .02), so the highest levels o CRP seem to increase the risk o AMD independently o smoking [ ].

In a subsequent study, Seddon et al. ound that smok-ing had a positive association with some proin ammatory cardiovascular disease biomarkers such as CRP, interleukin


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, soluble tumor necrosis actor alpha receptor , solubleintercellularadhesion molecule- (ICAM- ), and apolipopro-tein B (ApoB) but not with vascular cell adhesion molecule-(VCAM- ) or lipoprotein(a) in nonexudative AMD [ ].

Gibson et al. assessed the levels o plasmatic complementcomponent C inhibitor (C inh), and they ound that C inh

levels were higher in smokers compared to nonsmokers[ ]. Tese results highlight the importance o consideringsmoking status in AMD populations.

Other biomarkers have been studied separately in smok-ers versus nonsmokers and AMD patients versus normalpatients and a parallel increase (e.g., increased levels o lipidperoxidation products) anddecrease (e.g., decreased levels o antioxidants) o considered markers have been ound in bothkinds o studies [ , – ].

5. Treatment Considerations for AMD Smoking Patients

Tere is limited in ormation about the speci c treatment o dry and wet AMD in smokers. Te use o antioxidant supple-mentation consisting o vitamin C ( mg), vitamin E (international units), beta-carotene ( mg), zinc ( mg),and copper ( mg) demonstrated reduction o the risk o progression to advanced dry AMD in the AREDS Study withan average ollowup o . years. Some evidence suggestedthat smokers taking beta-carotene supplementation had anincreased risk o lung cancer [ , ]. However, at the end o the study, the in uence o treatment on mortality strati edby smoking status oundno effect orcurrent-smokerswho took antioxidants. Otherwise, the small proportion o deaths romlung cancer ( . %) in theAREDS Studyshowedno differencebetween treatments [ ].

More recently, the AREDS Study showed that the addi-tion o omega- atty acids and/or lutein+zeaxanthin to thethe original AREDS ormulation only reduces by % the risk o progression to advanced dry AMD or neovascular AMD[ ]. Moreover, there was no effect o beta-carotene elimi-nation or lower zinc dose to the original AREDS ormulationon progression to advanced AMD. Given the hypotheticrisk o lung cancer due to beta-carotene supplementation,current- or ormer-smokerswithin thepast year were allowedto participate in the study only in the groups not receivingbeta-carotene. Te incidence o lung cancer was higher inthe beta-carotene ( %) group than in the non-beta-carotenegroup ( . %), mainly in ormer-smokers ( % o partici-pants who developed lung cancer were ormer-smokers).Te simultaneous administration o high doses o beta-carotene and lutein+zeaxanthin may suppress serum andtissue levels o lutein+zeaxanthin due to the competitiveabsorptiono carotenoids.Te AREDS Study concludedthatlutein+zeaxanthin could be a sa e carotenoid substitute in theAREDS ormulation [ ].

In addition, the in uence o smoking on the visual out-comes in cases o neovascular AMD treated with intravitreal vascular endothelial growth actor inhibitors has also beenanalyzed. Lee et al. evidenced that smokers had a statistically signi cant higher risk ( - old increase) or a poor responseto intravitreal therapies [ ], whereas other authors ound

better unctional outcomes in nonsmokers compared withsmokers but without statistical signi cance [ ]. Te mech-anism or the negative in uence o cigarette smoking in theresponse to these therapies is poorly understood.

6. Conclusions

Age-related macular degeneration (AMD) is the commonestcause o irreversible visual loss in the Western World [ – ].AMD is a complex multi actorial disease with an uncertainetiology associated with genetic and environmental risk ac-tors. Te hypothesis that interventionstrying to minimize therole o such environmental actors may reduce the incidenceo AMDand/or theprogression to late stageshas ledto severalstudies evaluating their relevance in the clinical practice.

Among them, cigarette smoking is a proven risk actor orboth development and progression o AMD [ – ], as wellas or the clinical response in both atrophic and neovascular

orms o AMD [ – ]. As has been previously described,

smoking by itsel promotes molecular and pathologicalchanges that may establish an ideal macular microenviron-ment or the development o AMD: vascular in ammationand endothelial dysregulation [ – ], oxidative damage[ – ], toxic damage, and histopathological changes [ –

]. However, patients are not requently aware o the signi -cant role played by cigarette smoking in blindness associatedwith AMD. Sometimes, evenphysicians orget aboutadvisingpatients o the relevance to quit smoking. Quitting smokingreduces the risk o AMD, and afer years o cessationthe risk o developing AMD is the same as or nonsmokers[ , ].

Recently, genetic testing hasarisen as anoptionto providepatients with a certain risk pro le based on their own geneticphenotypes in the high-risk genes or AMD [ – ]. Tisis even more relevant in smoking subjects, as a genetic high-risk pro le might in uence their motivation to quit smoking[ ].

In the situation described above, we believe that institu-tional support to disseminate the relevance o cigarette smok-ing in terms o visual health is warranted. Very ew coun-tries show health warnings on cigarette packets related tothis issue (“SMOKING CAUSES BLINDNESS”), whereasseveral other health issues warnings are usually included.

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Smoking and Age-Related Macular Degeneration: Review and Update