1992 riesgo de mujeres obesas para litisi vesicular

8/4/2019 1992 Riesgo de Mujeres Obesas Para Litisi Vesicular

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65 2 Am J C /in Nuir l992 ;5 5 :652-8 . P rin ted in U SA . 1992 Am erican Soc ie ty fo r G in ica l N u trition

R isk o f sym p tom a tic ga lls tones in w om enw ith seve re o bes ity 3M eir J S tam p ftr , K M alco lm M ac lure, G raham A C old itz , JoA nn E M anson , an d W alte r C W ille tt

ABSTRACT A ltho ugh ob es ity is a w e ll-reco gn ized risk fac-to r fo r g allsto nes, the excess risks assoc iated w ith h igher leve lsof ob esity and recen t w e ig h t chan ge are p oorly qu an tified . W eeva lua ted th ese issu es in th e N urse s H ea lth S tu dy . Am ong90 302 w om en ag ed 34-59 y at base line fo llow ed from 1980 to1988 , 2122 cases o f new ly d iagn osed sym ptom atic ga llstonesoccurred during 607 104 person-y ears o f fo llow -u p . F rom 1980to 198 6 , 48 8 cases o f n ew ly d iagno sed unrem ov ed g alls tonesw ere docum en ted . W e observed a strik ing m ono ton ic inc rea sein ga llston e d isease risk w ith obes ity ; w om en w ith a b ody m assindex (BM I) > 45 kg /m 2 h ad a sev en fo ld excess risk com paredw ith those w hose BM I w as 24 kg /m 2. W om en w ith a BM I> 30 kg /m 2 had a yea rly ga lls to ne inc idence of1% and thosew ith a BM I 45 kg /m 2 had a ra te o f 2% /y . R ecen t w eigh tlo ss w as asso c iated w ith a m odestly inc rea sed risk afte r ad just-m en t fo r BM I b efo re w eigh t loss. C urren t sm okin g w as an in -depend en t risk fac to r ; w om en sm ok ing 35 c igare ttes /d had are la tive r isk o f 1 .5 (95% C I 1 .2 -1 .9 ). Am J C lin N u ir l992 ;55 :652-8.

KEY W ORD S Cholecystec tom y , ga lston es obesity , women ,c ig arette sm oking , w eig h t loss

In troduct ionO besity is a w ell-estab lish ed risk fac to r fo r g alls to nes (1 -7 ).

T he m agn itu de o fthe in c rea sed risk an d th e ra te s o fccurrenceo f sym p tom a tic g alls to nes, h ow eve r, hav e no teen w ell quan-tified , pa rticu la rly am ong the m ost o bese , w ho are a t h ighes tr isk . W om en w ho em bark on rap id w eig h t- lo ss p ro g ram s usingv e ry -low -ca lo r ie d ie ts a re ap pa ren tly a t inc rea sed risk fo r lith -ogenesis (8 , 9 ). H ow ever, because su ch w om en a re gene ra llyo bese , the ex cess r isk du e to th e ex trem e d iet is d iff icu lt to qu an-tify because ra tes of sym ptom atic ga lls tones am ong th e ve ryobese have n o t been p ub lished . In an ea rlie r repo rt from theNurses Hea lth S tu dy based on 4 y of fo llow -up , w e found tha tcom pared w ith w om en w ith a body m assndex (BM I m easu redin kg /m 2) < 20 , those w om en w ith a BM I of 3 2 had a re la tiverisk of sym ptom atic ga llston es of 6 .095 % con fid en ce in te rv al(C I) 4 .0 -9 .0 ] and th at 70% of the g alls tones in th ose w om enw ere attr ibu tab le to o besity (1 ) . In th is repo rt w e ex tend th efo llow -up to 8 y and ex am ine bo th th e ra tes o f occurrence andth e re la tive r isk s b y leve l o f o besity , p ay ing pa rticu la r atten tio nto the h ig hest leve ls o f o ve rw e igh t.

D a ta on the effec t o f w e igh t lo ss on g alls to ne d isea se in ag ene ra l p opu latio n a re a lso spa rse. H ence , w e a lso asse ss the

im pac t o f w eigh t change in a 2-y in te rva l on risk of c lin ica llysym p tom a tic ga lls tones in the su bsequ en t 2 -y in terva l. P rev iouswo rk sugges ted an asso cia tion b etw een sm ok in g and ga lls tones(4 ) . W e also ad dress th is is sue in o ur la rge p rosp ec tive coho rt o fw om en .

S ub jec ts and m e thod s

Th e N u rse s H ea lth S tudy coho rtThe N urses H ea lth S tud y began in 1 976 w hen 12 100 f ema l e

reg iste red nurse s liv ing in 1 1 large U S sta te s com ple ted a m a iledq uestion na ire th at inc luded item s abou t the ired ica l h isto ryand risk facto rs fo r co ron ary d isea se and can cer1 0 ) inc lud inghe igh t, w e igh t, cu rren t an d past sm ok ing hab its , an dse o f po st-menopausa l horm ones. H e igh t an d w e igh t w ere used to com puteBM I, de fin ed as w eig h t in k ilog ram s d iv ided by he igh t in m e tersto th e seco nd pow er, a s an in dex ofad ipo sity . Eve ry 2 y , fo llow -up questionn a ire s w ere m ailed to u pda te the in fo rm a tion onpo ten tial r isk fac to rs and to iden tify n ew ly d iagn osedcases ofva rio us illne sse s. In 1 980 a sem iqu an titativ e food frequencyqu estionn aire w as ad ded (1 1) .Iden tifica tion o fsym p tom atic g a lls ton es

S ta r tin g w ith the 19 82 fo llow -up question na ire , w e asked thepa rtic ip atin g nurse s to rep ort w h eth er they had h ad a cho lecys -tectom y or h ad been g iv en a d iagn osis o f ga lls ton es w itho u t re-m ov al. W e a lso inqu ired w he the r sym ptom s w ere p re sen t and ,fo r the cases w ithou t cho lecys tec tom y , w h eth er the d iagno sisw as co nfirm ed by x ray or u ltrasoun d . In th e 1 988 qu estio nna irethe qu estio n abo u t un trea ted g alls to nes w as om itted bu t the itemconce rn ing cho lecy stectom y w as reta ined .

