?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
%#"%FIHKMXG<B:GH=B:@G_LMB<H>FHGBMH
KBS:ZYHM>K:I]NMB<:=:I:MHEH@B:>G=_<KBG:
<?>AC0=24>=3806=>B8B0=3<>=8C>A8I0
C8>=>54=3>2A8=438B40B4B
&:<BGM:/:GMHL%L:;>E,:BO:"VMBF:(>BMYH):GN>E::KO:EA>BKH
=C4A=0><?;4<4=C0A34=3>2A8=>;>680
BB8BC4=C4>B?8C0;0AA03D03034=3>2A8=>;>680
BB8BC4=C4 >B?8C0;0A A03D030 34 &0C>;>680 ;S=820 "01>A0CTA8> 34 >A<>=>;>680 )4AE8P> 34 &0C>;>680 ;S=820 3>B >B?8C08B 30
+=8E4AB8303434>8<1A0&>8<1A0
8A42C>A03>)4AE8P>34=3>2A8=>;>6808014C4B4#4C01>;8B<>3>B>B?8C08B30+=8E4AB8303434>8<1A0&>8<1A0
<??3@=<;2Q;17/!028=C0)0=C>BZ)4AE8P>34=3>2A8=>;>6808014C4B4#4C01>;8B<>+&Z&A024C0#>C0&8=C>
>8<1A0
Z90B0=C>B6<08;2><
137A/ON<AC86>A424183>4<
A4E8BC>4<
40248C4?0A0?D1;820PO>4<
&')!#
A Hormona de Crescimento (GH) exerce efeitos directos nos tecidos periféricos, assim como
efeitos indirectos através da IGF-1. Devido à capacidade de ligação a proteínas de alta afinidade (IGFBPs), a IGF-1 possui uma semi-vida mais duradoura que a maioria das hormonas
polipeptídicas. A sua concentração sérica depende sobretudo do estado nutricional e da
secreção de GH, embora factores como a idade, sexo, factores genéticos e patologias crónicas associadas tenham alguma influência.
Devido à pulsatilidade da secreção de GH, a avaliação da sua produção é uma tarefa complexa. Os testes de estimulação, nomeadamente a prova da hipoglicemia insulínica e a prova da
clonidina, são considerados os métodos de eleição para estabelecer o diagnóstico de deficiência de GH. Devido à estabilidade da IGF-1, o seu doseamento assume extrema relevância
como adjuvante no diagnóstico desta patologia.
Em crianças, a eficácia da terapêutica com GH é avaliada através do crescimento linear. Na
população adulta, os estudos revelam efeitos benéficos na qualidade de vida, composição
corporal, densidade mineral óssea e risco cardiovascular. A monitorização dos valores da IGF1 permite avaliar a adesão à terapêutica. A titulação da dose de GH de acordo com os valores de IGF-1 previne elevações da IGF-1 acima dos valores de referência, reduzindo a possibilidade de efeitos adversos do tratamento.
Na acromegalia, o valor da IGF-1 correlaciona-se com a hipersecreção de HC, constituindo o
método com maior sensibilidade e especificidade no diagnóstico, uma vez que o seu nível se
encontra persistentemente elevado. A eficácia da terapêutica médica ou cirúrgica da acromegalia está associada à normalização da GH e IGF-1 sérica, embora possa ocorrer discordância
entre a GH e a IGF-1 em alguns doentes. A manutenção de valores elevados de IGF-1 está associada a um aumento da taxa de mortalidade. Este facto justifica a importância das terapêuticas instituídas com o objectivo de normalizar a IGF-1, o que permitirá reduzir a mortalidade.
$ *&'*
Hipófise; Eixo Somatotrófico; IGF-1; Deficiência de Hormona de Crescimento; Acromegalia;
Diagnóstico; Monitorização do Tratamento da Acromegália.
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
'(&(
Growth Hormone (GH) has direct and indirect effects at the peripheral tissues, through the action
of IGF-1. Because of its ability to bind to high affinity proteins (IGFBPs), IGF-1 has a substantially
longer half-life than many polypeptide hormones. Serum IGF-1 concentration depends primarily
on nutritional status and GH secretion, although other factors such as age, gender, genetic factors and associated chronic diseases have also some influence.
The stimulation tests, namely the insulin tolerance test and the clonidine test, are considered the
gold standard used to diagnose GH deficiency. Due to the pulsatility of the GH secretion, assessment of whether GH production is insufficient is a complex task. Because of IGF-1 stability, it’s
measurement presents great relevance as adjuvant to the diagnosis of the situation.
In children, the efficacy of GH therapy is evaluated through the linear growth. In the adult population, this evaluation is performed by indirect effects: improvement in the quality of life, body
composition, bone density and cardiovascular risk factors. In theses cases, IGF-1 monitoring allows
the evaluation of patient’s compliance to the treatment. GH dose titration according to IGF-1
levels prevents its elevation above the reference range, which could increase the adverse effects.
In acromegaly, IGF-1 correlates well with GH hypersecretion, and is considered the most sensitive
and specific test in diagnosis, since it’s measurement is persistently elevated. Successful medical or
surgical treatment of acromegaly is usually associated with normalisation of serum IGF-1, but in
some patients there is discordance between GH and IGF-1. The maintenance of high levels of IGF1 is associated with excess mortality. This fact justifies the importance of the therapeutic measures aiming at normalising IGF-1 and reducing the mortality rate.
-+#&'
Pituitary; Somatotropic Axis; IGF-1; Growth Hormone Deficiency; Acromegaly; Diagnosis;
Monitoring of Acromegaly Treatment.
"(&#)IW#
+=B:@G_LMB<H=:LI:MHEH@B:LK>LNEM:GM>L
=: :EM>K:ZYH =: L><K>ZYH =: AHKFHG: =>
<K>L<BF>GMH #$ ;:L>B:L> GH =HL>:F>GMH
=: <HG<>GMK:ZYH => %#" %GLNEBGEBD>
@KHPMA ?:<MHK
+ L>N =HL>:F>GMH L[KB<H
K>O>EHNL>K>QMK>F:F>GM>bMBEJN>KGHK:L
MK>BH =: =>?B<B]G<B: => #$ >F <KB:GZ:L >
:=NEMHLJN>KG:<HG?BKF:ZYH=H=B:@G_LMB
<H=>:<KHF>@:EB:
,:K:E>E:F>GM>:%#"[
M:F;[F bMBE G: FHGBMHKBS:ZYH =: K>LIHLM:
:HMK:M:F>GMH<HF#$>F<KB:GZ:L>:=NE
MHL>G:FHGBMHKBS:ZYH=:K>LIHLM:WLM>K:
I]NMB<:L BGLMBMN^=:L >F =H>GM>L <HF :<KH
F>@:EB:
#$[IKH=NSB=:>EB;>KM:=:I>E:L<[EN
E:L LHF:MHMK_?B<:L =: ABI_?BL> :GM>KBHK =>
FH=HINELVMBE<HF@K:G=>L?ENMN:Za>LG:L
LN:L<HG<>GMK:Za>LL[KB<:L:HEHG@H=H=B:
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
1F O:EHK >E>O:=H => #$ IH=> K>IK>L>GM:K
NFIB<HAHKFHG:EGNFBG=BO^=NHGHKF:E
=H F>LFH FH=H JN> NF O:EHK =>GMKH =HL
EBFBM>L =: GHKF:EB=:=> IH=> K>IK>L>GM:K
NF FHF>GMH => L><K>ZYH F^GBF: GNF
=H>GM> <HF :<KHF>@:EB:
>LM> FH=H H
=HL>:F>GMH ;:L:E =: #$ M>F NF O:EHK
FNBMHEBFBM:=HMHKG:G=HG><>LLVKBH=>L>G
OHEO>K=HL>:F>GMHL:EM>KG:MBOHL
1F: =:L IKBG<BI:BL :<Za>L ;BHE_@B<:L
=:#$[:>LMBFNE:ZYH=:IKH=NZYH=>%#"
GHL =BO>KLHL M><B=HL GHF>:=:F>GM> GH
?^@:=H <>K<: => =: %#" <BK<NE:GM>
M>F HKB@>F A>IVMB<:
L><K>ZYH A>IVMB
<: => %#" [ K>E:MBO:F>GM> <HGLM:GM> :H
EHG@H=H=B:I>KFBMBG=HJN>HL>N=HL>:
F>GMH GNF: :FHLMK: bGB<: => L:G@N>
L>C: >QMK>F:F>GM> bMBE GH K:LMK>BH => NF
<:LHLNLI>BMH=>:<KHF>@:EB:HN=>?B<B]G<B:
=>#$
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
$@
*H L:G@N> I>KB?[KB<H <>K<: => =:
%#" MHM:E >G<HGMK:L> EB@:=: : L>BL MBIHL
=BLMBGMHL => IKHM>^G:L :L %#",L %#"
;BG=BG@ IKHM>BGL JN> <HGMKB;N>F I:K: :
F:GNM>GZYH =: %#" >F <BK<NE:ZYH
=NK:GM>OVKB:LAHK:L
%#"K>LM:GM><BK
<NE: EB@:=: : HNMK:L IKHM>^G:L L>G=H JN>
F>GHL => <BK<NE: G: ?HKF: EBOK>
>OB=H W EB@:ZYH WL %#",L IKHM>^G:L <HF
>E>O:=::?BGB=:=>FNBM:L=:LO:KBVO>BLJN>
BG?EN>G<B:F:<HG<>GMK:ZYH=>#$EB;>KM:
ZYH INELVMBE >Q>K<^<BH ?ENMN:ZYH =HL G^O>BL
@EB<[FB<HLIKBO:ZYHGNMKB<BHG:EM]F>?>BMHL
F^GBFHL G: %#"
L %#",L ?NG<BHG:F
<HFH NF LBLM>F: => K>L>KO: AHKFHG:E
FH=NE:G=H : EB;>KM:ZYH => %#" I:K: HL
M><B=HL
!LM:LIKHM>^G:LBGM>K?>K>FGH=HL>:
F>GMH =: %#" =:^ JN> H IKH<>=BF>GMH
M[<GB<H => NF ;HF =HL>:F>GMH =: %#"
=>O> BG<ENBK H IK[MK:M:F>GMH =H LHKH I:K:
JN>>LM:LIHLL:FL>K>QMK:^=:L
%#",[K>@NE:=:I>E:BGLNEBG:>:
LN:<HG<>GMK:ZYHIE:LFVMB<:M>FNF:K>E:
ZYHBGO>KL:<HF:=:#$
HFH<HGL>JN]G
<B:HLG^O>BL=>%#",LYH;:BQHL>FBG=B
O^=NHL<HF:<KHF>@:EB:JN:G=H<HFI:K:
=HL <HF BG=BO^=NHL <HGMKHEHL >E>O:G=HL>
:I_L H MK:M:F>GMH =>LM: I:MHEH@B:
H
F>LFH FH=H : L^GM>L> => %#", [ M:F
;[FBGB;B=:I>E:#$
!GMK>MH=:L:L%#",L
:F:BL>LMN=:=:[:%#",NF:O>SJN>
: LN: IKH=NZYH [ BG?EN>G<B:=: I>E: #$ >
%#"
*H >GM:GMH >F <HFI:K:ZYH <HF
HNMKHL I:KXF>MKHL ;BHJN^FB<HL H L>N
=HL>:F>GMH K>O>EHN L>K IHN<H L>GL^O>E GH
=B:@G_LMB<H > FHGBMHKBS:ZYH =: :<MBOB=:=>
=:=H>GZ:>F=H>GM>L<HF:<KHF>@:EB:
+
=HL>:F>GMH=:L%#",>GYH:IK>L>G
M:F :<MN:EF>GM> K>E>OXG<B: <E^GB<: G:
:;HK=:@>FE:;HK:MHKB:E=:I:MHEH@B:ABIH
MVE:FHABIH?BLVKB:
'B0B;72/23K172<9K079 '
*HL:G@N>I>KB?[KB<H:%#"<BK<NE:?NG
=:F>GM:EF>GM>LH;:?HKF:=>NF<HFIE>
QHM>KGVKBH>F<HGCNGMH<HF:%#",>:
LN;NGB=:=>V<B=HEV;BE(/
(/[NF:
IKHM>^G:@EB<HLBE:=:JN>GYHL>EB@:=BK><M:
F>GM>W%#"F:L[G><>LLVKB:I:K::?HK
F:ZYH=H<HFIE>QHM>KGVKBH<NC:?NGZYH[
:NF>GM:K : L>FBOB=: =: %#" I:K: <>K<:
=> JNBGS> AHK:L F:GM>G=H HL L>NL G^O>BL
<HGLM:GM>LG:<BK<NE:ZYH
>LM>FH=H:(/
[M:F;[F=>I>G=>GM>=:#$L>G=H:O:EB:
=: <HFH F:K<:=HK =: IKH=NZYH =BVKB: =>
#$
L IHM>G<B:BL O:GM:@>GL =H L>N =HL>:
F>GMHL>KB:F:F:GNM>GZYH=>G^O>BLL[KB
<HL<HGLM:GM>L:HEHG@H=H=B:>NF:F>GHK
=>I>G=]G<B:=HL?:<MHK>LJN>BGM>K?>K>FGH
=HL>:F>GMH=>%#">%#",
(#&'%)" )"!'
#""(&IX'
/1A<?3@53;PA71<@
%#" K>LNEM: =: MK:GL<KBZYH => NF
@>G> EH<:EBS:=H GH <KHFHLLHF: !LM:
IKHM>^G:>LL>G<B:E:<MN::MK:O[L=:EB@:ZYH
:NFK><>IMHK>LI><^?B<H<HF<:K:<M>K^LMB<:L
L>F>EA:GM>L:HK><>IMHK=:BGLNEBG:
!LMN=HL >?><MN:=HL >F @[F>HL FHGHSB
@_MB<HL>=BSB@_MB<HL=>FHLMK:K:F:BFIHK
MXG<B:=HL?:<MHK>L@>G[MB<HLG:=>M>KFBG:
ZYH =HL G^O>BL => %#"
+;L>KOHNL> NF:
>E>O:=:<HKK>E:ZYHGH=HL>:F>GMH=:%#"
GHL @[F>HL FHGHSB@_MB<HL <HFI:K:MBO:
F>GM> :HL =BSB@_MB<HL <HF HL ?:<MHK>L
:F;B>GM:BL : K>IK>L>GM:K>F NF I>JN>GH
I:I>E
+L IHEBFHK?BLFHL B=>GMB?B<:=HL G:
K>@BYH IKHFHMHK: =H @>G> %#" M]F LB=H
:IHGM:=HL <HFH CNLMB?B<:ZYH
M^MNEH =>
>Q>FIEH HL IHKM:=HK>L =H :E>EH :IK>
L>GM:F NF F:BHK I>LH :H G:L<BF>GMH
F:BHKI>LH<HKIHK:E>G^O>BL=>%#"F:BL
>E>O:=HL
!F<HGMK:LM>HL?:<MHK>L:F;B>G
M:BLM]FF:BHKK>E>OXG<B:G:=>M>KFBG:ZYH
=HLG^O>BL=>BGLNEBG:>%#",
/1A<?3@47@7<9S571<@
%#">F;HK:L>C:=>I>G=>GM>?NG=:
F>GM:EF>GM> =: #$ [ M:F;[F K>@NE:=:
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
IHK=BO>KLHL?:<MHK>LGHLJN:BLL>BG<EN>F:
B=:=>HL>QHH:IHKM>GNMKB<BHG:E:LAHK
FHG:LMBKHB=>B:LHL>LMKH@[GBHLH<HKMBLHE>
HLG^O>BL=>%#",L
72/23 [ NF ?:<MHK =>M>KFBG:GM> =HL
G^O>BL=>%#"
2>KB?B<:L>NF:NF>GMHIKH
@K>LLBOH =>L=> H G:L<BF>GMH :M[ : IN;>K=:
=>FHF>GMH:I:KMBK=HJN:EHLG^O>BL<HF>
Z:F:=><EBG:K<HFH:O:GZ:K=:B=:=>
*:
IN;>K=:=> <HF : :<>E>K:ZYH =H <K>L<BF>G
MH:M:Q:=>L><K>ZYH=>#$:NF>GM:<>K<:
=> MK]L O>S>L H<HKK>G=H I:K:E>E:F>GM> NF
:NF>GMH => <>K<: => =N:L : MK]L O>S>L G:
L><K>ZYH=>%#"
,>EHLFHMBOHL:IHGM:=HL
[G><>LLVKBH>LM:;>E><>KO:EHK>L=>K>?>K]G<B:
> BGM>KIK>M:K HL =HL>:F>GMHL => %#" =>
:<HK=H<HFH@KNIH>MVKBH
*H=><NKLH=HIKH<>LLH=>>GO>EA><BF>G
MH H<HKK>F =BO>KL:L :EM>K:Za>L JN> <HGMKB
;N>FI:K:H=><E^GBH=:#$>%#"GHF>:
=:F>GM>FH=B?B<:Za>L=:K>LIHLM:=:L<[EN
E:LLHF:MHMK_?B<:L:H>LM^FNEH=:#$.$>W
BGB;BZYH =: LHF:MHLM:MBG: > :EM>K:Za>L =:
<HFIHLBZYH<HKIHK:E>Q>K<^<BH=B>M:>LHGH
!F;HK:HLF><:GBLFHLLN;C:<>GM>LGYH>LM>
C:F I>K?>BM:F>GM> >L<E:K><B=HL IKHO:O>E
F>GM>>GOHEO>FHL?:<MHK>L:MKVLK>?>KB=HL
BGO>LMB@:ZYH<E^GB<:M>F=>FHGLMK:=H
: H<HKK]G<B: => NF: =BFBGNBZYH =: L><K>
ZYH=>#$>FB=HLHLL:N=VO>BL<HFI:K:MB
O:F>GM> :HL :=NEMHL
L :EM>K:Za>L =: #$
K>LNEM:GM>L =H >GO>EA><BF>GMH BG<EN>F
NF: K>=NZYH =: ?K>JN]G<B: =HL IB<HL =>
L><K>ZYH =: LN: L>FBOB=: > =: M:Q: =>
