Micronutrients and Age-Related Macular Degeneration

by Emily Y. Chew, MD Age-related macular degeneration (AMD) is the most common cause of visual impairment in the US.1 The disease is projected to increase at an alarming rate as the longevit of the American population increases.! The treatment of AMD is currentl limited "ith the use of laser photocoagulation#$#% photod namic therap #&#' and surgical procedures. Although the pathogenesis of AMD is un(no"n# there is gro"ing evidence that o)idative stress ma pla a role.*#+ The results of the Age-,elated - e Disease Stud (A,-DS) sho"ed that oral supplements of high dose antio)idant vitamins .# -# and /eta-carotene and 0inc ("ith copper) reduced the ris( of progression to advanced AMD.1 Smo(ing is also a (no"n ris( factor associated "ith the ris( of AMD and smo(ing is (no"n to deplete the /od 2s antio)dative potential.13 These data further support the possi/le role of o)idative stress in AMD. Carotenoids: Lutein !ea"anthin The role of micronutrients in the pathogenesis of AMD "as e)plored in 11++.11 4nvestigators revie"ed the dietar inta(e of patients "ith and "ithout AMD in the first 56A5-S (5ational 6ealth and 5utritional -)amination 6ealth Surve ) and found that participants "ith the highest consumption of fruits and vegeta/les rich in vitamins A and . reduced their ris( of AMD / as much as %17 "hen compared to participants "ho did not eat such foods. The - e Disease .ase .ontrol Stud # conducted / the 5ational - e 4nstitute# compared /lood levels of carotenoids and other vitamins in patients "ho had neovascular AMD "ith those "ithout AMD.1! The stud found that patients "ith the highest /lood levels of carotenoids# compared "ith those "ith the lo"est levels# had the lo"est ris( of macular degeneration# "ith reductions as high as *3 percent. 8atients "ith moderate /lood levels of carotenoids had a &3 percent ris( reduction. 4n addition#

patients "ith a high dietar inta(e of the carotenoids lutein and 0ea)anthin# found in green leaf vegeta/les such as spinach and collard greens# had a %$ percent or more ris( reduction for AMD compared "ith those "ith lo" or minimal inta(e.1$ The higher consumption of these foods "as associated "ith a lo"er ris( of AMD# appearing to sho" a dose response. The lo"est ris( of AMD "as found in participants eating spinach si) times a "ee( "hen compared to those "ho never eat the vegeta/le. This association of dietar lutetin90ea)anthin "ith AMD "as also found in the third 56A5-S stud .1% :utein and 0ea)anthin are the major components of the ello" pigment found in the center part of the mammalian e e. :i(e other vitamins# lutein and 0ea)anthin are not manufactured / the /od # so the must /e consumed in the diet. The act as the major filter for ultraviolet radiation# and as such# might help prevent o)idative stress. 4n plants# lutein acts li(e a sunscreen; plants that are deficient in the vitamin /ecome scorched. :utein is often touted as a treatment for macular degeneration. 6o"ever# this is /ased upon o/servational# case-controlled studies and such information is inconclusive due to un(no"n# confounding factors that ma influence findings. <or e)ample# a person2s decision to ta(e vitamin supplements ma /e associated "ith their socioeconomic status or "ith patient compliance. 4n other "ords# patients "ho ta(e vitamins ma # in general# /e of higher socioeconomic status# or ma /e more compliant in ta(ing medicines for high /lood pressure or other conditions. 4n general# people "ho ta(e dietar supplements ma other"ise ta(e /etter care of themselves. Age-Related Eye Disease #tudy $ARED#% 4n 111!# the 5ational - e 4nstitute mounted a controlled clinical trial called the Age-,elated - e Disease Stud (A,-DS) to evaluate the role of antio)idant vitamins and 0inc in the treatment of age-related cataract and macular degeneration.1& =nl rigorous testing in controlled clinical trials that account for (no"n and un(no"n confounders can determine "hether a treatment is effective for a given disease or condition.