W e asse ssed th e va lid ity o fthe se lf-repo rt o f cho lecys tec tom yand un rem oved ga lls tones in tw o ran dom sam p les o f 5 0 n urseseach w ho repo rted these con d ition s. O f 43 w ho responded fo

I F rom the Ch ann ing L abora to ry , D epartm en t o fM edic in e , B righamand W om ens H osp ita l and H arvard M edica l S choo l, and th e D epart-m en ts o fE p idem io logy and N u tr ition , H arv ard S choo lo fP ub lic H ea lth ,Bos ton .

2 Suppo rted by re sea rch gran ts CA 40356 and DK 36798 from theN ationa l Ins titu tes o f H ea lth and by Sandoz Pharm aceu tica ls .

3 A dd re ss re prin t requ es ts to M J S tam pfer, 180 Longw ood Avenu e ,Bosto n , MA 02115 .

R ece iv ed M ay 20 , 1 991 .A ccep ted fo r pu b lica tion A ugus t 1 5 , 19 91 .


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GALLSTON ES IN W OM EN W ITH SEVERE OBES ITY 65 3cho lecys tectom y all re ite ra ted the in itia l report, and th is w ascon firm ed in a ll cases fo r w hich w e cou ld ob ta in record sn= 36 records rev iew ed). F or unrem ov ed g allsto nes the o rig ina ld iagn osis w as re ite ra ted by a ll 35 responden ts an d confirm ed in1 5 o f th e 1 6 m edica l records w e cou ld ob ta in (1 ).Population fo r analysis

The popu la tion w as lim ited to w om en w ho re tu rned the fo l-low -up questionn aires in 1 982 or in subsequen t fo llow -up cy c lesand w ho prov ided in fo rm ation on he igh t and curren t w eig h t.B ecause w e w ere in teres ted in new ly d iagno sed illness , w e ex-clud ed w om en w ith cho lecy stec tom y or a d iag nosis o f ga llstonesbefo re the re tu rn o fthe 19 80 question na ire. In our ea rlie r rep orts(1 , 12 ) th e m ain focus w as on d ieta ryde te rm in an ts o f ga llb ladd erd isease . T o avo id th e po ssib ility th at sym p tom a tic bu t u nd i-ag nosed g alls to nes m igh t in fluence the repo rt o fd iet, w e exc ludedfrom tho se earlier ana lyses a ll w om en w ho repo rted on the sup-p lem en ta ry ques tio nna ire tha t th ey had ex perienced sym p tom sofga llstones befo re re tu rn o fthe 1980 ques tion na ire even if thed iag nos is w as m ad e afte r the re tu rn oftha t ques tio nna ire . In thepresen t ana lysis th e fo cu s is o n inc idence ra tes and re la tive risksby ca teg ories o f overw eig h t; hence , w e on ly exc luded w om enwhose d iag nosis o f ga lls ton es p receded the retu rn o f th e 1980questionn a ire . Th e ear lie r exc lusions w ere justified in a d ie ta rystudy to avo id b ias becau se sym p tom s a ttribu ted to ga llston esby the sub jec t (w he ther co rrec tly o r no t) m ay have leder toa lte r he r d ie t. H ow ever, in the presen t ana lysis such an ex c lu sionwould re su lt in g ro ss u nde re stim atio n of in cid en ce rate s , e s-p ec ia lly b ecause the repor t o f sym ptom s due to g alls to nes isno to r io usly inaccura te ( 1 3). A lso , su ch an exc lusion w ou ld beu nnecessary b ecause the presence ofp red iag nostic sym p tom s o fga llb ladd er d isease w ould be un like ly to in flu ence b odyeigh t .E ven if it d id , such a chang e w ou ld be taken in to con side ra tionin th e an alys is because w eigh t is up da ted every 2 y on the fo llow -u p qu estionna ires. W e exc luded w om en w ho reported the d i-agn osis o fg allston es w ithou t sym ptom s, w hich usu a lly o ccu rredas an inc iden tal fin d ing d urin g an exam ina tion or su rge ry fo rano the r ind ica tion . S u ch w om en w ere ex clu ded from sub sequen tfo llow -u p and w ere n o t coun ted as casesn th is ana lysis .

W e v alid ated the se lf-rep o rt o f w e igh t in a sam ple o f B osto n -area p artic ipan ts b y com parin g th eir se lf-repo rted w eig h ts w ithtechn ic ian -m easu red va lues tak en 6- 1 2 m o afte r th e qu estion -n aire w as com ple ted . T he correla tion be tw een the se lf-repo rtan d m easu red v alues w as = 0 .97 ( 14). T h e m ean se lf-repo rtedw eigh t w as 1 .5 kg low er than the m easured w eigh t, com patib lew ith the d ifference be tw een a casua l w e ig h t w ith ligh t clo th ingan d a m orn ing pos tvo id nud e w e igh t.

In 1980 , 90 302 w om en en tered th e ana lys is fo r th e 19 80-1982 in te rva l. D uring the 8 y of fo llow -u p from the re tu rn o fth e 1980 questionna ire un til June 1 , 1 988 , w e accrued 607 104perso n-years o f fo llow -u p . T he fo llow -up fo r new ly d iagnosedsym p tom atic bu t unrem oved ga llstones ex ten ded from the retu rnof th e 1980 questionna ire u n til June 1 , 19 86 , fo r a to tal o f474 768 perso n-years o f fo llow -up .

O ur proced ures a re approv ed by the e th ic s comm ittee s o fB righ am and W om ens H osp ita l and H arv ardMed i c a l Schoo l ,and the H arvard S choo l o fP ub lic H ea lth , and are in accord w iththe H els ink i D ec laration .D ata analysi s

The prim ary ana lysis is based on inc idence ra tes using person-m onths o f fo llow -up as the d en om ina to r. F or each p ar tic ipan t,

p e rson -m onths w ere a llo ca ted acco rd ing to the I 980 exposu rev ariab les an d upd ated accord ing to sub sequen t fo llow -up -ques-tio nna ire in fo rm ation . Fo r w om en w ho w ere d iag nosed w ithga lls tones , pe rson-m onths w ere ass ig ned accord ing to the sta tusrep orted on the m ost recen tly com p le ted q uestionna ire bu t fo l-low -up w as te rm ina ted w ith the d iagnos is o f g allston es. If nques tion na ire w as re tu rned fo r a fo llow -up cy cle o r if w eigh tw as no t reported , tha t fo llow -up tim e w asss igned to the m is singcatego ry and w as no t in clud ed in the ana lys is. T hus , w e on lycons id ered in the ana lysis th e fo llow -u p w ith u p-to -da te reportso f bo dy w eig h t.