L><K>ZYH=BVKB:
BG?EN]G<B:=H@3E< GHLG^O>BL=>%#"
GYH>LMVMHM:EF>GM>>L<E:K><B=:
*H>GM:G
MH >LMV <HFIKHO:=H JN> : K>E:ZYH =: #$
<HF : %#" [ M:F;[F =>M>KFBG:=: I>EH
L>QH IHBL G:L FNEA>K>L I:K: L> :E<:GZ:
K>F O:EHK>L => %#" L>F>EA:GM>L :HL =HL
AHF>GL [ G><>LLVKB: NF: L><K>ZYH => #$
LB@GB?B<:MBO:F>GM> F:BHK
+L >LMKH@[GBHL
M]FNF>?>BMH=BK><MHG>@:MBOHG:IKH=NZYH
=> %#" K>@NE:=: I>E: #$ >GJN:GMH JN>
HL :G=KH@[GBHL M]F >?>BMHL IHM>G<B:EF>GM>
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
BGO>KLHL
,HK bEMBFH G: FNEA>K H =HL>:
F>GMH => %#" IH=> L>K BG?EN>G<B:=H I>E:
?:L>=H<B<EHF>GLMKN:E>FJN>L>>G<HGMK:
+LG^O>BL=>%#"LH?K>FNF:NF>GMHF:BL
LB@GB?B<:MBOH >F K>LIHLM: W #$ =NK:GM> :
?:L> ?HEB<NE:K <HFI:K:MBO:F>GM> W HONE:
ZYH>?:L>ENM>^GB<:
*H=><NKLH=:5?/C723G:L><K>ZYHINE
LVMBE=>#$I>E:ABI_?BL>[IKH@K>LLBO:F>G
M> LNIKBFB=: > LN;LMBMN^=: I>E: L><K>ZYH
<HGM^GN:=>#$IE:<>GM:KJN>GYH[B=>GMB
?B<:=:I>EHLF[MH=HLE:;HK:MHKB:BL=BLIHG^
O>BL
*H IKBF>BKH > L>@NG=H MKBF>LMK>L =>
NF:@K:OB=>SGHKF:E:LIKHM>^G:L=>EB@:
ZYH=:%#":NF>GM:F=>?HKF:KVIB=:>
LB@GB?B<:MBO: F:L HL G^O>BL => %#" MHM:E
LH?K>FNF:K>=NZYH<>K<:=>GHIKB
F>BKH>GHL>@NG=HMKBF>LMK>L
/1A<?3@=/A<9S571<@
+L4/1A<?3@;BA?717<;/7@ BG?EN>G<B:F:
L><K>ZYH => %#" BG=>I>G=>GM>F>GM> =:
#$
+L G^O>BL => %#" >E>O:FL> :I_L
BG@>LMYH=>IKHM>^G:L>E^IB=HL=BFBGNBG=H
>F <:LHL => =B>M:L IH;K>L >F AB=K:MHL =>
<:K;HGH HN ABIH<:E_KB<:L
!QBLM> M:F;[F
NF:<HKK>E:ZYH=BK><M:>GMK>HLG^O>BLL[KB
<HL=>%#">:BG@>LMYH=>FB<KHGNMKB>GM>L
<HFH H <VE<BH ?>KKH IHMVLLBH F:@G[LBH
?_L?HKHMB:FBG:>SBG<H
*:L LBMN:Za>L => :/9;BA?7ON< GHF>:
=:F>GM> :GHK>QB: G>KOHL: > <:JN>QB: HL
G^O>BL => %#" :IK>L>GM:FL> LB@GB?B<:MBO:
F>GM> =BFBGN^=HL >GJN:GMH JN> HL G^O>BL
=>#$LH?K>FNF:NF>GMH
HGMK:KB:F>GM>
:<03@72/23 <:K:<M>KBS:L>IHKNF:K>=NZYH
=:L><K>ZYH=>#$>F;HK:HLG^O>BLL[KB<HL
=> %#" LH?K:F NF: >E>O:ZYH IKHO:O>E
F>GM><HFH<HGL>JN]G<B:=HABI>KBGLNEBGBL
FH
+MBIH=>=BLMKB;NBZYH=:@HK=NK:<HK
IHK:E M:F;[F BG?EN>G<B: HL L>NL G^O>BL G:
F>=B=:>FJN>H:NF>GMH=:@HK=NK:OBL<>
K:E L> :LLH<B: : F>GHK>L <HG<>GMK:Za>L =>
%#"
+L>?>BMHL=:H;>LB=:=>GH>BQH#$n
%#" LYH K>O>KL^O>BL JN:G=H L> <HGL>@N>
NF:I>K=:IHG=>K:ELB@GB?B<:MBO:
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
+NMKHL:LI><MHLBFIHKM:GM>LJN>=>O>F
L>KE>O:=HL>F<HGLB=>K:ZYHG:BGM>KIK>M:
ZYH =HL O:EHK>L => %#" LYH :L 2<3;O/@
7;A3?1<??3;A3@I:KMB<NE:KF>GM>A>IVMB<:L>
K>G:BL
>OB=H:HI:I>E?NE<K:E=H?^@:=HG:
K>@NE:ZYH =HL G^O>BL => %#" : >QBLM]G<B:
=> NF: 63=/A<=/A7/ IKH@K>LLBO: K>LNEM:
IHK NF E:=H G: =BFBGNBZYH =HL G^O>BL =>
%#"MHM:E>EBOK>>IHKHNMKHGNF:K>=N
ZYH =: K>LIHLM: :HL >LM^FNEHL ?BLBHE_@B<HL
JN><HG=NS>FWL><K>ZYH=>#$
*HL =H>GM>L <HF 7;@B4717Q;17/ ?3;/9
I:K: :E[F => NF: K>=NZYH G:L <HG<>GMK:
Za>L=>%#"H<HKK>BGB;BZYH=:LN::<ZYH
;BHE_@B<: =><HKK>GM> =: :<NFNE:ZYH =>
%#",LIKBG<BI:EF>GM>=:%#",
!F BG=BO^=NHL <HF 67=<A7?<727@:< HL
G^O>BL => %#" LYH ;:BQHL IH=>G=H OBK :
GHKF:EBS:K:I_LM>K:I]NMB<:AHKFHG:ELN;L
MBMNMBO: <HF E>OHMBKHQBG:
HGMK:KB:F>GM>
GH67=3?A7?<727@:<:%#"IH=>>LM:KGHK
F:EHN>E>O:=:=BFBGNBG=H:I_LM>K:I]NMB
<:<HF:GMBMBKHB=>NLHNMBKHB=><MHFB:
:=FBGBLMK:ZYH => =HL>L LNIK:?BLBHE_
@B<:L => 1<?A71<@A3?S723@ <HG=NS : NF
:NF>GMH=:%#"L[KB<:F:L:LN:;BH=BL
IHGB;BEB=:=> K>=NSL>
HGMK:KB:F>GM> :
M>K:I]NMB<:<HF>LM>L?VKF:<HLIHKOB:BG:
E:M_KB: >F <KB:GZ:L :LFVMB<:L GYH I:K><>
:EM>K:KHLG^O>BL=>%#"
,HK bEMBFH I:K><> >QBLMBK NF: <HKK>E:
ZYHBGO>KL:>GMK>%#">BGLNEBG:=>OB=HW
BG?EN]G<B:=:BGLNEBG:GHLG^O>BL=>%#",
I>EH JN> G: 27/03A3@ :3997AB@ A7=< 3 F:E <HGMKHE:=: IH=> A:O>K =BFBGNBZYH =:
IKH=NZYHA>IVMB<:=>%#"
!J(##' #&(#&'$&
#'!"(#
+L IKBF>BKHL =HL>:F>GMHL =: %#"
>GMYH =>GHFBG:=: /HF:MHF>=BG: MBO>
K:FBG^<BHGH?BG:E=HL:GHLM>G=H:LN:
:IEB<:ZYH <E^GB<: G: :O:EB:ZYH =: L><K>ZYH
=> #$ L> @>G>K:EBS:=H : I:KMBK =: =[<:=:
L>@NBGM>
M><GHEH@B:>GMYHNMBEBS:=:>K::
.% K:=BHBFNGH>GL:BH NF F[MH=H BFN
GHE_@B<H >F JN> : K>O>E:ZYH =: ?HKF:ZYH
=H<HFIE>QH:GMB@[GBH:GMB<HKIHL>IKH<>L
L: :MK:O[L =: K:=B:ZYH @:F: >FBMB=: I>EH
:GMB@[GBHF:K<:=H<HF%H=H
.%NF:M[<GB<:=HMBIH<HFI>MBMBOH
NMBEBS:O: NF :GMB<HKIH FHGH<EHG:E :GMB
%#"I:K:HJN:E<HFI>MB:F:%#">QBL
M>GM> G: :FHLMK: > : %#" F:K<:=:
+KB@BG:O:FL> >GMYH <HFIE>QHL :GMB@[GBH
:GMB<HKIH F:K<:=HL > GYH F:K<:=HL JN>
IHLM>KBHKF>GM> IK><BIBM:O:F I:K: >EBFBG:K
HLH;K>G:=:GM><HF:GMB@[GBHLGYHEB@:=HL
,:K::JN:GMB?B<:ZYH=:%#"K><HKKB:L>:
NF: <NKO: => <:EB;K:ZYH L>G=H HL K>LNEM:
=HLBGO>KL:F>GM>IKHIHK<BHG:BLWK:=BH:<MB
OB=:=> =: :FHLMK:
,HK L>K NF: M[<GB<:
<HFI>MBMBO: > :I>L:K =H K><NKLH : @K:G=>L
=BENBZa>L=::FHLMK::BG=:I>KFBMB::BGM>K
?>K]G<B:=:LIKHM>^G:L=>EB@:ZYH:L%#",qL
*H BG^<BH =: =[<:=: => HL >GL:BHL
<HF>K<B:BL I:LL:K:F : :IEB<:K :H LHKH HN
IE:LF: =HL =H>GM>L NF: IKBF>BK: ?:L> =>
>QMK:<ZYH =:L IKHM>^G:L => EB@:ZYH :MK:O[L
=:LN:IK><BIBM:ZYHI>EH>M:GHELHENZYH>M:
GHEnV<B=HG:IKHIHKZYH
0K:M:L>
=:M[<GB<:F:BLLBFIE>L<HF;H:K>IKH=NMB
;BEB=:=> >QM>GL:F>GM> NMBEBS:=: F:L JN>
:IK>L>GM:<HFH=>LO:GM:@>FH?:<MH=>GYH
>EBFBG:K:L%#",qL=HLH;K>G:=:GM>
1F HNMKH F[MH=H => >QMK:<ZYH : <KH
F:MH@K:?B:=>?BEMK:ZYH>F@>EV<B=H>GMK>
M:GMHM:F;[F=>L>GOHEOB=::I>L:K=>I>K
FBMBK NF: L>I:K:ZYH JN:L> <HFIE>M: =:L
IKHM>^G:L=>EB@:ZYH>=>M>KLB=HLBFIEB?B<:
=: I>E: :NMHF:MBS:ZYH >OB=>G<B: ?:EM: =>
K>IKH=NMB;BEB=:=>
E[F =BLLH [ K>E:MBO:
F>GM><HFIE>Q:I>EHJN>>LMVK>L>KO:=:W
BGO>LMB@:ZYH > O:EB=:ZYH => GHOHL >GL:BHL
GHF>K<:=H
1FM>K<>BKHF[MH=H=BLIHG^O>EI:K:>OB
M:K : BGM>K?>K]G<B: =:L %#",qL <HGLBLM> G:
:=BZYH=>%#"WL:FHLMK:L:GM>L=>BGMKH
=NSBKH:GMB<HKIHHJN><HG=NSWL:MNK:ZYH
=:L %#",L I>KFBMBG=H H =HL>:F>GMH =>
%#"=>?HKF:F:BL?B=>=B@G:
!LM>F[MH=H
>EBFBG: <HFIE>M:F>GM> : BGM>K?>K]G<B: =:L
%#",LF:LBFIEB<::NMBEBS:ZYH=>:GMB<HK
IHL :GMB%#" :EM:F>GM> >LI><^?B<HL <HF
IHN<: K>:<ZYH <KNS:=: <HF : %#"
+
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
H;C><MBOH GYH ?HB <HGL>@NB=H G: MHM:EB=:=>
I>EHJN>[NMBEBS:=HLH;K>MN=H<HFHL>@NG=:
M[<GB<: :I_L NF: IKBF>BK: >QMK:<ZYH <HF
>M:GHEV<B=HHN<HFHNMK:F>MH=HEH@B:
!FF>:=HL=:=[<:=:=>:M[<GB<:=>
.%[LN;LMBMN^=:IHK%.)BFNGHK:=BHF[
MKB<: NMBEBS:G=H =HBL :GMB<HKIHL <HF :EM:
:?BGB=:=>NF=>E>LF:K<:=H<HF%H=H >H
HNMKH EB@:=H : NF: ?:L> L_EB=:
%#" =:
:FHLMK:[<:IMNK:=:>GMK>HL=HBL:GMB<HKIHL
M[<GB<:=>oL:G=N^<A>pL>G=HH=HL>:F>G
MH =BK><M:F>GM> IKHIHK<BHG:E W K:=B:ZYH
>FBMB=:
LM[<GB<:L=>>QMK:<ZYHBGB<B:EIK>
OB:F>GM>K>?>KB=:LF:GMBO>K:F:LN:NMBEBS:
ZYHG:IKVMB<:<E^GB<:
*H>GM:GMH:G><>LLB
=:=>=>NF:K>LIHLM::M>FI:=:BFIEB<:O::
G><>LLB=:=>=>:NMHF:MBS:ZYHHJN>GYH>K:
IHLL^O>E <HF :L M[<GB<:L => .% > %.)
*>LM> <HGM>QMH ?HB G><>LLVKBH =>L>GOHEO>K
M><GHEH@B:L:EM>KG:MBO:L<HFB=]GMB<:L>GLB
;BEB=:=>>>LI><B?B<B=:=>nM[<GB<:LBFNGH>G
SBFVMB<:L BFNGH?ENHK>L<>GM>L > BFNGHJNB
FBHENFBG>L<>GM>L
0K:M:FL> => F[MH=HL
MBIH oL:G=N^<A>p =B?>KBG=H GH MBIH => F:K
<:=HK K>LI><MBO:F>GM> >GSBF: LN;LMXG<B:
JN^FB<:>FBLLHK:=>?ENHK>L<]G<B:HN=>ENS
LO:GM:@>GLIKBG<BI:BL=>LM>LF[MH=HLLYH:
K:IB=>S=>>Q><NZYHBG?>KBHK:NF:AHK::
@K:G=>L>GLB;BEB=:=>>K>IKH=NMB;BEB=:=>
.>E:MBO:F>GM>W<HEA>BM:><HGL>KO:ZYH
=:L:FHLMK:L:%#"[K>E:MBO:F>GM>>LMV
O>EGHIE:LF:L>>LM>?HKIKH<>LL:=H:M[
AHK:L :I_L : <>GMKB?N@:ZYH
*H >GM:GMH
MK:M:G=HL>=HL:G@N>MHM:EGYHAV>LM:;B
EB=:=>=>OB=HWBGM>K?>K]G<B:=:LIKHM>:L>L
>LM> FH=H [ ?NG=:F>GM:E >?><MN:K :
<HEA>BM: I:K: MN;HL L>F IK>I:K:ZYH I:K:
>OBM:K:BGM>K?>K]G<B:=HL:GMB<H:@NE:GM>L>
IKH<>=>K :H MK:GLIHKM> BF>=B:MH I:K: H
E:;HK:M_KBH:;:BQ:LM>FI>K:MNK:L=>IK>
?>K]G<B:>F@>EH
#'!"(#
*&
>L=> AV OVKB:L =[<:=:L : :<MBOB=:=>
;BHE_@B<:=:%#"M>FLB=H:O:EB:=::MK:O[L
=HL>N=HL>:F>GMH:I_LK>FHZYHHNBG:<MB
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
O:ZYH =:L %#",L
*H >GM:GMH AV <>K<: =>
=>S :GHL ?HK:F =>L>GOHEOB=:L M[<GB<:L
E:;HK:MHKB:BL =>LMBG:=:L :H =HL>:F>GMH =:
%#" EBOK> <NC: IKBG<BI:E O:GM:@>F [ H
?:<MH => >EBFBG:K : BG?EN]G<B: =:L %#",L
,HK[F [ ;:LM:GM> =B?^<BE => >Q><NM:K =H
IHGMH=>OBLM:M[<GB<HGYHM>G=HFHLMK:=H
<E:K:LNI>KBHKB=:=>GH=B:@G_LMB<H=H>Q<>L
LHHN=>?B<B]G<B:=>#$
HGL>JN>GM>F>GM>
=B?B<BEF>GM>IH=>KVLN;LMBMNBKH=HL>:F>GMH
=:%#"MHM:E<HGLB=>K:=HHF[MH=H=>>E>B
ZYH
HFH >Q<>IZYH : >LM: K>@K: >QBLM>F
HL<:LHL=>:EM>K:ZYH=:L><K>ZYH=>#$>F
JN>H=H>GM>:IK>L>GM:<HFHK;BEB=:=>LJN>
IH=>F :?><M:K H >BQH LHF:MHMK_?B<H M:BL
<HFH:H;>LB=:=>>:BGLN?B<B]G<B:K>G:E<K_
GB<:
*>LM:LLBMN:Za>LI:KMB<NE:K>LH=HL>:
F>GMH=:%#"EBOK>;BH:<MBO:IH=>K>IK>
L>GM:KNF>E>F>GMHBFIHKM:GM>GH=B:@G_L
MB<H
L>@NG=:>Q<>IZYHH<HKK>GHL=H>GM>L
<HF:<KHF>@:EB:LH;M>K:I]NMB<:<HF:GV
EH@HL =: LHF:MHLM:MBG: >F JN> HL G^O>BL
L[KB<HL=>%#"EBOK>IH=>KYH>LM:KK>E:MBO:
F>GM> F:BL LNIKBFB=HL JN> : %#" MHM:E
=>OB=HW>E>O:ZYH=:%#",
#'!"(#
"#
"`'(#]"
+=B:@G_LMB<H=>=>?B<B]G<B:=>#$[<E^
GB<HE:;HK:MHKB:E>GOHEO>G=H:ABLM_KB:<E^
GB<:>Q:F>?^LB<H>LMN=HK:=BHE_@B<H>>Q:
F>LE:;HK:MHKB:BL
!F<KB:GZ:L>:=HE>L<>GM>L:>QBLM]G<B:
=> NF: ;:BQ: >LM:MNK: :LLH<B:=: : NF:
K>=NSB=: O>EH<B=:=> => <K>L<BF>GMH [ :
IKBG<BI:E F:GB?>LM:ZYH <E^GB<: JN> <HG=NS
:H >LMN=H => NF: >O>GMN:E =>?B<B]G<B: =>
#$
*: IHINE:ZYH :=NEM: >LM> =B:@G_LMB<H
=>O>KV L>K <HGLB=>K:=H L>FIK> JN> NF
=H>GM> M>GA: :GM><>=>GM>L => I:MHEH@B:
ABIHMVE:FHABIH?BLVKB:HNABLM_KB:=><BKNK
@B:K:=BHM>K:IB:HNMK:NF:MBLFH>GOHEO>G
=H:K>@BYHABIH?BLVKB:
HFHIK>OB:F>GM>K>?>KB=H::O:EB:ZYH
=: L><K>ZYH => #$ K>O>E:L> NF: M:K>?:
<HFIE>Q:I>E:LN:INEL:MBEB=:=>
1F::O:
EB:ZYHBGB<B:E=H>BQHLHF:MHMK_?B<HIH=>L>K
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
?>BM: LBFIE>LF>GM> I>EH =HL>:F>GMH L[KB<H
=:%#">%#",
HFH<HGL>JN]G<B:=:
LN: EHG@: L>FBOB=: > >LM:;BEB=:=> NF
bGB<H=HL>:F>GMH=>%#"IH=>:NQBEB:KGH
=B:@G_LMB<H =>L=> JN> HL O:EHK>L L>C:F
BGM>KIK>M:=HL=>:<HK=H<HFHL>QH>:B=:=>
=H =H>GM>
*H >GM:GMH GYH [ IHLL^O>E
>Q<ENBK H =B:@G_LMB<H => =>?B<B]G<B: => #$
<HF ;:L> >F :I>G:L NF =HL>:F>GMH =>
%#" GHKF:E L>G=H ?NG=:F>GM:E ?:S>K :
:GVEBL> >F <HGCNGMH <HF HL K>LNEM:=HL =:L
IKHO:L => >LMBFNE:ZYH
HGMK:KB:F>GM>
NFO:EHK=>%#";:BQHI:K::B=:=>IH=>
L>KNF>Q<>E>GM>BG=B<:=HK=>=>?B<B]G<B:=>
#$ G: :NL]G<B: => HNMK:L <:NL:L JN> IHL
L:FCNLMB?B<:K>LL>O:EHKM:BL<HFHF:EGNMKB
ZYHHNI:MHEH@B:<K_GB<:
+L M>LM>L => >LMBFNE:ZYH LYH >E>F>GMHL
<A:O> GH =B:@G_LMB<H => =>?B<B]G<B: => #$
!QBLM>:IHLLB;BEB=:=>=>K><HKK>K:=B?>K>GM>L
IKHO:L=>>LMBFNE:ZYHL>G=HHM>LM>=:ABIH
@EB<>FB:BGLNE^GB<:<HGLB=>K:=HHF[MH=H=>
>E>BZYH I:KMB<NE:KF>GM> >F :=NEMHL
!LM>
M>LM> >LMV <HGMK:BG=B<:=H >F =H>GM>L <HF
ABLM_KB: => I:MHEH@B: <:K=^:<: HN <KBL>L <HG
ONELBO:L
HFH :EM>KG:MBO: >G<HGMK:FL>
=BLIHG^O>BLHM>LM>=H@EN<:@HGHM>LM>=:<EH
GB=BG:>:IKHO:=:#$.$#KHPMA$HKFHG>
.>E>:LBG@$HKFHG>>GMK>HNMKHL
*: B=:=> I>=BVMKB<: > >F :=NEMHL <HF
=>?B<B]G<B:=>#$<HFBG^<BHG:BG?XG<B::
NMBEB=:=>=:%#"[F:BHK=HJN>>F:=NEMHL
<HF =>?B<B]G<B: => #$ BGB<B:=: CV G: B=:=>
:=NEM:
I_L BGM>KIK>M:ZYH =HL K>LNEM:=HL
M>G=H >F <HGM: : B=:=> O>KB?B<:L> JN> GH
bEMBFH<:LHHLG^O>BL=>%#"LYHK>E:MBO:
F>GM>F:BL>E>O:=HL
HGL>JN>GM>F>GM>:
L>GLB;BEB=:=> > : >LI><B?B<B=:=> =: %#" GH
=B:@G_LMB<H=:=>?B<B]G<B:=>#$LYHF>GH
K>L>F:=NEMHL
+ =HL>:F>GMH => %#" M>F M:F;[F
NFF:BHKO:EHKIK>=BMBOH=:=>?B<B]G<B:=>
#$G:IK>L>GZ:=>HNMKHL=[?B<>L=>AHKFH
G:L ABIH?BLVKB:L
>LM> FH=H : IKH;:;BEB
=:=> => =>?B<B]G<B: => #$ [ => <>K<: =>
>G:IK>L>GZ:=>K>L
I><MBO:F>GM>NF=HBLMK]LHNJN:MKH=[?B
<>L:=B<BHG:BL
#'!"(#
"
!#"(#&.IW#(&$])(
#!