A,-DS "as designed to e)amine the natural histor of macular degeneration and cataract# /ut an additional interest "as the investigation of the nutritional aspects of these diseases through a randomi0ed trial. >oals of the stud included determining "hether antio)idants or minerals could slo" the progression of lens opacit in cataract# and "hether these nutrients could prevent or slo" the progression of AMD. The %#*&* patients in the stud "ere randoml assigned to one of four treatment groups? place/o (a sham treatment); antio)idants; 0inc; or antio)idants plus 0inc. The antio)idants used in the stud "ere vitamin . (&33 mg9da )# vitamin - (%33 4U9da )# and /eta-carotene (1& mg9da or !&33 4U9da ). @hen the A,-DS "as designed# lutein and 0ea)anthin "ere not commerciall availa/le and thus not tested. Ainc (+3 mg9da ) "as given together "ith copper (! mg9da ). Ainc "as of interest /ecause man patients "ere alread ta(ing this mineral /ased on the results of just a single small stud done in the 11+3s that sho"ed /enefit in reducing minor vision impairment.1' Because 0inc at high doses can cause significant health pro/lems# including copper deficient-anemia# in the A,-DS stud # copper "as given to counter the harmful effects of 0inc. As of !331 "hen the major A,-DS results "ere announced# the patients had /een follo"ed for an average of more than si) ears. Cataract After five ears# cataracts developed in !1.+ percent of patients "ho too( antio)idants and $3.% percent "ho did not ta(e antio)idants. Thus# the antio)idants "ere neither /eneficial nor harmful in terms of cataract development# nor "ere the /eneficial in preventing surger for cataract. At five ears# 13.& percent "ho too( antio)idants# and 11.$ percent "ho did not# under"ent cataract surger . :oss of visual acuit "ith cataract at five ears "as virtuall the same in /oth groups C %.* percent in the antio)idant

group and %.+ percent in those not ta(ing antio)idants. These antio)idant vitamins are not recommended for the prevention or treatment of cataracts. Age-Related Macular Degeneration <our groups of patients "ith var ing ris( of AMD "ere enrolled in A,-DS. The ris( of AMD "as identified / an e)amination of the retina to evaluate the si0e and the area of drusen# or ello" spots. Although people "ith no ris( for macular degeneration normall develop a fe" drusen over their lifetime# patients "ith AMD have more and larger drusen. The four AMD groups included? 1) people thought to have no ris( for macular degeneration (fe" or no drusen); !) people at ris( for earl AMD (intermediate drusen); $) people "ith intermediate ris( for AMD (e)tensive intermediate or large drusen); and %) people "ho alread have AMD in one e e and one unaffected e e. 8atients at lo" ris( for macular degeneration "ere not given 0inc /ecause of its potential harmful effects. The stud of 0inc "as limited to those "ho had earl AMD or "orse. 4n all clinical trials# some of the most valua/le data includes information on the natural histor of the disease. 4n AMD# it "as found that people "ith small to moderate drusen had a ver lo" ris( of developing advanced disease. At five ears# onl 1.$ percent developed the advanced form of AMD. 8eople at intermediate ris(# "ho had moderate to large drusen# had an 1+ percent chance of developing advanced AMD in five ears. 8eople "ho alread had macular degeneration in one e e had the highest ris( C %$ percent C of developing advanced disease. The results of the randomi0ed# controlled clinical trial sho"ed that !+ percent of the patients ta(ing place/o developed advanced AMD C either the neovascular or the atroph ic form C after five ears. =f those ta(ing the com/ination of antio)idants and 0inc# onl !3 percent developed advanced disease in & ears. The com/ination