W e also assessed the change in risk assoc ia ted w ith w eigh tchange during th e preced ing 2-y in te rv a l. B ecause these an a ly sesreq u ired repo rt o fw eigh t bo th a t the beg inn ing ofa g iv en in te rva las w e ll a s on th e p rev ious q uestionn a ire , th e re w ere few ererson-y ears o f fo llow -up . M issing va lues resu lted in exc lusion of 4 .8%of p erson -y ea rs from the an aly sis o f ch o lecy stectom y (1980-1988) and 3 .6% from the ana lys is o fd iag nosed bu t unrem ovedga llstones (1980-1986 ).

W e used the re la tive r isk as the easure o fassoc ia tion , definedas th e inc idence ra te o f ga llston es or ch o lecy stec tom y am ongw om en in various ca tego ries o f BM I (estim ated as the num berofeven ts d iv ided by person-years o f fo llow -u p in tha t BM I ca t-egory ) d iv ided b y the correspond in g ra te am ong w om en in th ereferen ce ca tegory o f 24 kg /m 2 . T h is ca tegory w as cho sen asthe com pariso n grou p because in our p rev ious ana lys is w e foundtha t the re la tive risk fo r ga llstones w as essen tially no t assoc ia tedw ith BM I < 24 kg /m 2. A BM I of2 4 kg /m 2 in a w om an of averagehe igh t (165 cm ) correspon ds to a w eigh t o f6 5 .4 kg . A ge-sp ec ific(o r BM I-specific ) ra tes using 5-y ca tegories w ere ind iv idua llycalcu la ted and used to com pute age-ad jus ted (o r BM I-ad jus ted )re lative risks w ith 95% C Is (15). T o ad jus t fo r m ultip le risk fac to rssim ultaneous ly , p ro portiona l-hazards m ode ls (16) w ere used . A llP va lu es a re tw o -ta iled . T he inc idence ra tes w ere age standard izedby the d irect m etho d to the ag e d is tribu tion o fthe en tire coho rt.

Results

D uring 6 07 104 p erson -y ea rs o ffo llow -u p from 1980 to 19 88w e iden tified 21 22 cases o f cho lecystec tom y. T he fo llow -up fo rnew ly d iagno sed sym ptom atic b u t unrem ov ed ga lls tones ex-tended from th e retu rn of the 1 980 ques tion na ire u n til Ju ne1986 , fo r a to ta l o f 47 4 768 p erson -years o f fo llow -u p du ringw hich w e asce rtain ed 488 cases.

W e obse rv ed a s tron g lin ea r a ssoc ia tion b e tw een BM I and th einc idence ra te o f sym ptom atic ga lls tones (com bin in g cho lecys-tec tom y and unrem oved stones) (F ig) . T ab le 1 sh ow s thenum ber o fcases and age-s tandard ized ra te s and th e ag e-ad justedre la tive risks w ith 95% C I fo r ch o lecys tectom y and for un re -m oved sym ptom atic ga lls tones . T he inc idence ra te o f cho lecys-tec tom y rang ed e igh tfo ld from 202/100 000 person-years in therefe rence ca tego ry o fBM I of24 kg /rn2 to622 /100 000 p erson -years in th e 45+ kg /m 2 ca teg ory . (BM I of 45 kg /m 2 for a 16cm w om an correspo nds to a w eigh t o f 1 22 .5 k g .) T he in c id en cera tes o f un rem oved sym ptom atic ga lls tones are low er b u t risein a sim ila r m anner w ith in creas ing BM I. B ecause ofthe sm alle rnum ber o f cases the ra tes a re s ta tis tica lly less stab le than tho sefo r cho lecys tectom y . Fo r bo th end po in ts w e observ ed on ly m inord ifferences b etw een the c rude and ag e-standa rd ized ra te s , re-flec ting the w eak re la tion b e tw een age an d risk of ga llston es in


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654 STAM PFER ET A LInc#{232}dince Rat# {149 } .ofC l in i c a l l y S ym pto m at ic G a l l s t o n e s( p . r 100. 000 p e r so n - ye a r s )

( 24 - 25 -26 27 -29 -30 -3 5 -40 -45 45+B o d y M a s s In d ex (k g /r n )

TAB LE 1

260C --

2000

1500

1000 +500

c

*

+

E

I

FI G 1 . Inc idence ra tes o f cho lecystec tom y or new ly d iagn osed sym p -tom atic unrem oved ga lls to nes com bined by ca tegories o fbo dy m ass ind ex(BM I) in the N u rses H ea lth S tu dy . Theer tica l lines rep resen t the95 %confiden ce in te rva ls a rou nd th e es tim ated ra tes , assum ing a Po isson d is-tribu tion . T h e upper bound fo r the h ighes t BM I ca tegory is 3 016 p er1 00 ,0 00 p er so n- ye ar s.

th is coho rt (1 ). T hus , the e ffec t o fobes ity w as fa r m ore im portan tthan tha t o f ag e .

Inc idence ra tes fo r th e com bined endpo in t o f un rem ovedsym ptom atic ga llston es p lu s cho lecystec tom y are sh ow n in T ab le1 . W om en w ith a BM I 30 kg /m 2 h ad an annua l ra te o f> 1% ,and w om en in the h ighes t category of 45+ kg /m 2 had an m ci-dence ra te tha t exceeded 2% /y .