M>K:I]NMB<: LN;LMBMNMBO: <HF #$ M>F
LB=HNL:=:>?B<:SF>GM>=>L=>BGB<B:E
F>GM> >QMK:^=: : I:KMBK => ABI_?BL>L =>
<:=VO>K > F:BL M:K=> IHK M><GHEH@B: =>
*K><HF;BG:GM>
*: IHINE:ZYH I>=BVMKB<: HL H;C><MBOHL
IKBG<BI:BL=HMK:M:F>GMHLYHGHKF:EBS:K:
O>EH<B=:=> => <K>L<BF>GMH > :MBG@BK NF:
>LM:MNK: ?BG:E IK_QBF: =: >LM:MNK::EOH
?:FBEB:K
+L K>LNEM:=HL H;MB=HL =>I>G=>F
=:=HL>=>#$IK>L<KBM:=H>LM:=HGNMKB<BH
G:E=H=H>GM>=:K>LIHLM:=:%#">=:?:L>
>FJN>L>BGB<B:HMK:M:F>GMH
L=HL>LNMBEBS:=:L=>I>G=>F=HI>LH>
=:WK>:=>LNI>K?^<B><HKIHK:E
LN:MBMNE:
ZYH =>O> L>K =>M>KFBG:=: I>EHL G^O>BL =>
%#">F<HGCNGMH<HFHLI:KXF>MKHL<E^GB
<HL:O:EB:ZYH=:O>EH<B=:=>=><K>L<BF>G
MH NF: O>S JN> : GHKF:EBS:ZYH =: %#"
GYH BFIEB<: NF: G><>LL:KB:F>GM> NF:
F>EAHKB:<E^GB<:
>LM>FH=H:L=HL>LLYH
:CNLM:=:L => :<HK=H <HF H <K>L<BF>GMH
EBG>:KM>G=HL>FIK>>F:M>GZYH:IHLLB;BEB
=:=> => >?>BMHL :=O>KLHL
.><HF>G=:L> H
=HL>:F>GMH I>KB_=B<H =: %#" <HF =HBL
H;C><MBOHLIKBG<BI:BLFHGBMHKBS:ZYH=::=>
LYH W M>K:I]NMB<: > IK>O>GZYH =: :=FBGBL
MK:ZYH => =HL>L >Q<>LLBO:L M>G=H <HFH
H;C><MBOH : F:GNM>GZYH => G^O>BL => %#"
=>GMKH=HLO:EHK>L=>K>?>K]G<B:
*H>GM:G
MH GYH >LMV >LM:;>E><B=H L> =>O>F >LM:K
F:BL IK_QBFHL =H EBFBM> LNI>KBHK HN =H
EBFBM> BG?>KBHK I>EH JN> :L K><HF>G=:Za>L
F:BLK><>GM>LBG=B<:FJN>HLO:EHK>L::MBG
@BK=>O>KYH>LM:KIK_QBFHL=:F[=B:IKH<N
K:G=HFBGBFBS:KHL>O>GMN:BL>?>BMHL:=O>K
LHL =H MK:M:F>GMH
2:EHK>L I>KLBLM>GM>
F>GM>;:BQHL:I>L:K=:IK>L<KBZYH=>=HL>L
:=>JN:=:L=>#$LYH:EM:F>GM>BG=B<:MBOHL
=>FV:=>LYHWM>K:I]NMB<:
*: IHINE:ZYH :=NEM: : =>?B<B]G<B: =>
#$ [ : BGLN?B<B]G<B: :GM>ABIH?BLVKB: F:BL
IK>O:E>GM> >F =H>GM>L IHKM:=HK>L => E>La>L
ABIHMVE:FHABIH?BLVKB:LF:LHL>NK><HGA>
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
<BF>GMH <E^GB<H [ F:BL =B?^<BE
<E^GB<: [
BG>LI><^?B<:IH=>G=HA:O>KJN>BQ:L=>:LM>
GB::EM>K:Za>L=HLHGH:EM>K:Za>L=HANFHK
>:GLB>=:=>
*HL:=NEMHLHL>LMN=HL=>FHGLMK:FJN>
H MK:M:F>GMH <HF #$ <HG=NS : NF:
F>EAHKB:=:<HFIHLBZYH<HKIHK:E=HLF:K
<:=HK>L=>K>GHO:ZYH_LL>:=HI>K?BEEBI^=B
<H =H KBL<H <:K=BHO:L<NE:K > =: JN:EB=:=>
=> OB=:
=HL> => #$ : IK>L<K>O>K
=>O>KVL>K:F^GBF:IHLL^O>EGYHL_I>EHL
<NLMHL F:L I>EH ?:<MH => HL >?>BMHL <HE:M>
K:BL >=>F:L I>KB?[KB<HL :KMK:E@B:L <>?:
E>B:LL>K>F=>I>G=>GM>L=:=HL>
):GM[FL>>F=BL<NLLYH:IHLLB;BEB=:=>
=H:NF>GMH=H:I:K><BF>GMH=>G>HIE:LB:L
G: IK>L>GZ: => G^O>BL >E>O:=HL => %#"
I:KMB<NE:KF>GM> => <:K<BGHF:L =: F:F:
IK_LM:M: <_EHG > K><MH
HF ;:L> G>LM>L
=:=HL>QBLM>NFKBL<HM>_KB<H=>=>L>GOHEOB
F>GMH HN K><HKK]G<B: => G>HIE:LB:L >F
=H>GM>L LH; M>K:I]NMB<: LN;LMBMNMBO: <HF
#$
*H >GM:GMH G: IKVMB<: >LM>L K><>BHL
GYHM]FLB=H<HFIKHO:=HL<HFH=>FHGL
MK:F >LMN=HL => OB@BEXG<B: : EHG@H IK:SH
>F<KB:GZ:L>:=NEMHL
!FHIHLBZYHG^O>BL
K>=NSB=HL => %#" >LMYH :LLH<B:=HL :
:NF>GMH=HKBL<H=>=H>GZ:<:K=^:<:BLJN[
FB<:
NMBEBS:ZYH=:%#",G:FHGBMHKBS:
ZYH =: M>K:I]NMB<: <HF #$ BGB<B:EF>GM>
>G<:K:=: <HFH IKHFBLLHK: :IK>L>GM:
F:BHK>L?ENMN:Za>L=HJN>:%#"I>EHJN>
M>F BGM>K>LL> EBFBM:=H
.>E:MBO:F>GM> W
(/GYH>QBLM>F=:=HLLN?B<B>GM>LJN>CNL
MB?BJN>F:LN:NMBEBS:ZYH<E^GB<:
#'!"(#
"#
"`'(#&#! :<KHF>@:EB:[NF:I:MHEH@B:>G=_<KB
G: K>LNEM:GM> =: >QIHLBZYH IKHEHG@:=: :
G^O>BL:GHKF:EF>GM>>E>O:=HL=>#$<BK<N
E:GM>
IKBG<BI:E:<ZYH=:#$<HGLBLM>G:
BG=NZYH =: L^GM>L> => %#" JN> <HG=NS W
IKHEB?>K:ZYH<>ENE:K>BGB;BZYH=::IHIMHL>
>LM>FH=H:%#"[NFBFIHKM:GM>F:K
<:=HK=::<MBOB=:=>=:=H>GZ:
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
:<KHF>@:EB: >LMV :LLH<B:=: : NF
:NF>GMH =: FHK;BEB=:=> > : NF :NF>GMH
=><>K<:=>O>S>LG:FHKM:EB=:=><HF
I:K:MBO:F>GM> W IHINE:ZYH @>K:E
U ?NG
=:F>GM:E>LM:;>E><>KH=B:@G_LMB<HIK><H<>
F>GM> NF: O>S JN> H MK:M:F>GMH >?B<:S
IH=> K>O>KM>K : FHK;BEB=:=> :LLH<B:=: W
=H>GZ: I>KFBMBG=H K>LM:NK:K : >LI>K:GZ:
=>OB=:
LNLI>BM:<E^GB<:=>:<KHF>@:EB:BFIEB
<:HK><NKLH:NF<HGCNGMH=>F:K<:=HK>L
;BHJN^FB<HL<HFHH;C><MBOH=>>LM:;>E><>K
H=B:@G_LMB<H
!LM>LBG<EN>F:%#"L[KB<:
HI>K?BE=>#$G:LAHK:L>H=HL>:F>GMH
=: #$ GH =><NKLH => NF: IKHO: => LH;K>
<:K@:HK:E=>@EB<HL>,0#+
F:GNM>G
ZYH => G^O>BL >E>O:=HL => #$ GH =><NKLH
=>LM:IKHO:[:EM:F>GM>BG=B<:MBO:=H=B:@
G_LMB<H
*H>GM:GMHK><>GM>F>GM>H=HL>:
F>GMH =: %#" M>F LB=H :IHGM:=H <HFH
IKBF>BK: :;HK=:@>F G: BGO>LMB@:ZYH =:
:<KHF>@:EB:
HEHG@H=HLbEMBFHLOBGM>:GHL:%#"
MHKGHNL>NFBGLMKNF>GMH>LL>G<B:EG::O:
EB:ZYH=>LM>L=H>GM>L
+L<KBM[KBHL;BHJN^FB
<HL JN> >LM:;>E><>F H L>N =B:@G_LMB<H HN
K>FBLLYH M]F OBG=H : LH?K>K :EM>K:Za>L IKH
@K>LLBO:L<HFH<HGL>JN]G<B:=H=>L>GOHEOB
F>GMH => F[MH=HL E:;HK:MHKB:BL I:K: H
=HL>:F>GMH=:#$>%#"<HFF:BHKL>GLB
;BEB=:=>>>LI><B?B<B=:=>
%#"<HKK>E:<BHG:L><HF::<MBOB=:
=>=:#$G:LAHK:LJN>K>FBG=BO^=NHL
L:N=VO>BLJN>K>F=H>GM>L<HF:<KHF>@:
EB:
*>LM:I:MHEH@B::IK>L>GM:M:F;[F<HK
K>E:ZYH<HFHO:EHKF^GBFH=:#$H;MB=H
G:,0#+
L><K>ZYH=>%#"GYH[INELV
MBE >QB;BG=H NF: EB@>BK: O:KB:;BEB=:=> :H
EHG@H =:L AHK:L <HGMK:KB:F>GM> W #$
JN> F:GM[F : INEL:MBEB=:=>
,HK bEMBFH
JN:G=H?HKF:NF<HFIE>QHM>KGVKBH<HF:
%#",>:(/F:GM[FNF:L>FBOB=:=>
AHK:L :H I:LLH JN> : #$ I>KF:G><>
:I>G:L<>K<:=>FBGNMHL>F<BK<NE:ZYH
HGL>JN>GM>F>GM> NF =HL>:F>GMH BLHE:
=H K>?E><M> : :<MBOB=:=> > L>O>KB=:=> =:
=H>GZ:
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
!F LBMN:Za>L => :<KHF>@:EB: :<MBO: HL
=HL>:F>GMHL=>%#">LMYHI>KLBLM>GM>F>G
M>>E>O:=HL:H<HGMKVKBH=HLBG=BO^=NHLGHK
F:BLCNLMB?B<:G=H:LN:NMBEBS:ZYHGH=B:@
G_LMB<H=:I:MHEH@B:
%#"[F:BL>LI><^
?B<: =H JN> H I>K?BE =: #$ G:L AHK:L
LH;K>MN=H >F =H>GM>L <HF EB@>BK: ABI>KL>
<K>ZYHAHKFHG:E>FJN>IH=>A:O>KLH;K>
IHLBZYH => O:EHK>L IHGMN:BL <HF HL BG=BO^
=NHLGHKF:BL
l F>=B=: JN> HL F[MH=HL E:;HK:MHKB:BL
I:K: =HL>:F>GMH =: #$ :MBG@BK:F F:BHK
L>GLB;BEB=:=> H <KBM[KBH => =B:@G_LMB<H =>
:<KHF>@:EB: MHKGHNL> F:BL K>LMKBMBOH
HGMN=H :<MN:EF>GM> H O:EHK =: %#"
<HGMBGN: : L>K H M>LM> <HF F:BHK L>GLB;BEB
=:=> > >LI><B?B<B=:=> I:K: >LM:;>E><>K H
=B:@G_LMB<H
!LM> =HL>:F>GMH GYH =>O> L>K
NMBEBS:=H<HFHbGB<H<KBM[KBH=>OB=HWIHL
LB;BEB=:=> => =BL<HK=XG<B: >GMK> : #$ > :
%#"IHKO>S>LO>KB?B<:=:
!LM:=BL<HK=XG<B:
IH=>K>LNEM:K=:K><NI>K:ZYH=:L>GLB;BEB=:
=>W#$E>O:G=H:?ENMN:Za>L=:%#":M[
JN>L>>LM:;>E>Z:NFGHOH>JNBE^;KBH>GMK>
: L><K>ZYH > : K>LIHLM: W #$
-N:G=H L>
H;L>KO: NF: =BL<HK=XG<B: >GMK> HL O:EHK>L
=> %#" > #$ : =><BLYH M>K:I]NMB<: =>O>
L>K;:L>:=:GHLLBG:BL>LBGMHF:L=:=H>G
Z:
HFH<HG<ENLYHL>I>EHF>GHLNF=HL
=HL>:F>GMHL>LMBO>K:EM>K:=H[?NG=:F>G
M:E :O:GZ:K <HF HL >Q:F>L BF:@BHE_@B<HL
=:K>@BYHABIHMVE:FHABIH?BLVKB:
#'!"(#
"
* IW#^
(&$])(&#! !F<>K<:=>=HL<:LHL::<KHF>@:
EB: K>LNEM: =: IK>L>GZ: => NF :=>GHF:
ABIH?BLVKBHL><K>MHK=>#$I>EHJN>:M>K:
I]NMB<: => >E>BZYH <HGLBLM> G: ?3:<ON<
17?U?571/ 2< AB:<?
+ MK:M:F>GMH M>F
<HFHH;C><MBOHLK>FHO>K:F:LL:MNFHK:E
<HFK>LHENZYH=H>?>BMH=>F:LL:K>LM:NK:K
:L><K>ZYHGHKF:E=>#$>%#"IK>O>GBK:
K><B=BO:MNFHK:E>IK>L>KO:K:K>LM:GM>?NG
ZYHABIH?BLVKB:
+L <KBM[KBHL => K>FBLLYH BG<EN>F : K>L
M:NK:ZYH =: L><K>ZYH GHKF:E INELVMBE =>
#$%#"=>GMKH=HLEBFBM>L=:GHKF:EB=:
=> > LNIK>LLYH MHM:E =: #$ >F I:K:E>EH
<HF:K>@K>LLYH=:L<:K:<M>K^LMB<:L?>GHM^IB
<:L
+ FHF>GMH F:BL IKHI^<BH I:K:
>?><MN:KH=HL>:F>GMH=>%#"<HKK>LIHG=>
WjL>F:G:I_LHI>K:M_KB:NF:O>SJN>
: LN: L><K>ZYH FHLMK: :E@NF: ?ENMN:ZYH
G:L IKBF>BK:L L>F:G:L :I_L : <BKNK@B:
>LM:;BEBS:G=H:I_L>LL>I>K^H=H
*::<KHF>@:EB::>?B<V<B:=:M>K:I]NMB
<: F[=B<: HN <BKbK@B<: >LMV :LLH<B:=: W
GHKF:EBS:ZYH=HLG^O>BL=>%#"L[KB<:JN>
:I:K>GM>F>GM>[HF:K<:=HKF:BLL>GL^O>E
=>K>FBLLYH>F<HFI:K:ZYH<HF:#$
*H
>GM:GMH F:BL NF: O>S H =HL>:F>GMH =:
%#"GYH=>O>L>KHbGB<H<KBM[KBH=><NK:
IHBL HL K>LNEM:=HL =>O>F L>K BGM>KIK>M:=HL
<HGCNGM:F>GM>
K><B=BO:=:=H>GZ:[IHN<HA:;BMN:E
<:LHL>:MBGC:NFO:EHKF^GBFH=>#$BG?>
KBHK : i@( > %#" L[KB<: GHKF:E I:K: :
B=:=>
*>LM:L <BK<NGLMXG<B:L : F:BHKB:
=HL=H>GM>LI>KF:G><>>FK>FBLLYHIHKNF
EHG@HI>K^H=H
*H>GM:GMH:LK><B=BO:LH<:
LBHG:BLH<HKK>FLH;K>MN=HGHL<:LHL>FJN>
L> O>KB?B<HN =BL<HK=XG<B: >GMK> : %#" > :
#$
>E>O:ZYHBLHE:=:=:#$H<HKK>LH;K>
MN=H >F FNEA>K>L CHO>GL H JN> LN@>K> :
BG?EN]G<B: =: B=:=> L>QH > >LMKH@[GBHL
G>LM: =BO>K@]G<B: ;BHJN^FB<:
,HK HNMKH
E:=H:>E>O:ZYHBLHE:=:=:%#">LMV:LLH
<B:=::NFIBHKI>K?BEF>M:;_EB<HLN@>KBG
=HJN>:%#"M>FNF:F:BHK>LI><B?B<B=:
=>=HJN>:#$G::O:EB:ZYH=:I>KLBLM]G
<B:=>:<KHF>@:EB::<MBO:
+MK:M:F>GMH=::<KHF>@:EB:M>F<HFH
H;C><MBOH GHKF:EBS:K : L><K>ZYH => #$ >
%#"GHL>GMB=H=><HKKB@BK:H:NF>GMH=:
FHKM:EB=:=> H;L>KO:=H G>LM: I:MHEH@B:
!LMN=HLK><>GM>LFHLMK:FJN>H<HGMKHEH=:
ABI>KL><K>ZYH AHKFHG:E :MBG@BG=H NF:
<HG<>GMK:ZYH => #$ ;:L:E BG?>KBHK : i@(>LMV:LLH<B:=H:LH;K>OB=:GHKF:E
>E>O:ZYH=:M:Q:=>FHKM:EB=:=>I>KLBLM>
GHL=H>GM>LF:E<HGMKHE:=HLIHBL:F:GN
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
M>GZYH=>O:EHK>L>E>O:=HL=>%#":NF>G
M::M:Q:=>FHKM:EB=:=>
!F;HK::G><>LLB=:=>=>:E<:GZ:KO:EH
K>L=>%#"=>GMKH=:GHKF:EB=:=>L>C:NF
H;C><MBOH <HGL>GLN:E =BL<NM>L> :BG=: H
@K:N => LNIK>LLYH B=>:E : :MBG@BK
<MN:EF>GM> K><HF>G=:L> : F:GNM>GZYH
=HLO:EHK>L=>%#"IK_QBFHL=:F[=B:HN
G: F>M:=> LNI>KBHK =H GHKF:E :CNLM:=HL
I:K:HL>QH>B=:=>GHL>GMB=H=>>OBM:K:
>O>GMN:EIKH@K>LLYHI:K:NF=[?B<>=>#$
B@N:EF>GM>IK>CN=B<B:E
I_L : M>K:I]NMB<: <BKbK@B<: JN:G=H :
=H>GZ: L> F:GM[F :<MBO: [ G><>LLVKBH
K><HKK>K W M>K:I]NMB<: F[=B<: I:K: <HGMKH
E:K : ABI>KL><K>ZYH AHKFHG:E
*>LM> XF;B
MH HL /;K9<5<@ 2/ @<:/A<@A/A7;/ <HGLMB
MN>F H MK:M:F>GMH => IKBF>BK: EBGA:
H
BGB;BK>F : L><K>ZYH => #$ <HG=NS>F :H
<HGMKHEH;BHJN^FB<H<HFGHKF:EBS:ZYH=:
%#">F<>K<:=>=HL<:LHLGHL
F:<KH:=>GHF:L > GHL FB<KH:=>GH
F:L
+BG^<BH=:K>LIHLM:[KVIB=HI>KFB
MBG=H M:F;[F : K>=NZYH HN I>EH F>GHL
F:GNM>GZYH=HOHENF>MNFHK:E
*H>GM:G
MHMK:M:L>=>NF:M>K:I]NMB<:=BLI>G=BHL:
>=>NLHIKHEHG@:=H
?/27<A3?/=7/ [ A:;BMN:EF>GM> NF:
M>K:I]NMB<: => M>K<>BK: EBGA: K>L>KO:=:
I:K: HL =H>GM>L JN> :IK>L>GM:F I>KLBLM]G
<B:HNK><HKK]G<B:MNFHK:E>JN>LYHK>LBL
M>GM>L HN BGMHE>K:GM>L W M>K:I]NMB<: F[=B
<:
IK>O>GZYH =H <K>L<BF>GMH MNFHK:E
H<HKK> >F <>K<: => =HL =H>GM>L GH
>GM:GMH : K>=NZYH =: L><K>ZYH => #$ :H
EHG@H=HL:GHL[E>GM:>@K:=N:E:MBG@BG=H
<>K<:=>:HL:GHLI_LBKK:=B:ZYH
:=HL<:LHLIHK[FBFIa>L>:G><>LLB
=:=> => OB@BEXG<B: =: F:LL: MNFHK:E :
F[=BHIK:SH
#" )'X'
+ =HL>:F>GMH =: %#" [ ?NG=:F>GM:E
G: :O:EB:ZYH => <KB:GZ:L > :=NEMHL >F JN>
>QBLM:LNLI>BM:<E^GB<:=>=BL?NGZYH=:L><K>
ZYH=>#$
IKH=NZYHA>IVMB<:=>%#"[
K>E:MBO:F>GM> <HGLM:GM> :H EHG@H =H =B:
I>KFBMBG=H JN> H L>N =HL>:F>GMH GNF:
:FHLMK:BLHE:=:L>C:;:LM:GM>?B=>=B@GH
*H
L:G@N>I>KB?[KB<H<BK<NE:?NG=:F>GM:EF>G
M>LH;:?HKF:=>NF<HFIE>QHM>KGVKBHH
JN> <HGMKB;NB I:K: JN> : %#" I>KF:G>Z:
G:<BK<NE:ZYH=NK:GM>OVKB:LAHK:L
HFH=>FHGLMK:=H:=>M>KFBG:ZYH=:
<HG<>GMK:ZYHL[KB<:=>%#":LLNF>>E>O:
=:BFIHKMXG<B:GH=B:@G_LMB<H=:=>?B<B]G
<B:=>#$>FMH=HLHL@KNIHL>MVKBHL:LLBF
<HFH GH =B:@G_LMB<H => :<KHF>@:EB:
.>O>EHN:BG=:L>K?NG=:F>GM:EG:FHGBMH
KBS:ZYH=:M>K:I]NMB<:<HF#$G::O:EB:
ZYH =: K>FBLLYH :I_L MK:M:F>GMH <BKbK@B<H
=::<KHF>@:EB:>G:FHGBMHKBS:ZYH=:M>K:
I]NMB<:F[=B<:=>LM:I:MHEH@B:
+ =HL>:F>GMH =: %#" :LLNF> :BG=:
F:BHKBFIHKMXG<B:GHL=H>GM>LLN;F>MB=HL
: M>K:I]NMB<: F[=B<: <HF H :GM:@HGBLM:
=HL K><>IMHK>L =: #$ I>@OBLHF:GM>
!LM>
?VKF:<H :<MN: : G^O>E I>KB?[KB<H GYH BGB
;BG=H:L><K>ZYH=>#$I>EHMNFHK=:^JN>
:FHGBMHKBS:ZYH=:>?B<V<B:=>LM:M>K:I]NMB
<: L_ [ IHLL^O>E :MK:O[L =H =HL>:F>GMH =:
%#"
+I>@OBLHF:GM><HGL>@N>:GHKF:EB
S:ZYH=:%#"GNF:I>K<>GM:@>FLNI>KBHK
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
#&
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Clemmons DR. IGF-1 assays: current assay
methodologies and their limitation. Pituitary
2007; 10: 121-128.
Boguszewski CL. O laboratório no diagnóstico
e seguimento da acromegalia. Arq Bras
Endocrinol Metab 2002; 46 (1): 34-44.
Brabant G, Wallaschofski. Normal levels of serum
IGF-1: determinants and validity of current reference ranges. Pituitary 2007; 10: 129-133.
Casagrande A, Czepielewski. Ensaios para a
medida de GH e IGF-1: aspectos metodológicos e suas implicações no diagnóstico e seguimento da acromegalia. Arq Bras Endocrinol
Metab 2007; 51 (4): 511-519.
Frystyk J. Utility of free IGF-1 measurements.
Pituitary 2007; 10: 181-187.
Barkan AL. Defining normalcy of the somatotropic axis: an attainable goal? Pituitary 2007;
10: 135-139.
Sherlock M, Toogood A. Aging and the growth
hormone / insulin like growth factor-I axis.
Pituitary 2007; 10: 189-203.
Kwan AYM, Hartman ML. IGF-1 measurements
in the diagnosis of adult growth hormone deficiency. Pituitary 2007; 10: 151-157.
Roberts B, Katznelson L. Approach to the evaluation of the GH/IGF-1 axis in patients with
pituitary disease: which test to order. Pituitary
2007; 10: 205-211.
Toogood AA, Stewart PM. Hypopituitarism:
Clinical features, diagnosis and management.
Endocrinol Metab Clin N Am 2008; 37: 235-261.
Higham CE, Jostel A, Trainer PJ. IGF-1 measurements in the monitoring of GH therapy.
Pituitary 2007; 10: 159-163.
Vance ML, Mauras N. Growth hormone therapy in adults and children. N Engl J Med 1999;
341 (16): 1206-1216.
Abucham J, Vieira TCA, Barbosa ER, Ribeiro RS,
Martins MRA. Terapia de reposição hormonal
no hipopituitarismo. Arq Bras Endocrinol
Metab 2003; 47 (4): 492-508.
Brooke AM, Drake WM. Serum IGF-1 levels in
the diagnosis and monitoring of acromegaly.
Pituitary 2007; 10: 173-179.
Taboada GF, Haute FR, Corrêa LL, Casini AF,
Gadelha MR. Etiologic aspects and management of acromegaly. Arq Bras Endocrinol
Metab 2005; 49 (5): 626-640.
16. Bem-Shlomo A, Melmed S. Acromegaly.
Endocrinol Metab Clin N Am 2008; 37: 101-122.
17. Colao A, Ferone D, Marzullo P, Lombardi G.
Systemic complications of acromegaly: epidemiology, pathogenesis and management.
Endocrine Reviews 2004; 25 (1): 102-152.
18. Melmed S, Colao A, Barkan A, Molitch M,
Grossman AB, et al. Guidelines for acromegaly
management: an update. J Clin Endocrinol
Metab 2009; 94 (5): 1509-1517.
19. Alexopoulou O, Bex M, Abs R, T’Sjoen GT,
Velkeniers B, Maiter Dominique. Divergence
between Growth Hormone and Insulin-Like
Growth Factor-I concentrations in the followup of acromegaly. J Clin Endocrinol Metab
2008; 93 (4): 1324-1330.
20. Melmed S. Acromegaly. N Engl J Med 2006;
355 (24): 2558-2573.