treatment "ith 0inc and antio)idants reduced the ris( of advanced AMD / !& percent "hile 0inc alone reduced the ris( / !1 percent# and antio)idants alone reduced the ris( of advanced AMD / 1*. The com/ination treatment "as the /est. ,egarding vision loss# !1 percent of patients ta(ing place/o developed moderate vision loss at the end of five ears# "hereas !$ percent of patients ta(ing antio)idants and 0inc actuall had a reduction in terms of moderate vision loss. >iven alone# the antio)idants and 0inc "ere each effective to some e)tent in preventing macular degeneration and in preserving vision# /ut the com/ination therap again resulted in the most /eneficial effects. A,-DS is the first vitamin stud that has sho"n /eneficial effects for a disease of considera/le pu/lic health significance and is the first stud in "hich a treatment has /een sho"n to prevent the development of macular degeneration. Ris&s o' (itamin )hera*y The ris(s associated "ith the treatment used in A,-DS include? 1. 8ossi/le increased ris( of lung cancer in people alread at ris(. As "as sho"n in the 546 sponsored Alpha-Tocopherol Beta-.arotene Trial (ATB. trial)1* in <inland# heav smo(ers "ho too( /eta carotene significantl increased their ris( of developing lung cancer. 4n addition# the .A,-T Stud 1+ (the /eta-.arotene and ,etinol -fficac Trial)# "hich follo"ed the ATB. trial# replicated much of the findings of the former stud in patients "ho "ere either heav smo(ers or had e)posure to as/estos. This stud "as also sponsored / the 546. As in the ATB. trial# participants in .A,-T "ho too( /eta-carotene had an increased ris( of developing lung cancer and an increased death rate. Thus# /eta carotene therap for AMD "ould not /e recommended in smo(ers or others at ris( for lung cancer.

!. S(in ello"ing. Beta-carotene increased the ello"ing of the s(in. This discoloration has no health conseDuence. $. >enital9urinar pro/lems. Ainc use increased hospitali0ations for genital and urinar pro/lems. The most common pro/lem "as prostate enlargement in men. %. 8ossi/le adverse effects on cholesterol levels. Although the A,-DS stud found no treatment effect on cholesterol# previous studies have reported that 0inc ma cause a decrease in 6D: (EgoodF) cholesterol or an increase in :D: (E/adF) cholesterol. &. Anemia from Ainc. The A,-DS sho"ed no increase in anemia in those patients ta(ing 0inc. =verall# the A,-DS stud sho"ed that# at the '- ear follo"-up# com/ination therap "ith 0inc and antio)idants proved /eneficial for AMD "ith fairl fe" side effects. 8atients enrolled "ill /e follo"ed for additional ears to assess long-term effects. +ho #hould )a&e (itamin )hera*y 'or AMD, The American Academ of =phthalmolog recommends that people over age '& have a earl e e e)am "ith pupil dilation to screen for cataract# glaucoma# and macular degeneration. 8eople "ho are not at ris( for AMD# and even those at the lo" ris( end C those "ith fe" drusen C need not ta(e vitamins since# in five ears2 time# onl one percent of people in this group develop the disease. This ris( is determined / the ophthalmologist follo"ing a dilated e e e)am. 8atients "ho have a famil histor of AMD ma not necessaril /e in the higher ris( group for AMD and ma not /enefit from ta(ing these supplements.

4t is estimated that a/out && million people over the age of && in the United States toda ma /e at ris( for macular degeneration. =f these# eight million are at high ris( and are the people "ho are li(el to /enefit from com/ination 0inc and antio)idant therap . 4f all eight million people at high ris( for AMD too( supplement therap # more than $33#333 of them could /e saved from advanced AMD in the ne)t five ears. Re'erences 1 .ongdon 5# =2.olmain B# Glaver ..# Glein ,# Muno0 B# <riedman DS# Gempen H# Ta lor 6,# Mitchell 8; - e Disease 8revalence ,esearch >roup. .auses and prevalence of visual impairment among adults in the United States. Arch =phthalmol. !33%;1!!?%**-+&1 !. Th lefors B. A glo/al initiative for the elimination of avoida/le /lindness. Am H =phthalmol. 111+;1!&?13-1$. $. Macular 8hotocoagulation Stud >roup. Argon laser photocoagulation for senile macular degeneration. Arch. =phthalmol. 11+!;133?11!I11+. %. Macular 8hotocoagulation Stud >roup# 11+'. Argon laser photocoagulation for neovascular maculopath . Threeear results from randomi0ed clinical trials. Arch. =phthalmol. 11+';13%?'1%I*31. &. TA8 Stud >roup. 8hotod namic therap of su/foveal choroidal neovasculari0ation in age-related macular degeneration "ith verteporfin? one- ear results of ! randomi0ed clinical trials-TA8 report. Treatment of age-related macular degeneration "ith photod namic therap .(TA8) Stud >roup. Arch =phthalmol. 1111; 11*?1$!1-%& '. Jerteporfin therap of su/foveal choroidal neovasculari0ation in agerelated macular degeneration? t"o- ear results of a randomi0ed clinical trial including lesions "ith occult "ith no classic choroidal neovasculari0ation-