Tab le 2 show s th e in cid en ce of ch o lecy stectom y and sym p-tom atic u nrem oved ga llston es acco rd ing to w eig h t chang e in theprev iou s 2 y . T he h igh est ra tes w ere fou nd in th e ex trem e ca t-egories o f w eig h t change . H ow ever, the age-s tan dard ized ra tesa re co nfounded by the s trong assoc ia tion be tw een obesity an d

w eigh t loss; slender w om en are un like ly to lose10 kg in a 2 -y in te rva l (1 7). M oreover, in a prev io us ana ly sis o f p red ic to rsof w e igh t chang e w e fou nd tha t the best p red ic to r o f 2 -y fu tu rew eig h t g ain w as w e igh t lo ss in the p rev ious 2 -y in te rv al. O besew om en are a lso m ore like ly to h av e sub stan tia l w e igh t ga inha nw om en of av erage re la tiv e w e ig h t. H en ce , th e ex trem es o f bo thw eigh t loss and ga in are enriched w ith obese w om en . T h is con-found in g is q u ite ap paren t w hen d iffe rences in the age-s tan -dard ized ra tes a re com pared w ith the age- and BM I-ad ju stedre lative r isks , w hich es tim ate the asso cia tion w ith w eig h t ch angeapart from th e o besity ef fect. Fo r ex am ple the rate fo r cho le -cys tec tom y in th e 10+ kg w eigh t-ga in group w as 734 .7 /1 00 000person-years com pared w ith 2 98 . 1 fo r those w ith stab le w e igh t.This 2 .5 -fo ld -h igher ra te is reduced to a nons ign ifican t 4% increase in risk afte r ad justing fo r BM I. A fte r tha t ad jus tm en t wobserved m odera te bu t sig n if ican tly in creased risk s o fbo th ca t-ego rie s o f ga lls ton es w ith loss o f 4 kg in the prev iou s 2 y .W om en w ith a w e igh tlo ss o f 1 0 kg h ad a BM I-ad ju sted re la tiverisk of cho lecys tec tom y o f 1 .99 (95% C I 155-2 .56 ) comparedw ith w om en w ith a w e igh t ch an ge o f 4 kg and 1 .97 (9 5% C I1 .57-2 .4 7) fo r the com bined endpo in t o f ch o lecy stec tom y plusun rem oved sym p tom atic ga lls tones.

The ana lyse s o f w e igh t change in Tab le s 2 an d 3 com parerate s o f c lin ica lly sym ptom a tic g alls tones acco rd in g to w e igh tchange in the prev ious 2 y ad jus ting fo r cu rren t a tta ined w eigh t.Howev er , par t ofthe inc rea se in r isk am ong th ose w ho lo st w e igh tm ay be du e to the ir excess w eigh t 2 y befo re . T o assess tha t is sue ,w e com pared inc idence ra tes fo r w om en o f sim ila r w e igh t 2b e fo re w ho h ad m a in ta ined th eir w e igh ts o r lo s t10 kg in thesubsequen t 2 y . T he rela tive risk of cho lecys tec tom y in the 2 -yin te rva l a fte r a 10 -kg w eigh t loss , ad justing fo r BM I befo rethe w eigh t loss , w as 1 .17 (0 .82- 1 .67) (T ab le). T h e ap pa ren tlack of inc rease in r isk in the 8 5-kg w om en w ho d id no t losw eigh t (com pared w ith th e 6 5-k g ca tegory ) is m o st like ly a ch an cef in d ing a ttribu tab le to sm all num bers.

It is o f in te re st to a sse ss the ex ten t to w hich the elev ated ra teso f sym ptom atic g alls to nes am ong the obese w om en m ay be a t

A ge-standard ized inc idence ra tes p er 10 0 ,0 00 p erson-years, and re la tiv e risks and 95% confidence in te rv als fo r cho lecystec tom yan dsym ptom atic unrem ov ed ga lls tones in the N urses H ea lth S tudy

Cholecystectomy Sym p tom atic g alls to ne s, no t rem ovedChole cys tectom y plu ssym p tom atic gal lsto ne s

Inc idence R ela tive r isk Inc idence R ela tive risk Inc idence R ela tiv e riskBM I Cases ra te (95% C I) C ases rate (95% C I) ra te (9 5% C I)


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GA LLSTO N ES IN W OM EN W ITH SEV ERE O BES ITY 65 5TABLE 2W eig h t chan ge in prev ious 2 y5 and risk of ch o lecy stec tom y t and sym p tom atic unrem ov ed ga llston esf

C ho lecystec tom y Sym ptom atic g alls to n es, no t rem ovedC holecystec tom y orun rem oved g allston es

R ate p er BM I-ad jus ted R ate p er BM I-ad jus ted R ate per BM I-ad ju sted1 00 000 re la tive risk 100 000 rela tive risk 100 000 re la tiv e risk

W eigh t change C ases p erson -years (95% C I)II C ases person-years (95% C I)II p erson-years (95% C I)II10+ kg los s 6 3 839 .4 1 .99 (1 .55-2 .5 6) 14 259 .7 1 .8 7 (1 .1 0-3 .19 ) 10 99 .1 1 .97 (1 .57 -2 .4 7)4 .0 -9 .9 kg loss 194 505 .7 1 .38 (1 .1 9-1 .61) 5 8 197 .8 1 .75 (1 .33-2 .3 2) 703 .5 1 .45 (1 .2 7-1 .66)3 .9 kg ga in or loss 1 3 1 3 298 . 1 1 .0 ( re feren t) 3 1 1 92 .7 1 .0 (referen t) 392 .6 1 .0 ( re fe ren t)3 .9 -9 .9 kg ga in 365 466 .7 0 .9 4 (0 .83-1 .06) 7 4 126 . 1 0 .87 (0 .6 6-1 . I 3 ) 577 .2 0 .92 (0 .83 -1 .03)10+ kg ga in 76 734 .7 1 .04 (0 .8 0-1 .35) 2 2 269 .6 1 .12 (0 .69-1 .8 1) 1004 .3 1 .06 (0 .84 -1 .33)

a W om en w ith m issing da ta a re exc luded .t Follow -up from 1980 -1988 . Fo llow -up from 1980-19 86 . A ge-s tan dard ized to the d istribu tion of th e cohort, 19 80-19 88 .II A djus ted fo r BM I a t the beg in n ing ofeach fo llow -up in te rva l fo r the catego ries lis ted in T ab le I u sing s tratified ana lyses .