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
:K<BGHF:=:@EXG=NE:LNIK:K>G:E:LI><MHL
?NG=:F>GM:BLIKH@K>LLHL>BG<>KM>S:L
3A4=>2>AC820;20A28=><05D=30<4=C0;8BBD4B
03E0=24<4=CB0=3D=24AC08=C84B
$>E=>K/BFa>L&H:G:HLM::KEHL2:L<HG<>EHL(N^L.:IHLH%L:;>E,:BO:/>JN>BK:
N:KM>):<A:=H/:K:BO:
#Q382> =C4A=>34=3>2A8=>;>680)4AE8P>34=3>2A8=>;>6808014C4B4#4C01>;8B<>4=CA>>B?8C0;0A34"8B1>0%2834=C0;)#Y"%
BB8BC4=C4>B?8C0;0A34=3>2A8=>;>680)4AE8P>34=3>2A8=>;>6808014C4B4#4C01>;8B<>4=CA>>B?8C0;0A34"8B1>0%2834=C0;)#Y"%
745434)4AE8P>34=3>2A8=>;>680)4AE8P>34=3>2A8=>;>6808014C4B4#4C01>;8B<>4=CA>>B?8C0;0A34"8B1>0%2834=C0;)#Y"%
BB8BC4=C4 >B?8C0;0A A03D03> 34 =3>2A8=>;>680 )4AE8P> 34 =3>2A8=>;>680 8014C4B 4 #4C01>;8B<> 4=CA> >B?8C0;0A 34 "8B1>0
%2834=C0;)#Y"%
BB8BC4=C4>B?8C0;0AA03D03034=3>2A8=>;>680)4AE8P>34=3>2A8=>;>6808014C4B4#4C01>;8B<>>B?8C08B30+=8E4AB8303434>8<1A0
8A42C>A34)4AE8P>34=3>2A8=>;>680)4AE8P>34=3>2A8=>;>6808014C4B4#4C01>;8B<>4=CA>>B?8C0;0A34"8B1>0%2834=C0;)#Y"%
AD?>34BCD3>B3>B*D<>A4B30;N=3D;0)D?A0A4=0;)>2843034&>ACD6D4B034=3>2A8=>;>6804#4C01>;8B<>
<??3@=<;2Q;17/ 4;34A )8<U4B Z )4AE8P> 34 =3>2A8=>;>680 8014C4B 4 #4C01>;8B<> Z 4=CA> >B?8C0;0A 34 "8B1>0 %2834=C0;
)#Y"%Z(D030!D=@D48A0
"8B1>0Z74;34A55B6<08;2><
137A/ON<AC86>A424183>4<
A4E8BC>4<
40248C4?0A0?D1;820PO>4<
&')!#
Objectivos: rever os aspectos fundamentais e os últimos progressos no que respeita à etiopatogenia, diagnóstico, tratamento e seguimento do carcinoma do córtex da glândula supra-renal.
Métodos: pesquisa de bibliografia original ou de revisão publicada até Agosto de 2009.
Conclusões: Da escassez de evidência científica sólida sobre o assunto têm resultado várias
incertezas. Persistem dúvidas acerca da definição dos estádios III e IV, está por estabelecer o
lugar exacto das terapêuticas adjuvantes, assim como quais os esquemas de citotóxicos mais
eficazes. Os estádios avançados de doença associam-se a mau prognóstico, sendo a sobrevida global aos cinco anos baixa. A remoção cirúrgica de toda a massa tumoral constitui a única
hipótese de cura. O mitotano, alguns citotóxicos e até a radioterapia parecem ter um papel
importante como terapêutica adjuvante na doença avançada, e também nas recidivas. Os
últimos anos têm acrescentado novidades interessantes no tratamento, mas cujo papel definitivo está por estabelecer.
$ *&'*
Carcinoma; Supra-renal; Estadiamento; Suprarrenalectomia; Quimioterapia; Radioterapia.
'(&(
Objectives: to review the principal issues and recent progress in the pathogenesis, diagnosis,
treatment and follow-up of adrenocortical carcinoma.
Methods: Search of original and review data published until August of 2009.
Conclusions: The uncertainty in the management of adrenocortical carcinoma is a result of the
lack of solid scientific evidence in the field. Uncertainty persists in the definition of disease stages
III and IV, in the exact place of adjuvant therapy, and in establishing the most efficient cytotoxic
protocol. Advanced disease stages have a poor prognosis, and the five year survival rate is low.
The complete surgical removal of all tumoral tissue is the only chance of cure. Mitotane, cytotoxic
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
agents and radiotherapy may have an important role as adjuvant therapy in advanced disease
and recurrences. Recently some interesting discoveries in treatment have been published witch
definitive role is yet to be established.
-+#&'
Carcinoma; Adrenocortical; Staging; Adrenalectomy; Chemotherapy; Radiotherapy.
"(&#)IW#
!J(##'
!F;HK: HL MNFHK>L =: @EXG=NE: LNIK:
K>G:E /. L>C:F K>E:MBO:F>GM> <HFNGL G:
IHINE:ZYH:MBG@BG=H<>K<:=>=HLBG=B
O^=NHLH<:K<BGHF:=H<_KM>Q=:@EXG=N
E:LNIK:K>G:E/.[NF:=H>GZ:K:K:
LN:BG<B=]G<B::GN:E@EH;:EO:KB:>GMK>
: IHK FBEAYH => A:;BM:GM>L
,:K><>F
>QBLMBK=HBLIB<HL=>BG<B=]G<B:NFIKBF>BKH
>F<KB:GZ:L>NFL>@NG=H>GMK>:JN:KM:>
: JNBGM: =[<:=:L => OB=:
*: K>@BYH =>
NKBMB;:GH/NE=HK:LBE=>M><MHNL>NF:
BG<B=]G<B: :GN:E I:KMB<NE:KF>GM> >E>O:=:
>F<KB:GZ:L<HFI:K:MBO:F>GM>:HO>KB?B<:
=HGHK>LMH=HFNG=H:IHKFBEAYH
OLFBEAYHK>LI><MBO:F>GM>
!F@>K:E
:L FNEA>K>L LYH F:BL :?><M:=:L =H JN> HL
AHF>GL GNF: K:SYH => :IKHQBF:=:
F>GM>
:IK>L>GM:ZYH<E^GB<:=>I>G=>LH;K>MN
=H =: :<MBOB=:=> >G=_<KBG: =H MNFHK F:L
M:F;[F=:LLN:L=BF>GLa>L>=:>QM>GLYH
=:=H>GZ:
K>FHZYH<BKbK@B<:=:MHM:EB=:
=>=HM><B=HMNFHK:E<HGLMBMNB:bGB<:ABI_
M>L>=><NK:
>OB=H :H GbF>KH EBFBM:=H => =H>GM>L
H;L>KO:=HL G: F:BHK I:KM> =HL L>KOBZHL
F[=B<HL :L L[KB>L IN;EB<:=:L LYH :BG=:
K>=NSB=:L
+L <E^GB<HL =>;:M>FL> :BG=:
<HF BGbF>K:L BG<>KM>S:L LH;K> H /. JN>
OYH=>L=>H=B:@G_LMB<H:HMK:M:F>GMHI:L
L:G=H I>EH >LM:=B:F>GMH > L>@NBF>GMH
0H=:OB:GHLbEMBFHL:GHLM>FL>:LLBLMB=H
WIN;EB<:ZYH=>BFIHKM:GM>>OB=]G<B:<B>G
M^?B<: > => :E@NF:L M>GM:MBO:L => <HGL>GLH
LH;K>>LM:I:MHEH@B:
,:K:I>LJNBL:;B;EBH@KV?B<:K><HKK>NL>W
;:L>=>=:=HL,N;)>=>FAMMIPPP
G<;B
GEF
GBA
@HOIN;F>=
1MBEBS:K:FL> >F
<HF;BG:Za>L =BO>KL:L HL L>@NBGM>L M>KFHL
=> I>LJNBL: :=K>GH<HKMB<:E :=K>G:E <:K<B
GHF:MNFHKLG>HIE:LF<:G<>K=B:@GHLBL
LM:@BG@ MK>:MF>GM LNK@>KR K:=BHMA>K:IR
BF:@BG@ FBMHM:G>
"HK:F <HGLB=>K:=HL HL
:KMB@HLHKB@BG:BLHN=>K>OBLYHLH;K>HM>F:
>FANF:GHLIN;EB<:=HL>FE^G@N:BG@E>L:
:M[@HLMH=>
"HK:FB@N:EF>GM>MB=:L
>F<HGM:?HGM>L<HFHEBOKHL=>M>QMH:KMB@HL
<BM:=HL IHK HNMK:L IN;EB<:Za>L >G<HGMK:=:L
=NK:GM> : I>LJNBL: > HNMK:L <HFNGB<:Za>L
<B>GM^?B<:L <HFH IHK >Q>FIEH <HFNGB<:
Za>LHK:BL:IK>L>GM:=:L>FK>NGBa>L<B>GM^?B
<:L LH;K> H :LLNGMH
/>E><<BHG:K:FL> HL
:KMB@HL>IN;EB<:Za>LJN>=>:<HK=H<HF:
:GVEBL> =HL :NMHK>L =>LM: K>OBLYH FHLMK:
K:FF:BHKK>E>OXG<B:<E^GB<:G::;HK=:@>F
=>LM:I:MHEH@B:
$(#J"'
!QBLM>F IHN<:L <>KM>S:L :<>K<: =: >MBH
I:MH@>GB:=H/.
:=HL=HL>@NBF>GMH=>
BG<B=>GM:EHF:L =: @EXG=NE: LNIK:K>G:E
<HF <:K:<M>K^LMB<:L BGB<B:BL LN@>LMBO:L =>
:=>GHF: BG=B<:F JN> IKHO:O>EF>GM> HL
/. GYH L> HKB@BG:F : I:KMBK =>LM:L F:L
L:L
*H>GM:GMH>LMYHIN;EB<:=HL<:LHL
K:KHL => :I:K>GM> F:EB@GBS:ZYH => :=>GH
F:LHJN>IH=>KVH<HKK>K=>:<HK=H<HFH
I:K:=B@F: =:L =N:L FNM:Za>L L>JN]G<B:BL
>F@>G>LLNIK>LLHK>LMNFHK:BL
EBLM:=>
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
:EM>K:Za>L FHE><NE:K>L IKHIHLM: [ >QM>GL:
-N:=KH%
LF:BL<HFNGL=BS>FK>LI>BMH
:FNM:Za>LBG:<MBO:=HK:LGH,>>QIK>L
LYH>Q:@>K:=:=H%#"%%:<MN:G=HOB:K><>I
MHK=H%#"%
!LM:I:K><>M:F;[FL>K::EM>
K:ZYHFHE><NE:KBFIEB<:=:GHL<:LHL=>L<KB
MHL >F <KB:GZ:L G: K>@BYH /NE =H K:LBE
>F;HK: GYH L> M>GA:F =>FHGLMK:=H ?HK
F:L=>MK:GLFBLLYH?:FBEB:K
QUADRO I: Alterações moleculares mais implicadas na etiopatogenia do CSR15
Expressão exagerada de IGF-II actuando via receptor IGF-I
Mutações do P53
Activação da B-catenina
Mutações no oncogene RAS
Inactivação da subunidade R1A da proteína Cinase A
Mutações do receptor da ACTH
Mutações no gene MEN 1
$&'"(IW# _" #
&(#& !# `
!F;HK: H =B:@G_LMB<H => /. L>C: K:KH
>GMK> HL BG<B=>GM:EHF:L =: /. :<MN:EF>GM>
HL <:LHL => /. LYH B=>GMB?B<:=HL LH;K>MN=H
=NK:GM> : BGO>LMB@:ZYH => MNFHK>L =: /.
>G<HGMK:=HL => ?HKF: :<B=>GM:E >F OVKBHL
F[MH=HL => BF:@>F
I>L:K =BLLH <>K<: =>
=HL /. LYH >G=_<KBGH:<MBOHL >F;HK:
>LM: I>K<>GM:@>F O:KB> <HGLB=>K:O>EF>GM>
<HGLH:GM>:LL[KB>LIN;EB<:=:L
!GMK>HLMBIHL
ABI>KL><K>MHK>L H ABI>K<HKMBLHEBLFH [ H F:BL
?K>JN>GM>L>G=H:/^G=KHF>=>NLABG@<HF
HNL>FOBKBEBS:ZYH:?HKF:=>>QIK>LLYH<E^GB
<:F:BL<HFNF
"HKF:LIKH=NMHK:L=>>LMKH
@[GBHHN=>:E=HLM>KHG:LYHF:BLK:K:L
*:<KB:GZ::M[<>K<:=>=HL/.LYH
L><K>MHK>L>=>LM>L:F:BHKB:IKH=NS:G=KH
@[GBHL L>G=H : OBKBEBS:ZYH : :IK>L>GM:ZYH
<E^GB<:F:BL?K>JN>GM>
+JN:=KH%%FHLMK::LF:GB?>LM:Za>L<E^
GB<:L F:BL ?K>JN>GM>L :LLH<B:=:L : <:=:
?HKF:=>ABI>KL><K>ZYH>G=_<KBG:
L?HKF:L>G=_<KBGHBG:<MBO:LIH=>FL>K
=>L<H;>KM:L => ?HKF: :<B=>GM:E HN F:GB?>L
M:KL> IHK =HK GVNL>:L ?>;K> >G?:KM:F>GMH
HN>F:@K><BF>GMH=>I>G=>G=H=:L=BF>G
La>L=:E>LYH>HN=:>QM>GLYH=:=H>GZ:
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
QUADRO II: Manifestações clínicas associadas a cada tipo de hipersecreção hormonal no CSR.
Hiperandrogenismo
(Testosterona, DHEAs)
Hirsutismo, virilização, voz
grave, alopécia andrógena,
oligomenorreia
Estrogénio
Ginecomastia, atrofia testicular, disfunção eréctil, infertilidade.
Aldosterona
HTA, Hipocaliémia
Hipercortisolismo
Síndrome de Cushing, hipocaliémia
17-OHprogesterona,
$4-androstenediona
Podem apresentar-se como
endócrino-inactivo
=BF>GLYH F[=B: =HL /. KHG=: HL <FF:LM]FLB=HLN<>LLBO:F>GM>K>IHKM:=HL
<:LHL => E>La>L <:=: O>S F>GHK>L 0NFHK>L <HF F:BL => <F LYH :EM:F>GM>
LNLI>BMHL => F:EB@GB=:=>
0NFHK>L => : <F:IK>L>GM:FNFIHM>G<B:E=>F:EB@GB=:=>
BG<>KMH
HK=HL BKK>@NE:K>L BGO:LYH => >LMKN
MNK:L OBSBGA:L =>GLB=:=> >E>O:=: G:
0HFH@K:?B:HFINMHKBS:=:0HNP:LAHNM
=><HGMK:LM>>G=HO>GHLH:HLFBGNMHLBG?>
KBHK:G:0LYH<:K:<M>K^LMB<:L:EM:
F>GM>LN@>LMBO:L=>F:EB@GB=:=>
>GLB=:=>L
F>GHK>L=HJN>1GB=:=>L$HNGL?B>E=1$
G: 0 L>F <HGMK:LM> LYH <:K:<M>K^LMB<:L =>
;>GB@GB=:=> <HF >E>O:=H O:EHK IK>=BMBOH
G>@:MBOH>>F@>K:E<HKK>LIHG=>F::=>GH
F:L KB<HL >F E^IB=HL
*H >GM:GMH FNBM:L
F:LL:L ;>GB@G:L IH=>F :=JNBKBK O:EHK>L =>
:M>GN:ZYH=>n1$G:0L>F<HGMK:L
M>>:MBG@BKO:EHK>L1$G:0<HF<HG
MK:LM>
!QBLM> IHKM:GMH ;:LM:GM> LH;K>IHLBZYH
=>=>GLB=:=>L>GMK>F:LL:L;>GB@G:L>F:EB@
G:LGYH>LM:G=H=>?BGB=HNFEBFB:K=>=BLMBG
ZYH LN?B<B>GM>F>GM> L>GL^O>E > >LI><^?B<H
*:
K>LLHGXG<B:F:@G[MB<:.)*H/.:IK>L>G
M:L>FNBM:LO>S>LBLHBGM>GLH<HFH?^@:=H>F
0><HFBGM>GLB=:=>F[=B:::NF>GM:=:>F
0 <:IM: @:=HE^G>H <HF M>FIH => F0B7>DC
IKHEHG@:=H>M>F:LI><MHA>M>KH@[G>H
!FK>LNEM:=H=:?K>JN]G<B:>E>O:=:=:L
?HKF:L>G=_<KBGH:<MBO:LI>K:GM>:LNLI>B
M: => /. HN : =>M><ZYH BF:@BHE_@B<: =>
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
JN:EJN>K E>LYH G: @EXG=NE: /. =>O>F L>K
>?><MN:=HL =HL>:F>GMHL AHKFHG:BL JN>
I>KFBM:F B=>GMB?B<:K NF I:=KYH => L><K>
ZYHAHKFHG:E:G_F:EH
+JN:=KH%%%FHL
MK:HI>K?BE:G:E^MB<H:K>JNBLBM:KI>K:GM>NF
BG<B=>GM:EHF:BF:@BHE_@B<H=:/.
QUADRO IV: Características histológicas constituintes do Score de
Weiss.
Elevada taxa mitótica (>50 / CGA)
Mitoses Atípicas (r 6 / CGA)
Invasão venosa
Elevado padrão nuclear (grau 3 e 4)
Baixa % de células claras (b 25%)
QUADRO III: Doseamentos a requisitar perante o achado de uma
lesão da glândula SR.
Testosterona total
17-OHprogesterona,
$4-androstenediona
DHEAs
B-estradiol em homens e mulheres pós-menopausa
Metanefrinas e normetanefrinas plasmáticas fraccionadas
ou
Metanefrinas totais e catecolaminas fraccionadas na urina das 24h
Aldosterona
Renina
Rácio aldosterona/ renina ou actividade da renina plasmática
Ionograma
Prova de dexametasona com 1 mg
ACTH e cortisol plasmático ou cortisol salivar nocturno e cortisol Livre na Urina de 24h (se suspeita elevada de Cushing)
Adaptado a partir de 2 e 24.
+LF[MH=HL=>F>=B<BG:GN<E>:KIH=>F
=>L>FI>GA:KNFI:I>EBFIHKM:GM>GH>LMN
=H =HL MNFHK>L =: /.
MHFH@K:?B: IHK
>FBLLYH=>IHLBMKa>L,!0<HF?ENHKH=>
LHQB@EN<HL> " # IH=> I>KFBMBK =BLMBG
@NBK>GMK>E>La>L;>GB@G:L>F:EB@G:L=:/.
;:L>:G=HL>GNF:F:BHK:<MBOB=:=>F>M:
;_EB<: > <HGL>JN>GM> F:BHK <:IM:ZYH =H
K:=BH?VKF:<H IHK >LM:L bEMBF:L
,!0
<HF F>MHFB=:MH NF EB@:G=H =: B
AB=KHQBE:L><HGLMBMNBNF>Q<>E>GM>F[MH=H
I:K:<HG?BKF:K:HKB@>F/.=>E>La>L>I:K:
B=>GMB?B<:KF>MVLM:L>L=>/.
+ =B:@G_LMB<H => /. [ ABLMHI:MHEH@B<H
=B?>K>G<B:ZYH >GMK> F:EB@GB=:=> > ;>GB@
GB=:=>[;:L>:=:G:L<:K:<M>K^LMB<:LF:<KH
> FB<KHL<_IB<:L =H MNFHK
*: H;L>KO:ZYH
F:<KHL<_IB<: =H MNFHK : =>GLB=:=> >E>O:
=::>QM>GLYH>QMK:<:ILNE:K>:>QBLM]G<B:
=>?H<HLA>FHKKV@B<HLLYH<:K:<M>K^LMB<:L=>
F:EB@GB=:=>
*:FB<KHL<HIB::IK>L>GZ:=>
FBMHL>L :M^IB<:L => BGO:LYH O:L<NE:K > NF
GbF>KH :NF>GM:=H => FBMHL>L LNI>KBHK :
Necrose
Arquitectura tumoral difusa (>33%)
Invasão capsular
Invasão sinusoidal
A cada item é atribuída a pontuação de 1, caso esteja presente, e 0, caso
não se observe. CGA: campo de grande ampliação.
<:FIH=>QLYH:L<:K:<M>K^LMB<:L<HF
F:BHK O:EHK IK>=BMBOH => F:EB@GB=:=>
0]F
LB=H =>L>GOHEOB=HL LBLM>F:L => IHGMN:ZYH
<HF ;:L> G: H;L>KO:ZYH => OVKB:L <:K:<M>
K^LMB<:LABLMHE_@B<:L
+L<HK>=>3>BLLO:KB:
>GMK> [ H F:BL IHINE:K > NF: >E>O:=:
:<NB=:=> =B:@G_LMB<:
IK>L>GZ: => HN
F:BL<:K:<M>K^LMB<:LM>F>E>O:=HO:EHKIK>=B
MBOH IHLBMBOH I:K: F:EB@GB=:=>
0>F GH
>GM:GMH:LEBFBM:Za>LBG>K>GM>L:NFF[MH
=H=>I>G=>GM>=H>Q><NM:GM>
+ F:K<:=HK BFNGHABLMHJN^FB<H 'B [
NF BFIHKM:GM> :NQ^EBH G: <HG?BKF:ZYH =:
F:EB@GB=:=>>IH=>KVM>KNFO:EHKIKH@G_LMB
<H G: F>=B=: >F JN> : LN: >QIK>LLYH
:NF>GM:=: >F F:BL => =H MNFHK ?HB
:LLH<B:=: : IBHK IKH@G_LMB<H L>@NG=H =:=HL
=H BFIHKM:GM> K>@BLMH :E>FYH => /.
+
/M>KHB=H@>GB< ?:<MHK /" [ NF F:K<:=HK
BFNGHABLMHJN^FB<H IKHFBLLHK I:K: H /.
0>F:EM:L>GLB;BEB=:=>I:K:=>M>KFBG:K:HKB
@>FLNIK:K>G:E=:LF:LL:L>:LN:>QIK>LLYH
:NF>GM:=::LLH<B:L>:NF;:BQHO:EHKIKH@
G_LMB<H
+NMKHL F:K<:=HK>L BFNGHABLMHJN^
FB<HL<HFH F>E:G>KHFH@K:GBG:
I:K><>F M>K ;H: :<NB=:=> G: =>M>KFBG:ZYH
=:HKB@>F=:LF:LL:L=:/.F:LHL>NNLH
KHMBG>BKHGYH[<HGL>GLN:E
*H L>GMB=H => H;M>K F:BL ?:<BEF>GM>
F:M>KB:E ABLMHE_@B<H :E@NGL :NMHK>L M]F
IKHIHLMH:>Q><NZYH=>;B_ILB:=H<HK>MBIH
CAD2DC
!F L[KB>L => BG<B=>GM:EHF:L =: /.