verteporfin in photod namic therap report !. Am H =phthalmol. !331; 1$1?&%1-'3. *. Koung# ,.@.# 11++. Solar radiation and age-related macular degeneration. Surv. =phthalmol. 11++;$!; !&!I!'1. +. Beatt # S.# Goh# 6.-6.# 6enson# D.# Boulton# M. The role of o)idative stress in the pathogenesis of age-related macular degeneration. Surv. =phthalmol. !333; %&? 11&I1$%. 1. Age-related - e Disease Stud ,esearch >roup. A randomi0ed# place/ocontrolled# clinical trial of high-dose supplementation "ith vitamins . and -# /eta carotene# and 0inc for age-related macular degeneration and vision loss? A,-DS report no. 1. Arch =phthalmol. !331;111? 1%$1-&!. 13. Age-,elated - e Disease Stud ,esearch >roup. ,is( factors associated "ith age-related macular degeneration. A case-control stud in the agerelated e e disease stud ? age-related e e disease stud report num/er $. =phthalmolog . !333; 13*?!!!%-$!. 11. >old/erg H# <lo"erde" ># Smith -# et al. <actors associated "ith agerelated macular degeneration. An anal sis of data from the first 5ational 6ealth and 5utrition -)amination Surve . Am H -pidemiol. 11++;1!+?*3313. 1!. The - e Diseases .ase-.ontrol Sutd >roup. Antio)idant status and 5eovascular age related macular degeneration. Arch =phthalmol. 111$;111?1*31-1*3+. 1$. Seddon H# Ajani U# Sperduto ,# et al. Dietar carotenoids# vitamins A# .# and -# and advanced age-related macular degeneration. HAMA. 111%;!*!?1%1$-!3. -rratum in? HAMA. 111&;!*$?'!!.

1%. Mares-8erlman HA# <isher A4# Glein ,# et al. :utein and 0ea)anthin in the diet and serum and their relation to age-related maculopath in the third national health and nutrition e)amination surve . Am H -pidemiol. !331;1&$(&)?%!%-%$!. 1&. The Age-,elated - e Disease Stud ,esearch >roup. Design 8aper# the Age-,elated - e Disease Stud (A,-DS)? Design implication. A,-DS ,eport no. 1. .ontrol .lin Trials 1111;!3?&*$-'33. 1'. 5e"some DA# S"art0 M# :eone 5.# -lston ,.# Miller -. =ral 0inc in macular degeneration. Arch =phthalmol. 11++;13'?11!-11+. 1*. The Alpha-Tocopherol# Beta .arotene .ancer 8revention Stud >roup. The effect of vitamin - and /eta carotene on the incidence of lung cancer and other cancers in male smo(ers. 5 -ngl H Med. 111%;$$3?13!1-13$&. 1+. =menn >S# >oodman >-# ThornDuist MD# et al. -ffects of a com/ination of /etacarotene and vitamin A on lung cancer and cardiovascular disease. 5 -ngl H Med.111';$$%?11&3-11&&. -mil K. .he"# MD# Division of -pidemiolog and .linical ,esearch# 5ational - e 4nstitute95ational 4nstitutes of 6ealth# Bethesda# MD.