tribu tab le to o ther ga llstone risk fac to rs tha t m igh t be assoc ia tedw ith ad ipo sity . Th us, fo r exam ple , it is w e ll es tab lished tha theav ie r w om en tend to dr in k less a lcoho l than leaner w om en(18 ). B ecause alcoh o l in tak e is assoc ia ted w ith decreased risk ofga lls ton es (1), pa rt of th e effec t o f ob es ity m ay re flec t dec rea seda lcoho l in take . C onverse ly , heav ie r w om en ten d to use p ost-m enopausa l horm ones less frequen tly than leaner w om en (19 ).Estrog en u se in c rea ses th e risk o fga lls ton es (2 0 ) , so th is po ten tia lconfo und ing fac to r m ay b ias the ra tes in the opposite d irec tion .A lso , th ese fac to rs m ay confou nd the assoc ia tion be tw eeneigh tlo ss and ga lls tones. Tab le 3 sh ow s the re la tive r isks fo r ch o le -

cy stec tom y in the d if fe ren t ca teg ories o f BM I and recen t w eigh tch an ge a fte r sim u ltaneou s ad jus tm en t fo r know n or su spec tedga l ls tone r isk fac to rs : age , pa rity , po stm enopausa l ho rm one u se,a lcoho l in tak e , p o lyunsa tu ra ted fa tty acid in take (1 2), to ta l en -e rgy , and sm ok ing (1 ) , u sin g propo rtion a l hazards m ode ls . Th esead justed re la tive risk s fo r BM I a re g en era lly sim ilar to th oseobserv ed in T ab le 1 , sug gesting tha t on ly a sm all portion o f thedram atic r ise in risk w ith inc rea sing ad ipo sity can be a ttr ibu tedto con fo und ing fac to rs . S im ila rly , the e leva ted rela tive risks a s-soc ia ted w ith w eigh t loss w ere la rge ly unchang ed in th e m ulti-v a ria te an aly se s tha t ad justed fo r cu rren t atta ined w e igh t.

TA BLE 35 re la tive risks fo r cho lecys tec tom y , sym ptom atic un rem oved ga llstones , and bo th endpo in ts tog ether by BM I and w eig h t

chang e in the pas t 2 y , ad jus tin g s im ultaneou sly fo r various risk fac to rs fo r ga lls tonest

C ho lecy stec tom y G alls tones, unrem ovedC holecy stec tom y o r

unrem oved ga llston esBM I


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65 6 STAM PFER ET A LTAB LE 4The risk of ch o lecy stec tom y in re la tion to a 1 0-kg w eig hprev ous 2 y , ad jus tin g fo r BM I b efo re the w eig h t lo ss*

t lo ss in the

We i g h t 2 y a g o

65kg 75kg 85kg

Curren t w e igh t (kg ) 55 65 65 75 75 85W eigh t loss ( kg ) 10+ 4 10+ 40+ 4C a s e s 2 0 1 9 0 1 0 4 0 6 1 0Pe r s o n - y e a r s 2 3 1 9 2 2 1 3 7 1 0 4 8 5 3 4 1 3 8 9 1 4 1 2R isk nex t year (% ) 0 .86 2 0 .858 0 .954 0 .7 49.544 0 .708R elative risk fo r

1 0 k g we i g h t 1 . 0 0 1 . 2 7 2 . 1 8lo ss t (96% C I) (0 .63 -1 .59) (0 .64-2 .55 ) (0 .79-5 .99 )

a P ro jec ted fo r a w om an 140 cm in h e ig h t.t O vera ll rela tive risk fo r 10 kg w eigh t lo ss 1 .17 (0 .8 2-1 .67 ), by

using the M ante l-H aensze l m ethod .

In th is coho rt w e observed a h ighe r r isk o fga lls to nes fo r cu rren tsm ok ers (T ab le 5 ), pa rticu la rly fo r heavy sm okers . F or w om ensmok in g 35 c igare tte s per d ay , the re lativ e risk fo r sym ptom aticga lls tones (ch o lecy stec tom y and unrem oved) com pared w ith tha tfo r w om en w ho h ad n ev er sm ok ed w as 1 .5 1 ( 95% C I 1 .20-1 .89)afte r ad justm en t fo r BM I, w e igh t chang e, and o th er r isk fac to rs .

Discussion

In th is la rg e p ro spec tive coho rt s tud y w e con firm ed the im -portance o f obesity as a risk fac to r fo r ga llston e d isease and ,becau se of the size o f the s tudy , w e cou ld es tim ate ra tes fo rclin ica lly d iagnosed ga lls tones and cho lecys tec tom y at variousBM Is . R a te s o f ga lls ton e d isea se fo r o bese peo p le a re k now n tobe h igh bu t h av e no t p rev ious ly been quan tified in a la rge , w e ll-de fined popu la tion . T he inc idence ra tes inc reased m ono ton icallyw ith inc rea sin g ob esity , l% /y fo r w om en w ith a BM I of 30-35 kg /m 2 and ex ceed ing 2% /y fo r w om en w ith a BM I of45kg /m 2 . S ubs tan tia l w e igh t lo ss du rin g the p reced in g 2 y w as a lsoa sig n ifican t risk fac to r fo r ga lls ton es, independ en t o f cu rren tBM I, w ith a re la tive r isk o f 1 .9 4 (9 5% C I 1 .50 -2 .50 ) fo r a lossof > 10 kg . C om paring the risk am ong w om en w ith th at w eigh tloss to those of the sam e o rig in a l w eigh t, the im p ac t w as m uchless w ith a n onsig n if ican t rela tive r isk o f 1 . 1 7 (0 .82 -1 .6 7 ) . W ealso confirm ed an indepen den t assoc ia tion be tw een c igare ttesm ok in g and ga llston e d isease , as o thers have observed (4 ,21 , 22) .

It w as no t po ss ib le in th is s tudy to sc reen p ar tic ipan ts w ithu ltrasound or o ther techn iqu es fo r th e presence of g alls to nes.H en ce , w e focused on ch o lecy stectom y and d iag nos tica lly con-firm ed bu t u nrem oved sym p tom atic g a lls to nes. W e recogn izeth at the re w as subs tan tia l un derasce rta inm en t o f ga lls tones be-cause a la rge p ropor tion of p reva len t ston es a re com ple te lyasym ptom atic (6 , 1 3 , 23). For exam ple , Jo rgensen (1 3) observ edth at tw o -th irds o r m ore of ga llstones w ere asym ptom atic andth at it is d ifficu lt to d is ting u ish sym p tom atic f rom asym p tom aticstones . M oreover, it is like ly tha t in m any ofthe cases d iag nosedduring the fo llow -up in te rv al, ga lls tones w ere presen t bu tasym ptom atic a t b ase lin e. W e have no t a ttem p ted to estim ateth e inc idence o f ga llston e fo rm atio n bu t ra the r the inc idence o f

new ly sym p tom a tic ga lls ton e d is ea se , an en tity o fd irec t c lin ica land p ub lic hea lth im portance.