>LM:IKVMB<:I>KFBM>:E<:GZ:KNF=B:@G_LMB
<HLH;K>MN=H>F<:LHL=><E:K:;>GB@GB=:=>
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
=::FHLMK:HN=>LNLI>BM:=>F>MVLM:L>LG:
/. => MNFHK>L <HF HKB@>F =BO>KL:
!Q<EN^=HL HL <:LHL => :FHLMK:L BG:=>JN:
=:LJN>K>IK>L>GM:F>GMK>n:L>GLB
;BEB=:=>>LI><B?B<B=:=>>:<NB=:=>=B:@G_L
MB<:=:M[<GB<:G:=>M><ZYH=>F:EB@GB=:=>
=>E>LYH=:/.LYH>
K>LI><MBO:F>GM>
,H=> L>K <HGLB=>K:=: >F
<:LHL => LNLI>BM: => F>M:LMBS:ZYH I:K: :
LNIK:K>G:E=>G>HIE:LB:LIKBFVKB:L<HGA>
<B=:L=HKBFINEFYHHNF:F:
*H>GM:G
MH>LM:M[<GB<:IH=>BFIEB<:KKBL<H=>=BLL>
FBG:ZYH => =H>GZ: >F <:LHL => /. GYH
>QBLMBG=H >LMN=HL : =>FHGLMK:K>F : LN:
L>@NK:GZ: G>LM:L <BK<NGLMXG<B:L
;B_ILB:
I>K<NMXG>: IHLLNB M:F;[F ;:BQ: :<NB=:=>
=B:@G_LMB<: G: =B?>K>G<B:ZYH >GMK> :=>GH
F:L > /. IHK GYH I>KFBMBK : =>M><ZYH =>
BGO:LYH<:ILNE:K
!G<HGMK:L>:BG=:<HGMK:
BG=B<:=:G:IHLLB;BEB=:=>=>L>MK:M:K=>?>H
<KHFH<BMHF:
!LM: M[<GB<: [ IHKM:GMH =>L:
<HGL>EA:=:<HFHIKH<>=BF>GMHKHMBG>BKHG:
BGO>LMB@:ZYH=>F:LL:L=:/.
I>L:K => MH=:L >LM:L :KF:L =B:@G_LMB
<:LH=B:@G_LMB<H=>/.[=B?^<BEF>LFHH
ABLMHE_@B<H > IH=>KV L>K I:KMB<NE:KF>GM>
<HFIE>QH >F <:LHL => MNFHK>L =: /. GYH
BGO:LBOHL > GYH F>M:LMBS:=HL IH=>G=H =BL
<NMBKL>L>>LM>MBIH=>E>La>L<HKK>LIHG=>KV=>
?:<MH:/.
BG=::LLBF:M>G=>G=H:HF:N
IKH@G_LMB<H@EH;:E=:=H>GZ:>WBG?EN]G<B:
;>G[?B<:=>NF:<BKNK@B:<NK:MBO:G:LH;K>
OB=:=>O>FF:GM>KL>:LK><HF>G=:Za>L=>
HI>K:KF:LL:L=:/.JN>:IK>L>GM>F:LK>?>
KB=:L<:K:<M>K^LMB<:L=>LNLI>BZYH
'(!"(#'#&*
<E:LLB?B<:ZYH=>)<":KE:G>IKHIHLM:>F
>FH=B?B<:=:IHK/NEEBO:G>FM>F
LB=H:M[:JNB:F:BLNMBEBS:=:
"HB:=HIM:=:
I>E: 1GBYH %GM>KG:<BHG:E HGMK: H :G<KH
1% > I>E: +)/ >F JN:=KH 2
+
JN:=KH 2% FHLMK: : LH;K>OB=: :HL :GHL
:LLH<B:=: : <:=: >LMV=BH =: <E:LLB?B<:ZYH
1% >F =N:L <HHKM>L =B?>K>GM>L *H
>GM:GMHHO:EHKIKH@G_LMB<H=:LOVKB:L<E:LLB
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
QUADRO V: Classificação de McFarlane modificada.
Estádio Sullivan et al. 1978
I
T1, N0, M0
II
T2, N0, M0
III
T3, N0 M0 ou
T1-2, N1,M0
IV
T4, N0, M0 ou
T3, N1, M0 ou
T3-4, N0-1,M1
T1: Tumor < 5 cm
T2: Tumor > 5 cm
T3: Infiltração tumoral local
alcançando órgãos vizinhos
T4: Invasão tumoral de órgãos
vizinhos
N1: Gânglios linfáticos positivos
M1: Metástases distantes
QUADRO VI: Sobrevida associada a cada Estádio da classificação da
UICC.
Estádio
Sobrevida aos 5 anos
I
60 - 82%
II
58 - 61%
III
24 - 50%
IV
0 - 13%
?B<:Za>L>QBLM>GM>LIK><BL:=>L>KO:EB=:=HIHK
L[KB>L<HFF:BHKGbF>KH=>=H>GM>L
.><>GM>F>GM> : !NKHI>:G *>MPHKD ?HK
MA> /MN=R H? =K>G:E 0NFHKL !*/0 > H
=K>G:E :K<BGHF: .>@BLMKR #KHNI
.# IN;EB<:K:F =:=HL => NF: <HHKM>
=>=H>GM>LJN>FHLMK:FNFO:EHKIKH@
G_LMB<H EBFBM:=H =: <E:LLB?B<:ZYH 1%
*>LM> MK:;:EAH : LH;K>OB=: >LI><B?B<: =:
=H>GZ: L_ [ LB@GB?B<:MBO:F>GM> =B?>K>GM>
>GMK>HL>LMV=BHL%%%>%2L>G>LM>bEMBFHL>
BG<EN^K>F :I>G:L HL =H>GM>L <HF F>MVLM:
L>L W =BLMXG<B: > L> ?HK>F <E:LLB?B<:=HL >F
>LMV=BH%%%HL=H>GM>L<HFBGO:LYH@:G@EBH
G:K HN BGO:LYH => >LMKNMNK:L OBSBGA:L
"HB
IHK BLLH IKHIHLM: NF: GHO: <E:LLB?B<:ZYH
0*)I:K:H/.JN:=KH2%%
,:K: :E[F =: >QM>GLYH =: =H>GZ:
;BO>G >M :E
IN;EB<:K:F =:=HL => NF:
<HHKM> => =H>GM>L FHLMK:G=H JN> :
B=:=>:O:GZ:=:>:IKH=NZYH=><HKMBLHELYH
M:F;[F ?:<MHK>L BG=>I>G=>GM>L => IBHK
IKH@G_LMB<H
F>M:LMBS:ZYH W =BLMXG<B: [ ?K>JN>GM>
G: :EMNK: =H =B:@G_LMB<H > : =HL
=H>GM>L :IK>L>GM:L> >F >LMV=BH %2
+L
EH<:BLF:BL<HFNGLIHKHK=>F=><K>L<>GM>
=>?K>JN]G<B:LYH?^@:=HINEFYHHLLHL>
@XG@EBHLEBG?VMB<HL
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
QUADRO VII: Classificação proposta pela ENSAT com base na sobrevida especifica de doença da coorte de doentes ACCRG. Invasão local
inclui gânglios linfáticos, a veia cava inferior, veia renal ou órgãos adjacentes.
Estádio
Dimensão
Nódulos positivos
Invasão local
Metástases
TNM
I
< 5 cm
-
-
-
T1, N0, M0
II
> 5 cm
-
-
-
T2, N0, M0
III
qualquer
+
+
-
T1-2, N1,M0
IV
qualquer
+
+
+
T 1-2, N1, M1
(&(!"(#
&)&
+ MK:M:F>GMH <BKbK@B<H :E<:GZ:G=H :
K>FHZYH<HFIE>M:=>MH=HHM><B=HMNFH
K:E . K>IK>L>GM: H IKH<>=BF>GMH M>K:
I]NMB<H :LLH<B:=H : F:BHK IKH;:;BEB=:=>
=> <NK:
%G?>EBSF>GM> G: :EMNK: =H =B:@
G_LMB<H:F:BHKB:=HL=H>GM>LM>F=H>GZ:
:O:GZ:=: HN F>MVLM:L>L =BLM:GM>L H JN>
BFIHLLB;BEBM: ?K>JN>GM>F>GM> NF: <BKNK
@B:<NK:MBO:
IK>L>KO:ZYH=:<VILNE:
MNFHK:E [ NF ?:<MHK IKH@G_LMB<H BFIHK
M:GM>
H<HKK]G<B: => =BLL>FBG:ZYH =>
<[ENE:L HN => >QMK:O:L:F>GMH =H MNFHK
=NK:GM> : K>LL><ZYH LYH ?:<MHK>L => IBHK
IKH@G_LMB<H>IH=>FBFIEB<:K:I:LL:@>F
:NF>LMV=BH%2
E:LLB<:F>GM>MNFHK>L
<HFF:BL=><F=>O>KB:FL>KK>FHOB=HL
:MK:O[L=>E:I:KHMHFB:
<MN:EF>GM><HF
H=>L>GOHEOBF>GMH=:E:I:KHL<HIB:M>FL>
:LLBLMB=H : K>FHZYH => MNFHK>L =: /.
LN<>LLBO:F>GM> F:BHK>L IHK >LM: OB:
.><>GM>F>GM> ?HB IN;EB<:=H NF >LMN=H
<HFI:K:MBOH>GMK>::=K>G:E><MHFB:E:I:
KHL<_IB<:>:JN>E:K>:EBS:=:IHKE:I:KHMH
FB: >GOHEO>G=H =H>GM>L <HF /. >F
<:=:NF=HL@KNIHLMH=HL>F>LMV=BH%%%%
>0h<F=BF>GLYHF[=B:OL<F
>FI:K>EA:=HL JN:GMH : B=:=> L>QH :<MB
OB=:=> >G=_<KBG: >LM:=B:F>GMH > M>K:
I]NMB<: :=CNO:GM>
+ L>@NBF>GMH F[=BH
?HB=>F>L>L
*YHL>>G<HGMKHN=B?>K>G
Z:LB@GB?B<:MBO:>GMK>HL@KNIHLJN:GMH:H
M>FIH=>K><HKK]G<B:>LH;K>OB=:@EH;:E
M:Q: => <HGO>KLYH I:K: E:I:KHMHFB: ?HB
<HGMN=H >E>O:=: => !LM>L > HNMKHL
=:=HL :IHGM:F I:K: JN> : :;HK=:@>F
E:I:KHL<_IB<: IHLL: L>K <HGLB=>K:=: >F
/. F>GHK>L HN B@N:BL : <F bGB<HL >
<BK<NGL<KBMHL >LMV=BHL % > %% >F <>GMKHL
<HF >QI>KB]G<B: >F LNIK:KK>G:E><MHFB:L
IHK >LM: OB:
BG=: :LLBF : F:BHKB: =HL
<BKNK@Ba>L>G=_<KBGHLIK>?>K>::=K>G:E><
MHFB:IHKOB::;>KM::<BF:=HL<FIHBL
IHLLB;BEBM: :FIE: >QIHLBZYH => >LMKNMNK:L
>K>LL><Za>L>QM>GL:LL>G><>LLVKBH
-N:GMH W >QM>GLYH =: K>LL><ZYH [ ?K>
JN>GM> : G><>LLB=:=> => >Q><NM:K EBG?:=>
G><MHFB:L:@K>LLBO:L>>F<:LHL=>=H>GZ:
EH<:EF>GM> :O:GZ:=: IH=> L>K G><>LLVKBH
K><HKK>K : K>LL><Za>L :E:K@:=:L >HN >F
;EH<H
+ EBFB:K I:K: K>LL><:K >LMKNMNK:L
:=C:<>GM>L=>O>L>K;:BQHA:O>G=HBG=B<:
ZYH I:K: G>?K><MHFB: BILBE:M>K:E I>K:GM>
LNLI>BM:=>BGO:LYH=HKBFHN=:O>B:K>G:E
)>MVLM:L>L A>IVMB<:L bGB<:L > :<>LL^O>BL
IH=>F L>K IKHIHLM:L I:K: <BKNK@B: L> >LM:
K>IK>L>GM:KNF:IHLLB;BEB=:=>=><NK:
+ >FIK>@H =: <BKNK@B: G: K>=NZYH
MNFHK:E GH >LMV=BH %2 341D;:8=6 [ <HGMKH
O>KLHI>EHL>N>?>BMHEBFBM:=HG:LH;K>OB=:
*H>GM:GMHI>KFBM>K>=NSBKHL>?>BMHLG>?:L
MHL=:ABI>KL><K>ZYHAHKFHG:E>IHLLB;BEBM:K
: NMBEBS:ZYH => HNMK:L HIZa>L M>K:I]NMB<:L
*>LM> <HGM>QMH IH=> L>K <HGLB=>K:=: F:L
:I>G:LL>?HKIK>OBL^O>ENF:K>FHZYHLNI>
KBHK:=HM><B=HMNFHK:E
%)!#(&$%(
>OB=H :H >LMV=BH :O:GZ:=H >F JN>
FNBM:L O>S>L L> >G<HGMK:F HL =H>GM>L > W
BFIHLLB;BEB=:=>=>NF:<BKNK@B:<NK:MBO::
JNBFBHM>K:IB::LLNF>NFI:I>EBFIHKM:G
M> GH MK:M:F>GMH =: =H>GZ: > GH <HGMKHEH
=HABI>KL><K>ZYHAHKFHG:E
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
QUADRO VIII: Efeitos adversos devidos ao mitotano.
Sistema / órgão
Efeito adverso
Frequência
Leucopenia, tempo de coagulação prolongado
Muito comum
Anemia, trombocitopenia
Comum
Ataxia, parestesias, vertigens, miastenia, sonolência, confusão
Muito comum
Alterações cognitivas polineuropatia, cefaleias
Comum
Anorexia, mucosite, vómito, diarreia, náusea, dispepsia, elevação de
enzimas hepáticas
Muito comum
Hepatites tóxicas ou autoimunes
Comum
Insuficiência supra-renal, ginecomastia. Elevação de colesterol,
triglicéridos, SHBG, CBG e TBG. Indução da metabolização hepática
via microssoma.
Muito comum
Disfunção tiroideia, hipogonadismo masculino
Comuns
Rash
Muito comum
Cistite hemorrágica, proteinúria, hematúria
Desconhecida
HTA, hipotensão ortostática, flushing
Desconhecida
Micoses oportunistas
Desconhecida
Hematologia
Sistema nervoso
Gastrointestinal
Endócrino e metabólico
Pele
Uro-genital
Cardiovascular
Infecções
Adaptado de informação disponível em http://www.ema.europa.eu/. Muito comum (r1/10), Comum (r1/100 to <1/10), Invulgar, (r1/1,000 to <1/100), Raro
(r1/10,000 to <1/1,000), Muito raro (<1/10,000), Desconhecida (dados indisponíveis). SHBG – sex hormone binding globulin. CBG – cortisol binding globulin. TBG - thyroid binding globulin.
+ +Iq
7=B<EHKH><EHKH?>GBE
?>M:GH8 <HGA><B=H IHK FBMHM:GH [ =>
EHG@>H?VKF:<HF:BL>LMN=:=HGH/.
"HB
NMBEBS:=HI>E:IKBF>BK:O>S>FANF:GHLG:
=[<:=: => 0K:M:L> => NF :=K>GHE^MB<H
LH;K>MN=HI:K::SHG:K>MB<NE:K=:/.F:L
M:F;[F<HF:<MBOB=:=>G:SHG:?:L<B<NE:K
L>G=H F>M:;HEBS:=H G>LM:L K>@Ba>L >F ?HK
F:LM_QB<:LJN><:NL:F=>@>G>K:ZYHFBMH
<HG=KB:E > HKB@BG:F K:=B<:BL EBOK>L
0>F
:BG=:NF>?>BMHBGB;BM_KBHLH;:BAB=KH
QBE:L> > G: <EBO:@>F =H <HE>LM>KHE H JN>
>QIEB<: : LN: <:I:<B=:=> => <HGMKHE:K H
ABI>K<HKMBLHEBLFH
:;LHKZYH BGM>LMBG:E [
O:KBVO>E
+?VKF:<H>QBLM>LH;=N:L?HKFN
E:Za>L <HFIKBFB=H ERLH=K>Ge > FB<KHGB
S:=H >F <VILNE: <NC: :;LHKZYH [ F>GHK
G><>LLBM:G=H IHK BLLH => =HL>L :M[ =N:L
O>S>L LNI>KBHK>L
+ +Iq
[ :EM:F>GM>
EBIH?^EB<H > IH=> L>K =>M><M:=H G: <HKK>GM>
L:G@N^G>: :M[ F>L>L =>IHBL =: LN:
:=FBGBLMK:ZYH
+ ?VKF:<H >LMV BG=B<:=H GHL <:LHL =>
K>LL><ZYH.BFIHLL^O>EHN=H>GZ::O:GZ:
=:>LMV=BHL%%%>%2
LN:>?B<V<B:G:K>L
IHLM: MNFHK:E ?HB K>OBLM: IHK EEHEBH >
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
":LLG:<AM >F =BO>KLHL >LMN=HL IKHLI><MBOHL
<HF F:BL => =H>GM>L
*H MHM:E <>K<: =>
=HL =H>GM>L :IK>L>GM: :E@NF @K:N =>
K>LIHLM: MNFHK:E :IK>L>GM: NF: K>L
IHLM:I:K<B:E><>K<:=>NF:K>LIHLM:
<HFIE>M:
LN:NMBEBS:ZYHM>F:BG=:EN@:K
GHL>LMV=BHL%>%%I>K:GM>:BFIHLLB;BEB=:=>
<BKbK@B<:>FK>FHO>KMH=HHM><B=HMNFHK:E
,H=>KV :BG=: L>K <HGLB=>K:=H <HFH :=CN
O:GM>G>LM>L>LMV=BHL>F<:LHL=>>E>O:=H
KBL<H => K><B=BO: <HFH I>K:GM> MNFHK>L
F:BL OHENFHLHL ABLMHEH@B: FNBMH =>L?:OH
KVO>E HN ABI>KL><K>ZYH => <HKMBLHE .><>GM>F>GM>0>KSHEEH)
>M:EIN;EB<:K:F
NF>LMN=HFNEMB<]GMKB<H<HGMKHE:=HK>MKHL
I><MBOH JN> :G:EBLHN : :=FBGBLMK:ZYH =>
FBMHM:GH<HFHM>K:IB::=CNO:GM>=:<BKNK
@B: M>G=H =>FHGLMK:=H F:BHK LH;K>OB=:
EBOK> => K><HKK]G<B: F[=B: => F>L>L EB
F>L>L > F:BHK LH;K>OB=: @EH;:E F>L>L EB F>L>L GH @KNIH MK:M:=H <HF
FBMHM:GH
BG=: :LLBF H F>LFH @KNIH
K>IHKMHNF:BLM:K=>NF:M:Q:=>K><HKK]G
<B::HL:GHL>GMK>HLBG=BO^=NHLMK:M:=HL
<HF FBMHM:GH =: HK=>F =HL +
>FIK>@H =H ?VKF:<H <HFH :=CNO:GM> =>
$?K1A71/9R;71/
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
NF:<BKNK@B:<NK:MBO:>F>LMV=BH%>%%GYH
>LMV <HFIE>M:F>GM> O:EB=:=H IHBL GYH
>QBLM>F >LMN=HL <HGMKHE:=HL IKHLI><MBOHL
JN> =>FHGLMK>F <E:K:F>GM> : LN: O:GM:
@>F>HL=:=HL=BLIHG^O>BLLYH:E@H<HGMK:
=BM_KBHLn
+FBMHM:GHBG=NS=BO>KLHL>?>BMHL:=O>K
LHL > : LN: C:G>E: M>K:I]NMB<: [ >LMK>BM:
JN:=KH 2%%%
,HK BLLH : LN: <HG<>GMK:ZYH
L:G@N^G>:=>O>L>KFHGBMHKBS:=:>:L=HL>L
:CNLM:=:L => FH=H : :E<:GZ:K G^O>BL =>
FBMHM:G>FB:>GMK>F@(
=HL>BGB
<B:EKHG=::@=B:=>O>G=HL>K:NF>G
M:=: :M[ :HL : @=B: => :<HK=H <HF :
MHE>KXG<B:>HLG^O>BLIE:LFVMB<HL=>FBMHM:
GH JN> =>O>F L>K F>=B=HL :H ?BF => L>F:G:L > =>IHBL I>KBH=B<:F>GM>
*:L
<KB:GZ:L > :=HE>L<>GM>L : =HL> BGB<B:E K><H
F>G=:=:[=>:@F <HFHH;C><MBOH
=>:E<:GZ:KHL@FGYHL>=>O>G=HNEMK:
I:LL:KHLF@(
=NK:ZYH=:M>K:I]NMB
<:=>O>L>K=>I>EHF>GHL:GHL
LNLI>GLYH M>FIHKVKB: =H ?VKF:<H
I>KFBM> EBFBM:K HL >?>BMHL :=O>KLHL JN:G=H
>LM>LH<HKK>F
!QBLM>>OB=]G<B:=:M>K:MH@>
G><B=:=>ANF:G:=H?VKF:<H>IHKM:GMH:
<HGMK:<>IZYH [ K><HF>G=:=:
0K:M:G=HL>
=> NF ?VKF:<H :=K>GHE^MB<H [ ?K>JN>GM> :
G><>LLB=:=> => LN;LMBMNBZYH <HF <HKMB<_B
=>L
%)!#(&$(#(S,
+L>LJN>F:LM>K:I]NMB<HLNMBEBS:=HLLYH
OVKBHL F:L HL F:BL >?B<:S>L I:K><>F L>K :
<HF;BG:ZYH => <BLIE:MBG: , =HQHKKN;B<B
G: >>MHIHLB=H!HN:I>G:L>LMK>IMHSH
MH<BG:/>F:F;HLHL<:LHL:LLH<B:=HL:H
FBMHM:GH
U=B?^<BE<HFI:K:K>LM>L>LJN>F:L
JN:GMHW>?B<V<B:>L>@NK:GZ:IHBL:F:BH
KB:=HL=:=HL=BLIHG^O>BLIKHO[F=>>LMN=HL
K>MKHLI><MBOHL ;:LM:GM> A>M>KH@[G>HL K>LIHLM: MNFHK:E :H IKBF>BKH IKHMH<HEH
! , [ => >LF:@:=HK: F:BHKB:
=HL<:LHLLYHK>LIHG=>=HK>LI:K<B:BLL>G=H
:LH;K>OB=:F[=B:=>F>L>LL>@NG=HHL
K>LNEM:=HL>F=H>GM>L<HF/.>F>LMV
=BH%%%>%2
!LM>IKHMH<HEH>GOHEO>MHQB<B=:
=> LB@GB?B<:MBO:
BG=: :LLBF >LM> >LJN>
F: HN <HF :E@NF:L O:KB:GM>L M>F LB=H H
F:BL NMBEBS:=H >F <KB:GZ:L
+ L>@NG=H
IKHMH<HEH JN> NMBEBS: : >LMK>IMHSHMH<BG:
:LLH<B:=::HFBMHM:GHI:K><>:LLH<B:KL>:
F>GHL >?>BMHL :=O>KLHL
"HB M>LM:=H IHK
'A:G>M:E
>F=H>GM>L<HF/.F>M:L
MBS:=H HN EH<:EF>GM> :O:GZ:=H H;L>KO:G
=HL> :E@NF @K:N => K>LIHLM: MNFHK:E >F
=HL<:LHL
+F>LFH@KNIHIKHI`LNF
L>@NG=H >LJN>F: :LLH<B:G=H <BLIE:MBG:
OBG<KBLMBG: M>GBIHLB=H > <B<EH?HL?:FB=:
<HFH M>K:I]NMB<: L><NG=VKB: >F =H>G
M>L:I_L?:E]G<B::Hk>LJN>F:O>KB?B<:G
=HL>K>LIHLM:I:K<B:E>F:E@NGL=>E>L
+IKBF>BKH>GL:BH<E^GB<HK:G=HFBS:=H
IKHLI><MBOH H "%.)0 MKB:E >G<HGMK:L>
>F?:L>=><HG<ENLYH>BG<ENBK:FHL<HF