T he find in gs a re based en tire ly on self-repo rt o f w eig h t andth e occu rrence o fg a lls tone d is ea se o n the b ienn ial qu es tio nn aires .T he se lf-rep o rt o f w e igh t in th is co hort is qu ite accu ra te w hencom pared w ith m easured w eig h ts in a sam ple ofthe partic ipan ts(r = 0 .97) (1 4). B y com paring the ques tio nna ire rep orts w ithmed ica l reco rd s in a sam p le o f p artic ipan ts w e a lso fo und tha tth ese reg iste red n urses had a v ery h igh lev el o f accu racy in re -p o rtin g cho lecy stec tom y and d iagn ostically co nfirm ed bu t u n -rem oved ga llstones (1 ). S im ila r accuracy of repo rtin g w as dem -onstrated fo r sev era l o the r d iag noses (24 ). A lthou gh w e do no tkn ow th e com positio n of the ston es , w e m ay estim ate th at 85 -90% w ere cho le ste ro l sto nes (25 , 26 ) .

O ur re su lts a re co nsisten t w ith the lim ited d ata from prev iousstud ie s . The R om e G roup (7 ) and B arba ra e t a l (6 ) bo th fou ndth at BM I is a s ign if ican t p red icto r o fga lls to ne preva lence am ongw om en in a sc reened popu la tion bu t p rov ided no prev alen cerate s by leve l o fo besity . In a sm all sc reen ing stu dy of24 9beseand 60 nonobese w om en the p reva lence o f ga lls ton es w as 31%am ong th e obese vs 1 0% am ong the con tro ls (2 3 ) . Jo rgensen(21 ) sc reened 1680 D an ish w om en and prov id ed g a lls to ne p rey-a len ce ra tes sp ec if ic fo r ca tegorie s o f BM I. W om en w ith a BM Iof 3 0 k g /m 2 had a p reva lence o f 30% (41 of 13 5) a s com paredw ith 6% (13 of 231 ) am ong w om en w ith a BM I20 kg /m 2.A lthou gh th ese num bers cann o t be com pared d irec tly w ith in -c idence ra tes fo r sym ptom a tic ga lls ton es, a p rev alen ce o f 30%cou ld resu lt, fo r exam ple , from a ne t in cid en ce ra te o f s ilen tg alls to ne fo rm a tion o f 2% /y fo llow ed by an av erage d ura tio n o fga l ls tones of 17 y . U sing cross-sec tiona l da ta from a la rgecoho rt o fw eig h t-co nsc iou s w om en , B ern ste in e t a l (2 7 ) e stim atedinc idence ra te s o fd iagn osed ga lls ton es by us ing life -tab le m e th -ods . They fou nd tha t w om en in the h igh es t obesitya tegory(m ean BM I 3 8 .3 ) had an es tim a ted inc idence 2-6 .25 -fo ldh igher depend ing on age than the re fe rence ca tegory (m ean BM I23 .0 ) . T hese resu lts a re sim ila r to o ur f in d ings .

D ata from cohort s tud ie s a re a lso spa rse . In th e F ram in ghamS tudy (28 ) th e risk o f c lin ically d iag nosed ga lls to nesw as 77%h igh er than ave rage fo r w om en w ith w e igh t (ad ju sted fo r he igh t) 20% hig her than the coh ort m ed ian (49 cases ), b u t fo r thosein th e 10 -1 9% ex cess-w eig h t ca teg ory (15 cases ) the r isk w as

TABLESM ultiva ria te-ad ju sted5 re la tive risks fo r cho lecy stec tom y,sym ptom atic unrem ov ed ga llstones , and bo th en dpo in ts to ge ther byc igare tte sm oking

Unremoved,symptomatic

Cholecys tec tomy gal lsto nes B oth endpoin tsNever 1 .0 (re feren t) 1 .0 (referen t) 1 .0 (refe ren t)Past 1 .0 6 (0 .94-1 .18) 1. 09 (0 .89-1 .33) 1. 06 (0 .96-1 .17)Cur rent

1-1 4 c igare ttes /d 1 .13 (0 .94-1 .36 ) 1 .06 (0 .74-1 .50 ) 1 . 10 ( 0 .9 3 -1 . 29 )15-24 cig are ttes /d 1 .21 (1 .04 -1 .4 2) 0 .93 (0 .6 8-1 .29 ) 1 .03 (0 .9 0-1 .19 )2 5-3 4 c ig are tte s/d 1 .36 (1 .1 1-1 .67 ) 1 .21 (0 .81 -1 .31) 1 .31 (1.09-1.58)35+ cig are ttes /d 1 .5 9 (1 .2 4-2 .05 ) 1 .30 (0 .78 -2 .16) 1 .5 1 (1 .2 0-1 .89 )

S S im u ltan eou sly adju sted fo r B MI, weight change , age(5-y ca tego rie s), alcoh olin take ( fi ve c a te g or ie s) , poa tm enopausal horm one usecu rren t, p ast , never), sm oking(n eve r, p ast, and curren t a t four am oun ts ofcigaret tes p er day ), parity (sixcategor ies) ,ene rgy in take (fiv e categorie s), po lyun sa turated fa tty ac id in take ( five categories).


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GALLSTON ES IN W OM EN W ITH SEV ER E OBES ITY 65 736% low er than average . In a la rge cohort s tudy of w om en a t-tend ing a fam ily -p lann in g c lin ic in O xfo rd , U K , 22 7 youngw om en had a cho lcys tec tom y during nearly 1 55 000 person-years o f fo llow -up (22) . T he crude ra tes in tha t popu la tion w erelow er th an w e observed (p erh aps re flec tin g in parti f ferencesin su rg ica l p ractice ) and increased stead ily from 96/100 00025cases) fo r < 20 kg /rn2 to 626 fo r 30 kg /m 2 (22 cases ). H ow ever,the re la tive risks w ere sim ilar to w h at w e observ ed , particu la rlyg iven th e m od es t n um ber of casesn the O xfo rd stu dy , w h ichy ie lded fa irly u nstab le ra tes . T h ey found , as w e d id , tha t the riskd id no t m ate ria lly inc rease un til a BM I of24 kg jm 2 w as exceeded ,and in th eir s tu dy a re la tive risk o f6 .5 w as observed fo r BM I of 30 kg /m 2.

T he link b e tw een obesity and ga lls tones is exp la in ed by theincreased sa tu ra tion ofb ile w ith cho les tero l in o beseeop le (29 -3 1 ). T he sa tu ra tio n appears to b e in creased still fu rth er du ringrap id w e igh t lo ss(29 , 31 ), su ggesting tha t w e ig h tlo ss co u ld ind uceg a lls to ne fo rm ation (32 ). Jo rgensen (2 1) add ressed th is issue inh is po pu la tion sc reen ing survey and fou nd tha t s limm ing trea t-m en ts w ere asso cia ted w ith an increased p reva len ce of ga llston esin bo th sexes ; m o reover, the num ber of s lim m in g treatm en tsw as a lso asso cia ted w ith ga lls tone preva lence . H ow ever, su chtrea tm en ts w ere asso cia ted w ith ob esity and in m ultiva ria tean alyses ad justing fo r BM I, th e assoc ia tion w ith slimm ing trea t-m en ts w as attenua ted an d in w om en (bu t no t m en), no longers ta tistica lly sign ifican t. H is find ings a re qu ite com patib le w iththe m odera te assoc iation w e observ ed fo r subs tan tia l p rev iousw eig h t loss.

T he inc iden ce ofc lin ical g alls to ne fo rm a tion du rin g ve ry rap idw eig h t loss has been estim ated in severa l recen t sm all stud iestha t u sed 2 092-2 1 76-k J/d (500-520-k ca l/d ) d iets . Am ong 51pa tien ts in itia lly free from ga lls tones acco rd ing to u ltra soun d ,L idd le e t a l (8 ) foun d tha t a fte r 8 w k of d ie ting (m ean w eigh tloss, 16 .5 kg), 1 3 had deve loped ga lls tones an d 3 of those hadsym ptom s severe eno ugh to req u ire ch o lecy stec tom y. In a 1 6-w k tria l o f u rsodeoxycho lic ac id in rap id w e igh t lo ss (22 .6 kgm ean loss), 7 o f 3 3 pa tien ts o n p lacebo or asp irin deve lopednew gallstones , and 2 of them w ere sym ptom atic (33). Y ang e ta l (9 ) found tha t in a 16-w k rap id -w eigh t-loss p ro gram , 15 o f1 54 sub jec ts free from galls tones a t b ase lin e w ho com ple ted th ep rogram deve loped ga lls tones d iagn osed by u ltraso und onscre en ing . N o de ta ils w ere repor ted on th e proportion tha t w eresym ptom atic bu t the risk w as h igher fo r m en , fo r tho se w ithm ore w eigh t loss, and fo r thosewho w ere m o re obese a t b as elin e.Ifo ne assum es th e sam e ratio o fsym ptom atic to asym ptom atics tones in the Y ang e t a l s tu dy as ob served b y L idd le (8 ) an dBroomfield (3 3) e t a l, th en pu tting th e th ree s tud ies to ge thery ie lds a cum u la tive inc idence of 9 per 238 sub jec ts, o r 3 .8%(95% C I 2 .0 -7 .0% ) ove r a 2 -4 -m o w eig h t- lo ss p rog ram . Th isshou ld b e co nsidered a m axim um estim ate because theseub jectsw ere all und er in tense su rve illance and any sym ptom s w ouldbe like ly to b e a ttr ibu ted to the sto nes.

W e have n o da ta from the N u rse s H ea lth S tu dy on the in -c id en ce o f g allston es w ith rap id w eig h t lo ss and do no t kn ow ifany ofthe partic ipan ts w ere enro lled in such p rogram s . O u r da tasug gest tha t a h is to ry ofsubs tan tia l w eig h t loss over a 2-y periodis a r isk fac to r fo r c lin ica lly sym ptom atic ga llston es in dependen tof the effec t o f cu rren t ob es ity . Th e ana lysis tha t assesses th eim pact o fw eigh t lo ss ad jus ting fo r p rev ious ra the r than a tta inedw eigh t (T ab le 5 ) su gges ts th a t m uch of the apparen t e ffec t o fw eig h t loss m ay b e a ttribu tab le to the excess w eigh t p resen t b efo re

the loss. A lso , pa rt o f the risk assoc ia ted w ith w eigh t loss m aybe a ttribu tab le to the tend en cy of w om en w ho lost w e igh t in ag iv en 2-y in te rva l to ga inw eig h t in the su bsequ en t 2 -y in terva l(17 ). T he im pac t o f ob esity on r isk is fa r stro nger than th a tw eigh t lo ss in our coh ort. A ltho ugh w om en on a ve ry -low -ca lo ried iet ap pear to be a t inc rea sed risk fo r ga lls to nes, m uch o f theexcess r isk is p robab ly a ttrib u tab le to the u nde rly ing ob es ity . Ifsusta ined w eig h t red uc tio n even tua lly decreases the risk to theleve l o f the a tta ined w eigh t, a s one m igh t exp ec t, the ne t long -te rm im pac t o fw eigh t loss cou ld be a red uc tion in the in c id en ceo f ga lls tones d esp ite a transien t in crease in sh ort- te rm risk .{163}3

W e are g ra te fu l fo r the con tin u ing consc ien tio us he lp o fthearticipantsand fo r the expert ass istance o fK aren Co rsano , M ark Shneyder, S te fan ieB ech te l, and D ebb ie O S u lliv an . T he N u rses H ea lth S tudy is und er thegenera l d irec tion o f its p rinc ip a l inves tig ato r , F rank Spe izer .

R e f e r e n c e s1 . M aclu re MK , H ayes K C , C o ld itz G A , S tam pfer M J, S pe izer FE ,

W ille tt W C . W eig h t, d ie t, and the risk ofsym ptom atic ga lls tones inm idd le -aged w om en . N EngI J M ed 1989 ;32 1 :563-9 .

2 . K ern F Jr. E pidem io log y an d n atu ral h isto ry o f ga llstone s. Sem inLiver Di s l983 ;3 :87-96 .

3 . S cragg RK , M cM ich ae l A J , B aghu rst PA . D ie t, a lcoho l, an d re la tiv ew eigh t in ga lls tone d isease : a case -con tro l s tu dy . B r M ed J l984 ;28 8 :1 1 1 3- 9 .