I:K:G=HHL=HBLIKBG<BI:BLIKHMH<HEHL! ,
FBMHM:GH EB / FBMHM:GH >F =H>GM>L <HF
/.>F>LMV=BH%%%>%2>IH=>KVMK:S>KF:BL
<>KM>S:L:<>K<:=HI:I>E=>LM>L<BMHM_QB<HL
&#(&$&(
)>LFH :I_L <BKNK@B:L :I:K>GM>F>GM>
<NK:MBO:L.:M[=HL=H>GM>LIH=>F
:IK>L>GM:K :E@NF: ?HKF: => K><B=BO: HJN>=>FHGLMK::G><>LLB=:=>=>M>K:I]N
MB<: :=CNO:GM> >?B<:S
E@NGL :NMHK>L JN>
:;HK=:K:F H I:I>E =: .0 GH /. =><E:K:
K:F>LM>MNFHK<HFHK:=BHKK>LBLM>GM>
*H
>GM:GMH HNMK:L BGO>LMB@:Za>L <HGMK:KB:F
>LL: OBLYH
+L MK:;:EAHL IN;EB<:=HL G>LM:
VK>: MK:M:FL> NF: O>S F:BL => >LMN=HL
K>MKHLI><MBOHL GYH <HGMKHE:=HL ;:LM:GM>
=^LI:K>L IHK >Q>FIEH JN:GMH :H >LM:=B:
F>GMH MNFHK:E B=:=> =HL =H>GM>L MBIH =>
<BKNK@B:=HL>=>.0M>FIH=>L>@NBF>GMH
U IK><BLH =BLMBG@NBK >GMK> H I:I>E =: .0
<HFH M>K:I]NMB<: :=CNO:GM> G>H:=CNO:GM>
>I:EB:MBO:
*NF: K>OBLYH => OVKBHL >LMN=HL IHK
,HE:M>M:E
JN>BG<ENBN=H>GM>LLN;F>MB
=HL:.0:=CNO:GM>I:K:/.:I_L<BKNK@B:L
<NK:MBO:L.><BKNK@B:L<HFI>KLBLM]G<B:=>
=H>GZ:FB<KH>F:<KHL<_IB<:.>.K>L
I><MBO:F>GM> : M:Q: => K>LIHLM: <HGMKHEH
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
EH<:E=:=H>GZ:?HB=>
+F>LFH@KNIH
=> BGO>LMB@:=HK>L GNF >LMN=H <HGMKHE:=H
:G:EBLHN H >?>BMH =: .0 :=CNO:GM> >F =H>GM>L >F >LMV=BH %%%% I>KM>G<>GM>L :H
#>KF:G K>@BLMKR
+ M>FIH => L>@NB
F>GMH F[=BH ?HB => F>L>L
2>KB?B<HNL>
NF GbF>KH LB@GB?B<:MBO:F>GM> F>GHK =>
K><HKK]G<B:LEH<:BLGHL=H>GM>LLN;F>MB=HL:
.0:=CNO:GM>EB >:<HK=H<HF
>LM>L =:=HL : .0 :=CNO:GM> IH=>KV <HGLMB
MNBKNF:F:BLO:EB:I:K:<BKNK@B:L=>IHM>G
<B:E<NK:MBOHBG=>M>KFBG:=H.>.QHJN>
LN<>=> JN:L> L>FIK> >F <:LHL => MNFHK>L
OHENFHLHL F:BHK>L JN> <F F:N IKH@
G_LMB<H ABLMHE_@B<H =BLL>FBG:ZYH EH<:E
BGMK:HI>K:M_KB: =BLL>FBG:ZYH EBG?VMB<: >
BGO:LYH EH<:E
.0 :=CNO:GM> =>O>KV L>K
:=FBGBLMK:=::M[F>L>L:I_L:<BKNK@B:>
?K:<<BHG:=:>F=HL>L=BVKB:L=>:#R
=NK:GM> =B:LL>F:G: :H EHG@H => : L>F:G:L
=HL>MHM:E=>K:=B:ZYHIKHIHLM:
I:K:HE>BMHMNFHK:EO:KB:>GMK>#R
!QBLM>F>L<:LLHLMK:;:EAHLLH;K>:>?B<V
<B:=:.0G>H:=CNO:GM>JN>IHLL:F?:OHK>
<>K:LN:NMBEBS:ZYH
UF:BL<HGL>GLN:E:NMBEBS:ZYH=:.0G:
=H>GZ: >F >LMV=BH %2 I:EB:MBO: HN G:L
K><B=BO:LEH<HKK>@BHG:BL
*:K>OBLYH>?><MN:
=: IHK ,HE:M >M :E
: I:KMBK =: :GVEBL> => >LMN=HL =B?>K>GM>L GNF MHM:E => BG=BO^
=NHL BG<ENBG=H I:<B>GM>L <HF F>MVLM:L>L
_LL>:LEBG?VMB<:LINEFHG:K>L>K><HKK]G<B:L
EH<:BLHN=BLM:GM>LLN;F>MB=HL:.0I:EB:MB
O:I:K::E^OBHLBGMHFVMB<H=HL=H>GM>L
H;M>O>;>G>?B<BHLBGMHFVMB<H<HF:.0
!LM>
>?>BMH IHLBMBOH [ F:BL >OB=>GM> :H G^O>E =H
<HGMKHEH=:=HK>=>LBGMHF:LG>NKHE_@B<HL
+L IKHMH<HEHL F:BL >LMN=:=HL I:K: : .0
I:EB:MBO:<HGLBLM>F>F=HL>bGB<:=>#R
HN#R=BLMKB;N^=HLIHK=HL>L?K:<<BHG:
=:LI:K><>G=HGYH>QBLMBK=B?>K>GZ:LLB@GB
?B<:MBO:L >GMK> :F;HL I:K: :E[F => F:BHK
G><>LLB=:=> => K>I>MBZYH =H IKH<>=BF>GMH
GHIKBF>BKH<:LH
NK:GM>:.0[?NG=:
F>GM:EIKHM>@>KHKBF<HGMK:E:M>K:E>OB@B:K
:?NGZYHK>G:E
F:BHKB: =HL =H>GM>L BG=B<:=HL I:K:
.0M>KVBG=B<:ZYH<HG<HFBM:GM>I:K:MK:M:
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
F>GMH <HF FBMHM:GH
+L =HBL :@>GM>L
IHM>G<B:FL>IH=>G=HM:F;[F:@K:O:KHL
?>BMHL :=O>KLHL L>G=H H F:BHK KBL<H H =>
A>I:MBM> M_QB<:
*H <:LH => >E>O:ZYH =:L
MK:GL:FBG:L>LLNI>KBHK:O>S>LHGHKF:E
HFBMHM:GH=>O>KVL>KLNLI>GLH
NK:GM>:
.0 :L =HL>L => FBMHM:GH GYH =>O>F NEMK:
I:LL:KHL@=B:
M>G=>G=HW?:EM:=>
=:=HLLH;K>:L>@NK:GZ:=HNLHLBFNEMXG>H
=:.0>=:-0<HF<BMHM_QB<HL>LM>L:@>GM>L
GYH=>O>FL>K>FIK>@N>L>FI:K:E>EH
"#*'&!'(&$])('
lF>=B=:JN>OYHLNK@BG=H:O:GZHLGH
<HGA><BF>GMH =: ;BHEH@B: FHE><NE:K MNFH
K:E GHOHL :EOHL M>K:I]NMB<HL > IHLL^O>BL
GHOHL :@>GM>L OYH L>G=H IKHIHLMHL I:K: H
MK:M:F>GMH =H /.
!Q>FIEHL =BLLH LYH HL
:GMB<HKIHLFHGH<EHG:BL:GMB2!#"2:L<NE:K
>G=HMA>EB:E @KHPMA ?:<MHK <HFH H ;:O:<B
SNF:;>:GMB!#".>IB=>KF:E@KHPMA?:<
MHKK><>IMHK
*H>GM:GMHHLIKBF>BKHLK>LNE
M:=HL M>LM:G=H : >?B<V<B: =>LM>L :@>GM>L GH
/.?HK:F=><>I<BHG:GM>L
1FF><:GBLFH
=>K>LBLM]G<B:MNFHK:EW-0[:>QBLM]G<B:=:
)NEMB=KN@ .>LBLM:G<> ,KHM>BG ) .,
G:L<[ENE:L=H/.
:LLH<B:ZYH=>NFBGB
;B=HK =>LL: IKHM>^G: <HFH H M:KBJNB=:K
IH=>>FM>HKB:NEMK:I:LL:K>LL>H;LMV<NEH
HFHGHNMKHLMNFHK>LH@KNIH=>?VKF:<HL
=HL BGB;B=HK>L =: MBKHLBG: <BG:L> M>F M:F
;[F LB=H BGO>LMB@:=H GH /.
+L IKBF>BKHL
>GL:BHL <HF LNGBMBGB; > LHK:?>GB; >LMYH >F
<NKLH
,:KMB<NE:KF>GM> IKHFBLLHK: I:K><>
L>K : NMBEBS:ZYH => :GMB<HKIHL FHGH<EHG:BL
BGB;B=HK>L =H K><>IMHK %#" :<MN:EF>GM>
M:F;[F>F?:L>=>>GL:BH<E^GB<H
:;E:ZYH IHK K:=BH?K>JN]G<B: ."
I>KFBM> =>LMKNBK <[ENE:L MNFHK:BL NL:G=H
>E[<MKH=HL:@NEA: JN> =BLMKB;N>F <HKK>GM>L
LBGNLHB=:BL =: HK=>F =HL : '$S
<KB:G=H :LLBF M>FI>K:MNK:L IK_QBF:L =HL
k
!LM: M[<GB<: [ NL:=: I:K: =>LMKNBK
F>MVLM:L>L HN K><HKK]G<B:L EH<:BL => OVKBHL
MNFHK>LG><>LLBM:G=H=><HGMKHEHBF:@BHE_
@B<H A:;BMN:EF>GM> IHK ><H@K:?B: HN 0
/YH >L<:LL:L :L L[KB>L K>IHKM:G=H : >?B<V<B:
$?K1A71/9R;71/
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
=:M[<GB<:GH/.
3HH=>M:E
IN;EB
<:K:FK>LNEM:=HL=HMK:M:F>GMH<HF."=>
=H>GM>L<HF/.:O:GZ:=H>>F:E@NGL
<:LHL<HFK><HKK]G<B:L
+MK:M:F>GMHH;M>O>
LN<>LLH>F=HL=H>GM>L
."I:K>
<>M:F;[FL>K>?B<:SGH:E^OBH=:=HK<:NL:
=: IHK F>MVLM:L>L _LL>:L :H =>LMKNBK :L
I>JN>G:L M>KFBG:Za>L G>KOHL:L K>LIHGLV
O>BL I>E: MK:GLFBLLYH =: =HK
1F >GL:BH
FNEMB<]GMKB<H NMBEBSHN : ." >F =H>GM>L
<HF F>MVLM:L>L _LL>:L > =HK <HF L<HK>
F[=BH=>=>:K>?K:<MVKB:W.0
+L
=H>GM>L H;MBO>K:F K>=NZYH => IHGMHL G:
>L<:E:=:=HK>F=HL<:LHL:H?BF=>
NF:L>F:G:>F:H?BF=>L>F:G:L
> H;MBO>K:F :E^OBH LBGMHFVMB<H >F
:E@NF::EMNK::HEHG@H=HL>@NBF>GMH
JNBFBH>F;HEBS:ZYH MK:GL:KM>KB:E =>
F>MVLM:L>LA>IVMB<:L[NF:HIZYHI:EB:MBO:
I:K:E>La>LABI>KO:L<NE:KBS:=:L>F=H>GM>L
GYH <:G=B=:MHL : <BKNK@B: HN ."
:>K> >M
:EK>IHKM:K:FHLK>LNEM:=HL=HMK:M:F>GMH>
L>@NBF>GMH => =H>GM>L <HF F>MVLM:L>L
A>IVMB<:L => /.
I_L : L>LLa>L ?HB
H;MB=:K>LIHLM:I:K<B:E>F=H>GM>L>LM:;B
EBS:ZYH=:=H>GZ:?HBIHLL^O>E>F<:LHL>
: IKH@K>LLYH GYH I`=> L>K >OBM:=: >F =H>GM>L
=NK:ZYH =: >LM:;BEBS:ZYH ?HB >F
F[=B: => F>L>L F^GBFH > FVQBFH =>
F>L>L K>LI><MBO:F>GM>
+L <:LHL =>
K>LIHLM:<HFIE>M:H<HKK>K:F>FF>MVLM:L>L
BG?>KBHK>L : <F
"HB :BG=: H;L>KO:=H NF
=><K[L<BFH=>GHLG^O>BLAHKFHG:BL>F
=><:LHL=>MNFHK>L>G=_<KBGH:<MBOHL
+
IKBG<BI:E>?>BMH:=O>KLH[NF:LN;B=:MK:GLB
M_KB:=:LMK:GL:FBG:L>L:O>S>LHGHK
F:E>LBGMHF:L=>F:E>LM:K@>K:E
1FIKBF>BKH>GL:BH>LMN=HN:NMBEBS:ZYH
FIGURA 1: Esquema de tratamento e Follow-up
Tx – terapêutica.
QT engloba mitotano isolado ou associado a EDP ou a S.
* O mitotano ou a RT adjuvantes devem ser considerados mesmo após ressecções R0 nos tumores de maiores dimensões, de pior prognóstico histológico e no
estádio III.
(Os doentes em estádio IV, mesmo após cirurgia curativa, têm elevado risco de recorrência e devem sempre ser submetidos a terapia adjuvante, pelo menos,
com mitotano).
Adaptado a partir de 15 e 24.
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
=> %%H=HF>MHFB=:MH %%)0+ >F =H>GM>L <HF /. F>M:LMVMB<H > :IK>L>GMHN
K>LNEM:=HL=HL>@NBF>GMH=>=>E>L
HL>L
:M[#J?HK:FNMBEBS:=:LH;L>KO:G=HL>
>E>O:=: <:IM:ZYH > :?BGB=:=> =H K:=BH?VK
F:<HI>E:LE>La>L
!F=H>GM>LO>KB?B<HNL>
K>=NZYH HN >LM:;BEBS:ZYH =:L E>La>L
+ ?VK
F:<H [ >F @>K:E ;>F MHE>K:=H F:L H
=>L>GOHEOBF>GMH => E>N<H > MKHF;H<BMHI>
GB:MK:GLBM_KB:LLYH>?>BMHL:=O>KLHLK>IHKM:
=HLG:F:BHKB:=HL=H>GM>L
')!"(#
<NK:
%G<>KM>S:L:<>K<:=:=>?BGBZYH=HLbEMB
FHL>LMV=BHL=:NMBEBS:ZYH:IKHIKB:=:=>
-0 > .0 I>KF:G><>F <HFH H;LMV<NEHL
*H
>GM:GMH :L M>GM:MBO:L => <HGL>GLHL <HF>
Z:F:LNK@BK>HLIKBF>BKHL>GL:BHL<HFI:K:
MBOHL K:G=HFBS:=HL >LMYH >F F:K<A:
+L
bEMBFHL :GHL M]F :<K>L<>GM:=H =>L<H;>KM:L
K>E>O:GM>L>GHO:L>LI>K:GZ:L
&!"(#'
HL F>F;KHL =H #KNIH => !LMN=HL =HL
0NFHK>L=:@EXG=NE:/NIK:K>G:E
+KBL<H=>K><HKK]G<B:F>LFH:I_LNF:
<BKNK@B: IHM>G<B:EF>GM> <NK:MBO: > H
>FIK>@H=>-0>HN.0:=CNO:GM>[>E>O:
=H LH;K>MN=H GHL IKBF>BKHL :GHL
LLBF
NF :I>KM:=H ?HEEHPNI >LMV BG=B<:=H
>O>FL>K>?><MN:=HL=HL>:F>GMHLAHKFH
G:BL GHL MNFHK>L ?NG<BHG:GM>L > 0 M_K:
<H:;=HFBG:BL K>I>MB=HL : <:=: HN F>L>LI>EHF>GHL:HEHG@H=HLIKBF>BKHL
:GHL
:^>F=B:GM>>LM>LIKH<>=BF>GMHL
=>O>F L>K F:GMB=HL <HF BGM>KO:EHL F:BL
:E:K@:=HL I>EH F>GHL :M[ :HL :GHL =>
L>@NBF>GMH
LK><HKK]G<B:L=>O>FL>K<HG
LB=>K:=:L I:K: GHO: BGM>KO>GZYH <BKbK@B<:
L>FIK> JN> IHLL^O>E > H >FIK>@H => -0
>HN.0=><HGLB=>K:K>F:LLH<B:ZYHW<BKNK
@B:HN>F:EM>KG:MBO::>LM:
#" )'W#
+/.[NF:=H>GZ:K:K:<NCH=B:@G_LMB
<H<HGMBGN:=B?^<BE>HLMK:M:F>GMHL=BLIHG^
O>BL GYH M]F :E<:GZ:=H H LN<>LLH =>L>C:=H
=>?HKF::<HGMK:KB:KHF:NIKH@G_LMB<H@EH
;:E
+L =HL>:F>GMHL AHKFHG:BL > HL F[MH
=HL=>BF:@BHEH@B:<:=:O>SF:BLL>GL^O>BL>
=BLIHG^O>BLM]FI>KFBMB=H=B:@G_LMB<HLF:BL
IK><H<>L
>QBLM]G<B: => >JNBI:L <BKbK@B<:L
=>=B<:=:LWK>FHZYH<HFIE>M:=>LM>LMNFH
K>L>:NMBEBS:ZYH:=>JN:=:=:-0>.0=BL
IHG^O>BL <HGLMBMN>F :L bGB<:L ABI_M>L>L =>
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
$?K1A71/9R;71/
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
&&]"' #&^'
1.
Barzon L, Sonino N, Fallo F, Palu G, Boscaro M.
Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 2003;
149:273–285.
2. Zeiger M, Thompson G, Duh QY, Hamrahian
A, Angelos P, Elaraj D, et al. AACE/AAES
Adrenal Incidentaloma Guidelines, Endocr
Pract. 2009;15(suppl 1).
3. Young, William. The Incidentally Discovered
Adrenal Mass. N Eng J Med 2007; 356:601 – 10.
4. National Cancer Institute. Third national cancer survey. DHEW publication no 1; 1975
(NIH) 75 – 787. Mon 41.
5. Soreide JA, Brabrand K, Thoresen SO. Adrenal
Cortical Carcinoma in Norway, 1970-1984.
World J Surg 1992;16:663-667; discussion 668.
6. Ribeiro RC, Sandrini F, Figueiredo B, Zambetti
GP, Michalkiewicz E, Lafferty AR, et al.
Inherited p53 mutation that contributes in a
tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 2001;
98:9330-9335.
7. Michalkiewicz E, Sandrini R, Figueiredo B,
Miranda EC, Caran E, Oliveira-Filho AG, et al.
Clinical and Outcome characteristics of children
with adrenocortical tumors: a report from the
International Pediatric Adrenocortical Tumor
Registry. J Clin Oncol 2004; 22:838 – 845.
8. Pianovski MA, Maluf EM, de Carvalho DS,
Ribeiro RC, Rodriguez-Galindo C, Boffetta P et
al. Mortality rate of adrenocortical tumors in
children under 15 years of age in Curitiba,
Brazil. Pediatr Blood Cancer 2005 Sep 30;
10.1002/pbc.20624.
9. Luton JP, Cerdas S, Billaud L, Thomas G,
Guilhaume B, Bertagna X et al. Clinical features
of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Eng
J Med 1990; 322:1195-1201.
10. Icard P. Adrenocortical carcinomas: surgical
trends and results of a 253-patient series from
the French Association of Endocrine Surgeons
Study Group. World J Surg 2001; 25:891-897.
11. Barzon L, Scaroni C, Sonino N, Fallo F, Paoletta
A, Boscaro M. Risk factors and long-term follow-up of adrenal incidentalomas. J Clin
Endocrinol Metab 1999; 84:520–526.
12. Bernini GP, Moretti A, Oriandini C, Bardini M,
Taurino C, Salvetti A. Long-term morphologi-
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
cal and hormonal follow-up in a single unit on
115 patients with adrenal incidentalomas. Br J
Cancer 2005; 92:1104–1109.
Bernard MH, Sidhu S, Berger N, Peix JL, Marsh
DJ, Robinson BG et al. A case report in favor of
a multistep adrenocortical tumorigenesis. J
Clin Endocrinol Metab 2003; 88:998–1001.
Cofield KR, Cantley LK, Geisinger KR, Zagoria
RJ, Perrier ND. Adrenocortical carcinoma arising from a long-standing adrenal mass. Mayo
Clin Proc 2005; 80:264–266.
Libe R, Fratticci A, Bertherat J. Adrenocortical cancer: pathophysiology and clinical management.
Endocrine Related Cancer 2007; 14: 13-28.
Abiven G, Coste J, Groussin L, Anract P, Tissier
F, Legmann P. Bioclinical features in the prognosis of adrenocortical cancer: poor outcome
of cortisol-secreting tumors from a series of
202 consecutive patients. J Clinical Endocrinol
Metab 2006; 91 2650–2655.
Barzon L, Boscaro M. Diagnosis and management of adrenal incidentalomas. J Urol; 2000;
163:398–407.
Koschker AK, Fassnacht M, Hahner S,
Weismann D, Allolio B; Adrenocortical carcinoma: improving patient care by establishing
new structures. Exp Clin Endocrinol Diabetes
2006; 114:45–51.
Luton JP, Martinez M, Coste J, Bertherat J.
Outcome in patients with adrenal incidentaloma selected for surgery: an analysis of 88 cases
investigated in a single clinical center. European
J Endocrinology 2000; 143; 111–117.
Mansmann G, Lau J, Balk E, Rothberg M,
Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: update in diagnosis and
management; Endocr Rev; 2004; 25:309–340.