4 . D ieh l AK , Hakkn e r SM , H azuda H P , S te rn M P. C o ro na ry risk facto rsand c lin ica l ga llb ladder d isease : an ap proach to the preven tion ofgallsto ne s? Am J P ub lic H ea lth l9 87 ;7 7 :8 4 l-S .

S. W ysow sk i D K , G oldb erg EL , C om stock GW , D iam ond EL . A stu dyofa p oss ib le assoc ia tion be tw een breast can cer and ga llb lad der d is-ease . A m J Epid em io l l986 ;l23 :5 32-43 .

6 . B arbara L , Sam a C , M orse lli-L aba te A M , e t al. A popu la tion s tudyofthe p reva lence o fga llstone d isease: th e S im ione study . H epa to log y1987 ;7 :9 13 -7 .

7 . Th e Rom e G roup fo r Ep idem io lo gy and Prev en tion of C ho le lith ias is(G REPCO ). T he ep idem io log y ofgal lsto ne d isea se in R om e, Ita ly .Part I I. Fac to rs assoc ia ted w ith the d isease . H epa to logy l98 8 ;8 :907-13 .

8 . L idd le RA , G olds tein R B , Sax ton J. G a llstone fo rm ation dur in gw eigh t red uc tio n d ie ting . A rch In te rn M ed l9 89 ;l49 :175 0-3 .

9 . Y ang H Y , Pe te rsen GM , M ark s JW , R oth M P , S choenfie ld U . R iskfac to rs fo r ga lls tone fo rm ation during rap id w eigh t loss. G astro en -te ro logy l9 90 ;98(supp l S ) :A 266 (abstr).

10 . C o ld itz G A . T he N urses H ea lth S tu dy : find in gs during 1 0 years o ffo llow -up of a coh ort o f U S w om en . C u rr P ro b l O bs te t G yn eco lF ertil 1990 ; 13 :1 29-74 .

1 1. W ille tt W C , Sam pson L , S tam pfer M J, e t a l. R epro duc ib ility andva lid ity o f a sem iqu an tita tive fo od frequency questionn a ire . A m JEpidem io l l98 5 ;l2 2 :S 1-6 5 .

12 . M ac lure KM , H aye s K C , Co ld i tz GA , S tam pfe r M J, W ille tt W C .D ie ta ry pred ic to rs o fsym ptom -assoc ia ted ga lls tonesi n m id dl e- ag edw om en . A m J G in N utr l990 ;5 2 :916-2 2 .

13. Jo rgensen T . A bdom ina l sym ptom s and g a lls to ne d isease : an ep i-d em io lo g ic inv est iga tion . H ep ato log y 1989;9 :85 6-6 0 .

14 . R imm EB , S tam p fer M J, C o ld itz G A , L itin L , W ille tt W C . V alid ityo f se lf-repor ted w aist an d h ip c ircum ferences in m en and w om en .Ep idem io lo gy 1990; 1 :466 -73 .

15 . Rothm an K i, B o ice JD Jr . E p idem io log ic ana lysis w ith a p rog ram -m able ca lcu la to r. W ash ing ton , D C : P ub lic H ea lth S erv ice , 197 9 .[N IH pub lica tion 79 -1 649 ).

16. C ox DR . R eg ressio n m ode ls a nd l if e- ta bl es . J R S ta t S oc [B ) 1972 ;34 :187-220 .


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658 STAM PFER ET A L17 . C old itz G A , W ille tt W C , S tam pfer M J, London SL , Seg al M R .

Spe ize r FE . P a tte rns o f w eigh t change an d the ir rela tion to d ie t ina coh ort o f hea lthy w om en . A m J C lin N utr l990 ;S l:l 10 0-S .

18 . C o ld itz G A , G iovannu cc i E , R imm EB , e t a l. A lcoho l in take inre lation to d iet an d obes ity am ong m en and w om en . Am J G inN utr 1 99 1 ;54 :49-55 .

19 . S tam pfer M J, C o ld itz G A . E strog en rep lacem en t th erap y and cor-onary heart d isease : a quan titative assessm en t o f the ep idem io log icev idence . P rey M ed l9 90 ;20 :47 -63 .

20 . A R eport from the Bos to n C ollab ora tiv e D rug Su rve illance P rog ram ,B os ton U n iv ersity M edica l C en te r. S urg ica lly confirm ed ga llb ladd erd ise ase , v en ous throm boem bolism , an d b rea st tum ors in re la t ion topos tm enopausa l es tro gen th erap y . N Eng l J M ed l974 ;290 : 15 -9 .

21 . Jo rg ensen T . G allsto ne s in a D anish populatio n . R elatio n to w eigh t ,phys ica l activ ity , sm oking , co ffee con sum ption , and d iabe tes m ellitu s.G u t l 98 9; 30 :5 28 -3 4.

22 . L ayd e PM , V essey M P, Y eate s D . R isk factors fora ll-b ladd er d isease :a coho rt s tudy o f young w om en a ttend ing fam ily p lan n ing c lin ics .J E p idem io l C omm unity H ea lth l9 82 ;36 :274 -8 .

23 . T uck er LE , Tangedah l TN , N ewm ark SR . P revalenc e of ga llstone sin obese Cauca sian Am e rican w om en. m t J O be s l 98 2; 6: 24 7- Sl .

24 . C old itz G A , M ar tin P , S tam p fer M J, et a l. V a lid atio n ofues t ionna irein fo rm atio n o n risk fac to rs and d isease ou tcom es in a pro spec tivecoh ort s tudy in w om en . Am J Epidem io l l98 6 ;l2 3 :894-9 00 .

25 . T ro tm an BW , Solow ay RD . P igm ent v s cholestero l ch o lelith ias is:c lin ica l and ep idem io log ical aspec ts. A m J D ig D is 19 75 ;20 :73 5-40 .

26 . S o low ay RD , T ro tm an BW , O strow JD . P igm ent ga llstones . G as-troen tero log y 1977 ;72 : 16 7-8 2 .

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33 . B room fie ld PH , C hopra R , S he inbaum RC , e t a l. E ffec ts o f u rso -deox ycho lic ac id and asp irin o n the fo rm ation o flitho gen ic b ile andga l ls tones during loss o fw e igh t. N E ng I J ed l988 ;3 19 :1 567-7 2 .

1992 riesgo de mujeres obesas para litisi vesicular

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