Ribeiro RC, Figueiredo B; Childhood adrenocortical tumours. Eur J Câncer 2004;
40;1117–1126.
Dackiw AP, Lee JE, Gagel RF, Evans DB Adrenal
cortical carcinoma. World J Surg; 2001;
25:914–926.
Fassnacht M, Johanssen S, Quinkler M, Bucsky
P, Willenberg H, Beuschlein F, et al. Limited
Prognostic Value of the 2004 International
Union Against Cancer Staging Classification for
Adrenocortical Carcinoma. Cancer 2009 Jan
15;243 – 250.
Allolio B. Fassnacht M. Clinical Review:
Adrenocortical Carcinoma: Clinical Update; J
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
Clinical Endocrinol Metab 2006; 91(6):20272037.
Honigschnabl S, Gallo S, Niederle B, Prager G,
Kaserer K, Lechner G, et al. How accurate is MR
imaging in characterisation of adrenal masses:
update of a long-term study. Eur J Radiol 2002;
41:113–122.
Al-Hawary MM, Francis IR, Korobkin M. Noninvasive evaluation of the incidentally detected
indeterminate adrenal mass. Best Pract Res Clin
Endocrinol Metab 2005; 19:277–292.
Schteingart DE, Doherty GM, Gauger PG,
Giordano TJ, GD Hammer, Korobkin M, et al.
Management of patients with adrenal cancer:
recommendations of an international consensus conference. Endocrine Related Cancer
2005; 12; 667-680.
Yun M, Kim W, Alnafisi N, Lacorte L, Jang S,
Alavi A. 18F-FDG PET in characterizing adrenal
lesions detected on CT or MRI. J Nucl Med
2001; 42: 1795–1799.
Jana S, Zhang T, Milstein DM, Isasi CR, Blaufox
MD. FDG-PET and CT characterization of adrenal lesions in cancer patients. Eur J Nucl Med
Mol Imaging 2006; 33:29–35.
Minn H, Salonen A, Friberg J, Roivainen A,
Viljanen T, Langsjo J et al. Imaging of adrenal
incidentalomas with PET using (11)C-metomidate and (18)F-FDG. J Nucl Med; 2004;
45:972–979.
Khan TS, Sundin A, Juhlin C, Langstrom B,
Bergstrom M, Eriksson B. 11C-Metomidate PET
imaging of adrenocortical cancer. Eur J Nucl
Med Mol Imaging. 2003; 30:403–410.
Sean K Lau MD, Weiss MD. The Weiss system for
evaluating adrenocortical neoplasm: 25 years
later. Human Pathology 2009; 40: 757-68.
Sbiera S, Schmull S, Voelker HU, Kraus L,
Beuschlein F, Willenberg H, et al. Steroidogenic
factor 1 – a valuable diagnostic and prognostic
tool in patients with adrenocortical carcinoma.
P181;
11th
European
Congress
of
Endocrinology Symposia, Istambul, 2009, April.
Welch TJ, Sheedy PF, Stephens DH, Johnson
CM, Swensen SJ. Percutaneous adrenal biopsy:
review of a 10-year experience. Radiology
1994;193:341–344.
Gaboardi F, Carbone M, Bozzola A, Galli L;
Adrenal incidentalomas: what is the role of fine
needle biopsy? International Urology and
Nephrology; 1991; 23: 197–207.
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
36. Fassnacht M, Brix D, Fensk W, Langer P, Nies C,
Ayman A, et al. Long-term outcome of laparoscopic versus open adrenalectomy for adrenocortical carcinoma. Oral communication presented
in11th European Congress of Endocrinology
Symposia, Istambul, 2009, April 26th.
37. Dousset B, Gaujoux S, Thillois JM. Surgical treatment of adrenal cortical carcinoma in Adrenal
Cancer. John Libbey Eurotext 2006; 71 – 95.
38. Goldwasser F, Bertagna X. Chemotherapy for
adrenal cortical cancer in Adrenal Cancer;
Montrouge (France): John Libbey Eurotext
2006; 59-70.
39. Terzollo M, Angeli A, Fassnacht M. Daffara F,
Tauchmanova L, Conton PA, et al. Adjuvant
Mitotane Treatment for Adrenocortical
Carcinoma. N Eng J Med 2007; 356: 2372-80.
40. Terzollo M, Berruti A. Adjunctive treatment of
adrenocortical
carcinoma.
Curr
Opin
Endocrinol Diabetes Obes. 2008; 15: 221-226.
41. Dickstein G, Shechner c, Arad E, Best LA, Nativ
O. Is there a role for low doses of mitotane as
adjuvant therapy in adrenocortical carcinoma?
J Clin Endocrinol Metab 1998; 83 (9): 3100-3.
42. Barzon L, Fallo F, Sonino N, Daniele O, Boscaro
M. Adrenocortical carcinoma: experience in 45
patients. Oncology 1997; 54: 490-6.
43. Kasperlik-zaluska AA. Clinical results of the use
of mitotane for adrenal cortical carcinoma.
Braz J Med Biol Res 2000; 33: 1191-6.
44. Disponível em: http//:www.ema.eu.int/
45. Ahlman H, Khorram-Manesh A, Jansson S,
Wangberg B, Nilsson O, Jacobsson CE, et al.
Cytotoxic treatment of adrenocortical carcinoma. 2001; World J Surg 25:927–933.
46. Allolio B, Hahner S, Weismann D, Fassnacht M.
Management of adrenocortical carcinoma.
Clin Endocrinol (Oxf) 2004; 60:273–287.
47. Berruti A, Terzolo M, Sperone P, Pia A, Casa SD,
Gross DJ, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced advanced adrenocortical carcinoma: a
large prospective phase II trial. 2005 Endocr
Relat Cancer 12:657–666.
48. Zancanella P, Pianovski M, Oliveira B; Ferman
S, Piovezan G, Lichtvan L, et al; Mitotane
Associated With Cisplatin, Etoposide, and
Doxorubicin
in
Advanced
Childhood
Adrenocortical
Carcinoma:
Mitotane
Monitoring and Tumor Regression. Journal of
Pediatric Hematology/Oncology 2006; August;
$?K1A71/9R;71/
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
Vol 28 (8): 513-524.
49. Khan TS, Imam H, Juhlin C, Skogseid B,
Grondal S, Tibblin S, et al. Streptozocin and
o,p_DDD in the treatment of adrenocortical
cancer patients: long-term survival in its adjuvant use. Ann Oncol 2000; 11:1281–1287.
50. Khan TS, Sundin A, Juhlin C, Wilander E, Oberg
K, Eriksson B. Vincristine, cisplatin, teniposide,
and cyclophosphamide combination in the
treatment of recurrent or metastatic adrenocortical cancer. Med Oncol 2004; 21: 167–177.
51. The FIRM-ACT trial. Informação disponível em:
http//:www.firm-act.org.
52. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma. Surgery
1992; 112: 961-970.
53. Stojadinovic A, Ghossein RA, Hoos A, Nissan A,
Marshall D, Dudas M, et al Adrenocortical carcinoma: clinical, morphologic, and molecular
charaterization. J Clin Oncol 2002; 20: 941-950.
54. Fassnacht M, Hahner S, Polat B, Koschker AC,
Kenn W, Flentje M, et al. Efficacy of adjuvant
radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J Clin
Endocrinol Metab. 2006; 91: 4501 – 4504.
55. Percarpio B, knowlton AH. Radiation Therapy
of adrenocortical carcinoma. Acta Radiol Ther
Phys Biol. 1976; 15:288-292.
56. Hartsell WF, Scott C, Bruner D, Scarantino C,
Ivker R, Roach M, Suhet J, et al. Randomized
trial of short- versus long-course for palliation
of painful bone metastasis. J Natl Cancer Inst.
2005; 97: 798 – 804.
57. Van der Linden, Steenlandb E, Houwelingenc
H, Posad W, Oeie B, Marijnenb C, et al.
Patients with a favourable prognosis are equally palliated with single and multiple fraction
radiotherapy: results on survival on the Dutch
Bone Metastasis Study. Radiother Oncology.
2006; 78: 245-253.
58. Lawrence K. Review: Emerging Treatment
Strategies for Adrenocortical Carcinoma: A
New Hope. J Clin Endocrinol Metab. 2006.
91(1):14–21.
57. Quinkler M. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J
Clin Endocrinol Metab. 2008 Jun;93(6):2057-62.
60. Fassnacht M, Hahner S, Polat B, Allolio B.
Chemotherapy and radiotherapy for adrenocortical carcinoma. Oral communication presented in 11th European Congress of
Endocrinology Symposia, Istambul 2009, Abril.
61. Wood BJ, Abraham J, Hvizda JL, Alexander HR,
Fojo T. Radiofrequency ablation of adrenal
tumors and adrenocortical carcinoma metastasis. Cancer 2003; 97: 554-60.
62. Goetz MP, Callstrom MR, Charboneau JW,
Farrell MA, Maus TP, Welch TJ, et al. Percutaneos
image-guided radiofrequency ablation of painful metastasis involving bone: a multicenter
study. J Clin Oncol 2004; 22: 300-6.
63. de Baere T. Local treatment of adrenocortical
carcinoma metastases with interventional
radiology techniques in Adrenal Cancer.
Montrouge (France): John Libbey Eurotext
2006; 102 -105.
64. Hahner S, Kreissl M, Fassnacht M, Johanssen S,
Haenscheid H, Reiners C, et al. 131IIodometomidate radiotherapy for metastatic
adrenocortical carcinoma: first clinical experience. Oral communication presented in11th
European Congress of Endocrinology Symposia,
Istambul, 2009, April.
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
!?>BMHL,E>BHMK_IB<HL=:L!LM:MBG:L
n-N:E:>OB=]G<B:
&;48>CA>?8245542CB>5BC0C8=B
Y-70C8BC744E834=24
G:/H?B:.B;>BKH&HK@> HK>L
=C4A=0><?;4<4=C0A34#43828=04A0;40<8;80A30+=8303434)0V340<8;80A,8E4A#08BY)#080
BB8BC4=C4>B?8C0;0AA03D03>3>)4AE8P>34=3>2A8=>;>6808014C4B4#4C01>;8B<>3>4=CA>>B?8C0;0A3>&>AC>Y>B?8C0;34)0=C>
=CT=8>
<??3@=<;2Q;17/=0)>580(8148A>Z+=8303434)0V340<8;80A,8E4A#08BZ(D0&A>54BB>A"050H4C4(>3A86D4B,848A0340BCA>
Y)0=C0#0A803>E8>B># Z0=0B>580A8148A>6<08;2><
137A/ON<AC86>A424183>4<
A4E8BC>4<
40248C4?0A0?D1;820PO>4<
&')!#
Introdução: Os efeitos das estatinas sobre a redução dos níveis de colesterol LDL são amplamente conhecidos e cientificamente comprovados. Recentemente, vários ensaios clínicos têm
levantado a questão das estatinas possuírem efeitos ditos pleiotrópicos, isto é, independentes de qualquer alteração/diminuição dos níveis de colesterol.
Objectivo: Rever a evidência clínica dos benefícios da terapêutica com estatinas, distintos dos
seus efeitos sobre o perfil lipídico.
Metodologia: Pesquisa de artigos na Pubmed e sítios de Medicina Baseada na Evidência, publicados entre 2001 e 2009, nas línguas portuguesa, inglesa, francesa e espanhola. Para avaliação do nível de evidência, foi aplicada a Escala SORT (Strength of Recommendation Taxonomy)
da American Academy of Family Physicians.
Resultados: As estatinas apresentam efeitos pleiotrópicos a nível vascular, cardíaco e extra-cardiovascular secundários, na sua maioria, à inibição da síntese de isoprenóides. Existe evidência científica da melhoria da função endotelial e da diminuição da inflamação vascular (SORT
A) com redução dos níveis séricos dos marcadores de inflamação aguda. Estudos sugerem
efeitos positivos na hipertensão arterial, resposta trombogénica e estabilidade da placa aterosclerótica (SORT B).
Recentemente têm sido atribuídas propriedades imunomoduladoras, anti-demenciais, antiosteoporóticas e anti-neoplásicas que carecem de evidência clínica (SORT C).
Conclusão: A redução do colesterol LDL continua a ser o mecanismo primário na base da
redução do risco cardiovascular atribuído às estatinas. São necessários mais estudos com
enfoque nos efeitos pleiotrópicos das estatinas como end points primários.
$ *&'*
Estatina; Efeito pleiotrópico.
'(&(
Introduction: The effects of statins on reducing levels of LDL cholesterol are widely known and
scientifically proven. Recently, several clinical trials have raised the issue of statins have pleiotropic
effects, ie independent of any change/decrease in cholesterol levels.
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<@23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
Aim: Review the clinical evidence of the benefits of statin therapy, as distinct from its effects on
the lipid profile.
Methodology: Research articles in Pubmed and sites of Evidence Based Medicine, published between 2001 and 2009, in Portuguese, English, French and Spanish. To assess the level of evidence was applied to scale SORT (Strength of Recommendation Taxonomy) of the American Academy
of Family Physicians.
Results: Statins have pleiotropic effects at the vascular, cardiac and extra-cardiovascular side,
mostly due to the inhibition of isoprenoid synthesis. There is scientific evidence of improved endothelial function and decreasing vascular inflammation (SORT A) with decreases in serum markers
of acute inflammation. Studies suggest positive effects on hypertension, thrombogenic response
and stability of atherosclerotic plaque (SORT B).
Recently there have been ascribed immunomodulatory properties, anti-dementia, anti-osteoporotic and anti-neoplastic that lack of clinical evidence (SORT C).
Conclusion: The reduction of LDL cholesterol remains the primary mechanism at the base of cardiovascular risk reduction attributed to statins. Further studies are needed focusing on the pleiotropic effects of statins as primary end points.
-+#&'
Statins; Pleiotropic effects.
"(&#)IW#
!F H FB<KH;BHEH@BLM: C:IHG]L
DBK:!G=H>F;NL<:=>NFGHOH:GMB;B_MB
<HH;L>KOHN:<B=>GM:EF>GM>JN><>KMHL?NG
@HL >K:F <:I:S>L => IKH=NSBK NF IHM>GM>
BGB;B=HK=:IKH=NZYH=H<HE>LM>KHE
/>@NG=H
>E>>LM:LN;LMXG<B::<MN:O:<HFHNF:=>?>
L: <HGMK: IK>=:=HK>L A>K;^OHKHL JN> :H
BG@>KBK>FHLK>?>KB=HL?NG@HLIH=B:FFHKK>K
=:=: : =BL?NGZYH F>M:;_EB<: <:NL:=: I>E:
K>=NZYH:<>GMN:=:=H<HE>LM>KHEL[KB<H
>LM:
?HKF:!G=HBLHEHNNF<HFIHLMH:I:KMBK=H
JN:E?HBLBGM>MBS:=:>FE:;HK:M_KBH:FHE[<N
E:JN>=:KB:HKB@>FWF:MKBS=:L>LM:MBG:L
IKBF>BK: : L>K E:GZ:=: GH F>K<:=H ?HB :
EHO:LM:MBG: >F >L=> >GMYH OVKB:L
>LM:MBG:L ?HK:F <KB:=:L L>G=H : LN: :<ZYH
LH;K>HLG^O>BL=><HE>LM>KHE( (">F4=B8CH
"8?>?A>C48=B BGJN>LMBHGVO>E
.><>GM>F>GM>
OVKBHL>GL:BHL<E^GB<HLM]FE>O:GM:=H:JN>L
MYH =:L >LM:MBG:L IHLLN^K>F >?>BMHL =BMHL
IE>BHMK_IB<HL BLMH [ BG=>I>G=>GM>L => JN:E
JN>K :EM>K:ZYH=BFBGNBZYH =HL G^O>BL =>
<HE>LM>KHE
0>G=H<HFH;:L>HF><:GBLFH=>:<ZYH
=:L >LM:MBG:L n : OB: =H V<B=H F>O:E_GB<H
"B@NK:n>LM:L:<MN:FBGB;BG=H:>GSBF:
AB=KHQBF>MBE@ENM:FBE<H>GSBF:$)#
HK>=NM:L>JN>=>M>KFBG::O>EH<B=:=>=>
L^GM>L>=H<HE>LM>KHEGH?^@:=H>GHNMKHLM><B
=HL <HF <HGL>JN>GM> K>=NZYH =HL G^O>BL =>
<HE>LM>KHE ( ( GH A>I:M_<BMH
H BGB;BK :
$)#H K>=NM:L> LYH B@N:EF>GM> K>=NSB
=HLHLG^O>BL=HLK>LM:GM>LBGM>KF>=BVKBHL=:
OB:=HV<B=HF>O:E_GB<HHL<A:F:=HLBLH
IK>G_B=>L K>LIHGLVO>BL IHK NF: L[KB> =>
OB:LBGMK:<>ENE:K>L
!FI:KMB<NE:K:BGB;BZYH
=>I>JN>G:LIKHM>^G:LEB@:GM>L=>#0,.AH
.:L > .:< <NC: EH<:EBS:ZYH G: F>F;K:G:
<>ENE:K>?NGZYH=>I>G=>=:BLHIK>GBE:ZYH
=>L>FI>GA: NF I:I>E BFIHKM:GM> G:
F>=B:ZYH =HL >?>BMHL <>ENE:K>L =BK><MHL =:L
>LM:MBG:L LH;K> H >G=HM[EBH O:L<NE:K
HFH
>Q>FIEHL : BGB;BZYH =: IKHM>^G: .AH
I>E:L >LM:MBG:L :NF>GM: : >QIK>LLYH =:
>GSBF: >*+/ =3>C74;80; $8CA82 %G834
)H=C70B4>:BGB;BZYH=:IKHM>^G:.:<=BFB
GNB:IKH=NZYH=>>LI[<B>LK>:<MBO:L=>HQB
@[GBH BG=NSB=: I>E: :G@BHM>GLBG: %% G:L
<[ENE:L=HFbL<NEHEBLHO:L<NE:K>=HLFB_
<BMHL <:K=^:<HL
!LM> ?:<MH ?HKG><>N : ;:L>
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<@23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
FIGURA 1: Via do ácido mevalónico e mecanismo de acção das
estatinas (PP: Pirofosfato).
F>=B<:=HLNF<HFF@=B:=>LBGO:LM:MB
G:>IE:<>;H>HHNMKH<HFF@=B:=>LBG
O:LM:MBG: > F@=B: => >S>MBFB;>
"HB
H;L>KO:=:NF:=BFBGNBZYHLB@GB?B<:MBO:=:
<HG<>GMK:ZYH L[KB<: => <HE>LM>KHE ( ( LNI>
KBHK GH @KNIH MK:M:=H <HF : :LLH<B:ZYH =>
?VKF:<HLL>FJN>BLLHL>MBO>LL>K>I>K<NMB=H
:HG^O>E=::O:EB:ZYH=>O:KB:ZYH=:>LI>L
LNK: ;:L:E =: ^GMBF: F[=B: <:KHM^=>: >F
JN> GYH AHNO> =B?>K>GZ: >LM:MBLMB<:F>GM>
LB@GB?B<:MBO: >GMK> HL @KNIHL
!LM> ?:<MH
<HGMKB;NB I:K: K>?HKZ:K JN> NF <HGMKHEH
HIMBFBS:=H=HLG^O>BL=><HE>LM>KHE( (GYH
[IHKLBL_LB@GB?B<:MBOH=:F>EAHKB:=>KBL<H
<:K=BHO:L<NE:K@EH;:E>JN>I:K:BLLHIH=>
KYH <HGMKB;NBK HL >?>BMHL IE>BHMK_IB<HL =:L
>LM:MBG:L
!F <HFIE>F>GMH : K>=NZYH =HL
G^O>BL=HLBLHIK>G_B=>L>LMV:LLH<B:=::BGb
F>KHL>?>BMHL;>G[?B<HL=HLJN:BLL>=>LM:<:
:K>LM:NK:ZYH=:?NGZYH>G=HM>EB:E:>LM:;B
EBS:ZYH =: IE:<: => :M>KHF: > : LNIK>LLYH
=:K>LIHLM:BG?E:F:M_KB:>F=BO>KL:LI:MHEH
@B:L
*: IKVMB<: <E^GB<: HL >?>BMHL IE>BHMK_
IB<HL =:L >LM:MBG:L L>KYH =>LM> FH=H K>L
IHGLVO>BLIHKNF:=BFBGNBZYH=HKBL<H<:K
=BHO:L<NE:K <HF BFIEB<:Za>L :H G^O>E =:L
LN:LBG=B<:Za>LM>K:I]NMB<:L
;BHE_@B<: I:K: : oABI_M>L> =: IE>BHMKHIB:
=:L>LM:MBG:Lp
=BL<KBFBG:ZYH>GMK>HL>?>BMHLIE>BHMK_
IB<HL > :JN>E>L =><HKK>GM>L =: =BFBGNBZYH
=H<HE>LM>KHE( (MHKG:L>>OB=>GM>=NK:GM>
: ?:L> BGB<B:E => MK:M:F>GMH <HF >LM:MBG:L
G:JN:EHLG^O>BL=>V<B=HF>O:E_GB<H=BFB
GN>F G:L IKBF>BK:L : AHK:L :H
I:LLHJN>:K>=NZYH=><HE>LM>KHE( (:I>
G:L[=>M><MVO>E:I_LA>MHKG:L>LB@GB?B
<:MBO::=B:L=>IHBL
>LM>FH=H:IKB
O:ZYH=HL=>KBO:=HLBLHIK>G_B=>L>F<BK<N
E:ZYH GNF: ?:L> IK><H<> =H MK:M:F>GMH
IH=>L>K:K>LIHGLVO>EI>EHL>?>BMHLIE>BHMK_
IB<HL:MKB;N^=HLWL>LM:MBG:L
*H>LMN=H!*$*!NF>GL:BH<E^GB<H
:E>:MHKBS:=H =NIE:F>GM> <>@H <HF =NK:
ZYH=>F>L>LI:<B>GM>L<HFABI>K<H
E>LM>KHE[FB:?HK:F=BOB=B=HL>F=HBL@KNIHL
#(*#'
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
+H;C><MBOHIKBG<BI:E=:IK>L>GM>K>OBLYH
;:L>:=: G: >OB=]G<B: <HGLBLM> >F K>O>K :
>OB=]G<B:<E^GB<:=HL;>G>?^<BHL=:M>K:I]NMB
<: <HF >LM:MBG:L =BLMBGMHL =HL L>NL >?>BMHL
LH;K> H I>K?BE EBI^=B<H :G:EBL:G=H H I:I>E
=:L>LM:MBG:L>FI:MHEH@B:LGYH:LLH<B:=:L
MK:=B<BHG:EF>GM> <HF G^O>BL >E>O:=HL =>
<HE>LM>KHE;>F<HFH:F:@GBMN=>=H;>G>
?^<BH<E^GB<HH;L>KO:=HGYHK>E:<BHGVO>E<HF
H@K:N=>K>=NZYH=HLG^O>BL=><HE>LM>KHE
!(## #
.>:EBS:ZYH=>I>LJNBL:;B;EBH@KV?B<:G:L
;:L>L => =:=HL *74 >27A0=4 "81A0AH *( &
<10B40=3>;84A(#43B20?4 >#43;8=4
?A75<@23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
=> :KMB@HL => K>OBLYH > GHKF:L => HKB>GM:
ZYH<E^GB<:
"HK:F<HGLB=>K:=HL<KBM[KBHL=>
BG<ENLYH:IN;EB<:ZYH>GMK>&:G>BKH=>
> >S>F;KH => :KMB@HL K>E:MBOHL :
ANF:GHL>L<KBMHLG:LE^G@N:LBG@E>L:?K:G
<>L:>LI:GAHE:>IHKMN@N>L:<HF:LI:E:
OK:L<A:O> I:E:OK:L #4) oBC0C8=B *
?;48>CA>?82 45542CBp
,:K: :O:EB:ZYH =H G^O>E
=> >OB=]G<B: ?HB :IEB<:=: : !L<:E: /+.0
)CA4=6C7 >5 (42><<4=30C8>= *0G>=><H =:
<4A820=2034<H>50<8;H&7HB8280=B
"HK:F>G<HGMK:=HLNFMHM:E=>:KMB
@HL =HL JN:BL ?HK:F L>E><<BHG:=HL :KMB@HL => K>OBLYH >GL:BHL <E^GB<HL > F>M::GVEBL>L
"HK:F<HGLB=>K:=HL<KBM[KBHL
=>>Q<ENLYHHL:KMB@HLK>I>MB=HL=BL<HK=XG
<B:<HFHLH;C><MBOHL=:K>OBLYH>HL>LMN=HL
I:MKH<BG:=HLI>E:BG=bLMKB:?:KF:<]NMB<:
&') (#'
L>LM:MBG:L:IK>L>GM:F>?>BMHLIE>BHMK_
IB<HL:G^O>EO:L<NE:K<:K=^:<H>>QMK:<:K
=BHO:L<NE:K
(#'*') &'
H G^O>E =H >G=HM[EBH :L >LM:MBG:L
:NF>GM:F:IKH=NZYH>:<MBO:ZYH=:>GSB
F: >*+/ JN>K IHK BGB;BZYH =: :<ZYH =:
<:O>HEBG: NF: IKHM>^G: => F>F;K:G:
JN>KK>=NSBG=H:<HG<>GMK:ZYHBGMK:<>ENE:K
=> BLHIK>G_B=>L K>LIHGLVO>BL IHK :<MBO:K :
IKHM>^G: .AH JN> :<MN: <HFH BGB;B=HK =:
>GSBF: >*+/
>LM: :<ZYH K>LNEM: NF
:NF>GMH=:EB;>KM:ZYH>;BH=BLIHGB;BEB=:=>
=H _QB=H G^MKB<H =8CA82 >G834 *+ JN> IHK
L>N MNKGH ?:<BEBM: : O:LH=BE:M:ZYH BGB;> :
IKHEB?>K:ZYH>IKH=NZYH=><HE:@[GBHI>E:L
<[ENE:L=HFbL<NEHEBLHO:L<NE:K=BFBGNB:
:@K>@:ZYH IE:JN>MVKB: IHK =BFBGNBZYH =:
>QIK>LLYH => FHE[<NE:L => :=>LYH BGB;> :
:IHIMHL> => <[ENE:L >G=HM>EB:BL =BFBGNB H
LMK>LL HQB=:MBOH > :NF>GM: : IKH=NZYH =>
IKHM>^G:L=:F:MKBS>QMK:<>ENE:K
L >LM:MBG:L FH=NE:F : EB;>KM:ZYH =>
LN;LMXG<B:L O:LH<HGLMKBMHK:L <HF =BFBGNB
ZYH =HL G^O>BL => >G=HM>EBG: >F <BK<NE:
ZYHNFIHM>GM>O:LH<HGLMKBMHKK>LIHGLVO>E
IHKNF:=BFBGNBZYH=:K>LBLM]G<B:O:L<NE:K
> F>EAHKB: =H ?ENQH L:G@N^G>H =HL E>BMHL
O:L<NE:K>L<HKHGVKBHL>LBLM[FB<HL
!QBLM> K>@BLMH => K>=NZYH =: FB<KH:E;N
FBGbKB: 0:;>E:%<HF:NMBEBS:ZYH=>>LM:
MBG:L=>OB=HWF>EAHKB:=:LK>LIHLM:LO:L<N
E:K>L A>FH=BGXFB<:L BG=NSB=:L I>EH *+
=BFBGNBZYH =: :<NFNE:ZYH => F:<K_?:@HL
JN><HGLMBMN>FNF:?HGM><09>A =><BMH<BG:L
IKHEB?>K:MBO:L IKH>L<E>K_MB<:L > =BFBGNBZYH
=:>QIK>LLYH=H@>G>),<>=>2HC4274
<>0CA02C0=C ?A>C48= JN> M>F NF I:I>E
BFIHKM:GM>G:G>?KHMHQB<B=:=>IHKE^IB=HL
+L K>?>KB=HL >?>BMHL :H G^O>E =: ?NGZYH
>G=HM>EB:EIH=>F>LM:KG:;:L>=:F>EAHKB:
=:=H>GZ:F:<KH>FB<KHO:L<NE:KL><NG=V
KB:L W =B:;>M>L F>EEBMNL >F I:<B>GM>L <HF
>LM:I:MHEH@B:
H IHGMH => OBLM: BG?E:F:M_KBH 0:;>E:
%% H NLH => >LM:MBG:L >LMV :LLH<B:=H : NF:
=BFBGNBZYH=HGbF>KH=><[ENE:LBG?E:F:M_
KB:LG:LIE:<:L:M>KHL<E>K_MB<:L=>OB=HWK>=N
ZYH=:<HG<>GMK:ZYHBGMK:<>ENE:K=HLBLHIK>
G_B=>L K>LIHGLVO>BL I>E: :<MBO:ZYH =:L IKH
M>^G:L .AH <HF K>=NZYH =: :=>LYH FB@K:
ZYH>:<MBO:ZYHE>N<H<BMVKB:
G:EBMB<:F>GM>
H<HKK> K>=NZYH =HL F:K<:=HK>L => BG?E:F:
ZYH :@N=: IKHM>^G: K>:<MBO: ,. BGM>K
E>N<BG:%(>?:<MHK=>G><KHL>MNFHK:E:E?:
0*"A ;>F <HFH FH=NE:ZYH =: IKH=NZYH
=>HNMK:L<BMH<BG:L
+L >?>BMHL :GMBHQB=:GM>L :MKB;N^=HL WL
>LM:MBG:L M]F G: ;:L> : G>NMK:EBS:ZYH =>
>LI[<B>L K>:<MBO:L => HQB@[GBH FBGBFBS:G
=H :L E>La>L IHK K:=B<:BL EBOK>L L><NG=VKB:
:H:NF>GMH=:;BH=BLIHGB;BEB=:=>=H*+>
W =BFBGNBZYH =: I>KHQB=:ZYH =HL E^IB=HL
IHK BGB;BZYH =: L^GM>L> =HL BGM>KF>=BVKBHL
BLHIK>G_B=>L
M>K:I]NMB<:<HF>LM:MBG:L>LMV:LLH<B:
=::NF:NF>GMH=:>LM:;BEB=:=>=:IE:<:
:M>KHL<E>K_MB<: 0:;>E: %% JN> L> K>E:<BHG:
<HF:=BFBGNBZYH=:<HG<>GMK:ZYH=>F>M:
EHIKHM>:L>L<HE>LM>KHE( (HQB=:=H>=H<HG
M>b=H <>GMK:E => E^IB=HL > F:<K_?:@HL =:
F:MKBS=:IE:<:LN;LMBMN^=HIHK<HE:@[GBH
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<@23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
TABELA I: Artigos de revisão centrados nos efeitos pleiotrópicos das estatinas.
Efeito
Artigo
Metodologia
Resultado/Conclusão
Microalbuminúria
Estatinas e Microalbuminúria5
Dias P et al, 2003
Artigo de revisão
13 ensaios clínicos
1991 – 2002
(9 em DM1 ou 2)
5 ensaios: diminuição estatisticamente significativa da microalbuminúria
- Parece haver tendência para n na microalbuminúria com a terapêutica hipolipemiante
Estenose
aórtica
O Papel das Estatinas
Revisão de 6 estudos
na Estenose Valvular retrospectivos não aleatoAórtica Calcificada.
rizados
Mito ou Realidade?14
(2001 – 2004)
Moura et al, 2007
Are statins effective
for simultaneously
treating dyslipidemias
Antiand hypertension?7
hipertensor
Kwang K K et al, 2008
Fibrilhação
auricular
Imunomodulador
Diabetogénico
Vasoespasmo
cerebral
Uso no
pré-operatório
Artigo de Revisão
É perceptível a utilidade
e a eficácia da terapêutica com estatinas em
doentes com estenose aórtica ligeira a
moderada (<1.5 cm2) e com valores de LDL
> 100 mg/dl.
- Estatinas estão associadas a n modesta da
TA em pacientes HTA, independentemente
dos níveis de colesterol
- Uso combinado de estatina com IECAs ou
antagonistas da AT como prevenção de
arteriosclerose e DC em pacientes HTA
controlados
Nível de evidência
3
(Grande heterogeneidade
nos resultados dos ensaios;
Estudos pequenos)
3
2
3
Pleiotropic effects of
statins in atrial fibrillation patients: the
evidence15
Hadi AR et al, 2009
Revisão
4 meta-análises
5 estudos randomizados
27 estudos prospectivos
Relativa efectividade do uso de estatinas na
3
prevenção de FA após cardioversão electrica, inserção de pacemaker ou CDI e na ICC; (Estudos com metodologias e
objectivos dispares)
Uso perioperatório associado com outcome
pos-operatório favoravel.
Statins – are they
potentially useful in
rheumatology?16
Bielinska A et al, 2007
Artigo de revisão
Spotlight on statins17
Weber M S, 2007
Artigo de revisão
7 ensaios clínicos
(2002 – 2006)
LES – n proteinúria e deposição glomerular
de imunoglobulina
AR – n parâmetros inflamatórios
EM – n nº e volume de lesões de novo na
ressonância magnética
3
Statin Therapy and
Risk of Developing
Type 2 Diabetes:
A Meta-Analysis12
Rajpathak S et al, 2009
Meta-análise
57 593 pacientes
3 anos e 9 meses
Estudo WOSCOPS
– l 6% Risco relativo
2
Statins and risk of
incident diabetes: a
collaborative metaanalysis of randomised statin trials11
Sattar N et al, 2010
Meta-análise
91 140 pacientes
4 anos
(1994 – 2009)
l 9% Risco relativo
- Em ensaios com indivíduos>65 anos
- Independentes do IMC e do LDL
> Tratamento de 255 pacientes em 4 anos
– 1 caso de DM2
Role of statins in
cerebral vasospasm18
Sugawara T et al,
2008
Artigo de revisão
Uso de estatinas após uma hemorragia
subaracnoideia é seguro e melhora o vasospasmo cerebral.
Perioperative statins:
More than lipidlowering?19
Feldman L S, 2008
Artigo de Revisão
10 estudos
(2003 – 2007)
n Progressão da aterosclerose
- Efeito positivo na AR e LES (?)
3
(Não há estudos exclusivos)
Uso aceitável em pacientes que se irão submeter a cirurgia cardíaca ou vascular
(ACC/AHA 2007)
Efeitos benéficos CV cessam após paragem
da toma, com possível efeito rebound
2
3
(Estudos limitados)
2
Legenda: n- diminuição; l- aumento; TA – tensão arterial; FA – fibrilação auricular; HTA - hipertensão arterial; IECA -inibidores da enzima de conversão da angiotensina; AT - angiotensina; DC - doença coronária; CDI - cardiodesfibrilador implantável; ICC - insuficiência cardíaca congestiva; IMC - índice de massa corporal;
DM2 - diabetes mellitus tipo 2; DM1 – diabetes mellitus tipo 1; LES – lúpus eritematoso sistémico; AR – artrite reumatóide; EM – esclerose múltipla.
BGB;BZYH =: K>LIHLM: MKHF;H@[GB<:
0:;>E:%%=>O>L>:H:NF>GMH=:;BH=BLIH
GB;BEB=:=>=H*+>G=HM>EB:E<HFBGB;BZYH=:
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
:@K>@:ZYHIE:JN>MVKB:>:NF>GMH=:>QIK>L
LYH=>MKHF;HFH=NEBG:BGB;BZYH=:>QIK>L
LYH=H?:<MHKM><B=N:E>=HBGB;B=HK=H:<MBO:
?A75<@23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
=HK =H IE:LFBGH@[G>H <HF <HGL>JN>GM>
:NF>GMH =H :<MBO:=HK =H IE:LFBGH@[G>H
M><B=N:E=BFBGNBZYH=::@K>@:ZYHIE:JN>MV
KB:>=::<MBO:ZYHIE:JN>MVKB:M>FIH>=HL>
TABELA II: Ensaios clínicos nos quais foram observados efeitos pleiotrópicos das estatinas.
Efeito
Antiinflamatório
Metodologia
Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering20
(MIRACL)
Schwartz et al, 2001
n=2 402– Prevenção Secundária – 24
semanas
Atorvastatina 80 mg/dia vs. placebo
nn PCR (p<0,001)
- n 86% em EAM
- n 71% Angina instável
- n 60% LDL
- n 37% triglicerídeos
Pravastatin Inflammation CRP
Evaluation21
(PRINCE)
Albert et al, 2001
n1=1702 – Prevenção Primária – 24
semanas
n2=1182 – Prevenção Secundária –
12 semanas
Pravastatina 40mg/dia vs placebo
n1: n16,9% PCR (p<0,001)
n2: n14,7% PCR (p<0,001)
Ø associação entre os níveis
basais de PCR e de LDL
Atorvastatin vs. Simvastatin on
Atherosclerosis Progression22
(ASAP)
Van Wissen et al, 2002
n=325 com hipercolesterolémia familiar – 2 anos
Atorvastatina 80 mg/dia vs.
Sinvastatina 40mg/dia
nn PCR (p<0,02)
- n 34% Atorvastatina
- n 9% Sinvastatina
nn Espessura da intima-média
carotidea
- n 40,1% Atorvastatina
- n 19,7% Sinvastatina
1
n=133 diabéticos tipo 2 sem DCV –
30 semanas
Atorvastatina 10 mg vs. 80 mg/dia
10mg – n 15% PCR
(p=0,012)
80mg – n 47% PCR
(p<0,001)
2
Atorvastatin and thrombogenicity of
the carotid atherosclerotic plaque24
(ATROCAP)
Cortellaro et al, 2002
n=59 com estenose carotídea bilateral
elegíveis para endarterectomia em 2
passos – 5 meses
Atorvastatina 20 mg/dia vs. placebo
nn Atorvastatina (p<0,02) na
placa de ateroma de:
- Macrofagos
- Antigénio e actividade do
factor tecidual
> nFenótipo inflam./trombogénico das placas ateroma
2
Reversing Atherosclerosis with
Aggressive Lipid Lowering25
(REVERSAL)
Nissen, 2004
n1=654 com doença coronária sintomática e estenose r 20% na angiografia coronária – 18 meses
Pravastatina 40mg/dia vs
Atorvastatina 80mg/dia
nn LDL (p<0,001)
-25,2% Pravastatina
-46,3% Atorvastatina
Volume do ateroma (p=0,02)
- l 2,7% Pravastatina
- n 0,4% Atorvastatina
nn PCR (p<0,001)
-5,2% Pravastatina
-36,4% Atorvastatina
2
Increase in circulating endothelial pro- n=15 com doença coronária – 4
genitor cells by statin therapy in
semanas
patients with stable coronary artery Atorvastatina 40 mg/dia
disease26
Vasa M et al, 2001
l Células endoteliais progenitoras derivadas da medula
óssea vermelha (p<0.05)
- 1,5x após 1 semana
- 3x após 4 semanas
3
Effects of atorvastatin on bone in postmenopausal women with dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial13
Bone HG et al, 2007
n= 626 Mulheres pós-menopausa
com dislipidémia – 1 ano
Atorvastatina 10, 20, 40, ou 80
mg/dia vs placebo
Não houve diferença significativa na densidade mineral
óssea entre os grupos com
atorvastatina ou placebo,
independentemente dos efeitos anti-dislipidémicos
2
n=40 com SOP e hiperandrogenemia
– 12 semanas
Atorvastatina 20mg/dia vs placebo
n
n
n
n
n
n
2
Diabetes Atorvastatin Lipid
Intervention Study23
(DALI)
Van de Ree et al, 2003
Anticoagulante
Placa arterios-clerótica
Neovascularização miocárdica
Anti-osteoporótico
Síndrome
do Ovário
Policístico
The Effect os Atorvastatin in Patients
with Polycystic Ovary Syndrome: A
Randomized Double Blind Placebo
Controlled Study27
Sathyapalan T et al, 2008
Resultado
Nível de
evidência
Ensaio Clínico
Colesterol total (p<0,01)
LDL (p<0,01)
Triglicerídeos (p<0,01)
PCR (p=0,04)
Testosterona (p<0,01)
Resistência à insulina
1
1
Legenda: n - amostra; n - diminuição; l - aumento; PCR - proteína C reactiva; EAM – enfarte agudo do miocárdio; Ø – ausência; DCV – doença cardiovascular;
SOP – síndrome do ovário poliquístico.
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<@23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
=>I>G=>GM>L
*H JN> K>LI>BM: :H bEMBFH
IHGMH?HBH;L>KO:=H>FI:<B>GM>L<HF=B:
;>M>L F>EEBMNL MBIH F>=B<:=HL <HF >LM:MB
G:NF:=BFBGNBZYH=HL?K:@F>GMHL=>IKH
MKHF;BG:"BG=>I>G=>GM>F>GM>=HLO:EH
K>L=><HE>LM>KHE
!FK>E:ZYHWM>GLYH:KM>KB:E0:;>E:%%
:K>=NZYH=HLG^O>BL=><HE>LM>KHEIH=>E>O:K
:NF:K>=NZYH=HLO:EHK>LM>GLBHG:BL>GMK>
:FF$@
ABI>K<HE>LM>KHE>FB:>F<HF
;BG:ZYH <HF ABI>KM>GLYH :KM>KB:E :IK>L>G
M:F NF >?>BMH LBG[K@B<H G>@:MBOH LH;K> H
>G=HM[EBH JN>K IHK :NF>GMH =H LMK>LL HQB
=:MBOHJN>KIHK:<MBO:ZYH=HLK><>IMHK>L=:
:G@BHM>GLBG: %% IHM>G<B:G=H H L>N >?>BMH
O:LH<HGLMKBMHK
<MN:EF>GM> L:;>L> JN> :L
>LM:MBG:L I:K:E>E:F>GM> W FH=NE:ZYH =:
EB;>KM:ZYH=>O:LH<HGLMKBMHK>L=BFBGN>F:
=>GLB=:=>=HLK><>IMHK>L=>:G@BHM>GLBG:%%
GH>G=HM[EBHHJN>IH=>KVCNLMB?B<:KH>?>BMH
:GMBABI>KM>GLHKH;L>KO:=H
(#'&_#'
G^O>E<:K=^:<H:L>LM:MBG:L:IK>L>GM:F
>?>BMHL IHLBMBOHL >F <:LHL => BGLN?B<B]G<B:
<:K=^:<: <HG@>LMBO: ABI>KMKH?B: =H FBH<VK
=BH>LH;K>:G>HO:L<NE:KBS:ZYHFBH<VK=B<:
*:BGLN?B<B]G<B:<:K=^:<:<HG@>LMBO::L
>LM:MBG:L=BFBGN>FH>LM:=HIKHMKHF;_MB<H
:LLH<B:=HIHK=BFBGNBZYH=:BG?E:F:ZYH>
:<MBO:ZYH IE:JN>MVKB: ;>F <HFH I>E:
F>EAHKB:=:?NGZYH>G=HM>EB:E>LMBFNE:F:
K>@>G>K:ZYH <:K=^:<: IHK :NF>GMH =H
GbF>KH => <[ENE:L >G=HM>EB:BL IKH@>GBMHK:L
=>KBO:=:L =: F>=NE: _LL>: O>KF>EA: >F
<BK<NE:ZYHI:K><>G=HM>KNFI:I>EG:IK>
O>GZYH=>:KKBMFB:L<:K=^:<:L
*:IK>L>GZ:=>ABI>KMKH?B:=HFBH<VK=BH
:L >LM:MBG:L :IK>L>GM:F >?>BMHL O:L<NE:K>L
IHLBMBOHL F>=B:=HL I>E: BLH?HKF: @:F: =H
K><>IMHK:<MBO:=HI>EHIKHEB?>K:=HK=>I>KHQBL
LHF:L,,.GJN>K>@NE::K>LIHLM:FHE><N
E:K:H>LM^FNEHABI>KMK_?B<H=H<HK:ZYH
L >LM:MBG:L <HFH K>?>KB=H IKHFHO>F
:IKHEB?>K:ZYHFB@K:ZYH>LH;K>OBO]G<B:=>
<[ENE:L >G=HM>EB:BL IKH@>GBMHK:L =>KBO:=:L
=: F>=NE: _LL>: O>KF>EA: <HF >LMBFNE:
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
ZYH =: OB: DM =: ?HL?HKBE:ZYH K>LNEM:G=H
GNF>?>BMHIHLBMBOHLH;K>:G>HO:L<NE:KBS:
ZYHFBH<VK=B<: 0:;>E:%%
(#',(&&#*') &'
.><>GM>F>GM> ?HK:F :MKB;N^=:L IKHIKB>
=:=>L BFNGHFH=NE:=HK:L WL >LM:MBG:L
0:;>E: %
> ?:<MH GNF >LMN=H K>:EBS:=H
<HFLBGO:LM:MBG:?HBH;L>KO:=:NF:BGB;BZYH
=:>QIK>LLYH=H<HFIE>QHIKBG<BI:E=>ABLMH
<HFI:MB;BEB=:=> => <E:LL> %% H JN> M>KV =>
?NMNKH BFIEB<:Za>L IHLBMBO:L G: :;HK=:@>F
=>I:MHEH@B:L:NMHBFNG>L<HFH:>L<E>KHL>
FbEMBIE: HN : :KMKBM> K>NF:M_B=>
"HB B@N:E
F>GM> H;L>KO:=H GHNMKHL >LMN=HL NF:
=BFBGNBZYH=:>QIK>LLYH=H0*"A >=:%(B
I>EHLF:<K_?:@HL<HFK>=NZYH=HL<:LHL=>
K>C>BZYHM:K=B:I_LMK:GLIE:GM>;>F<HFH:
BGB;BZYH=:IKHEB?>K:ZYH=><[ENE:LFHGHGN
<E>:K>LGHL:G@N>I>KB?[KB<H
HIHGMH=>OBLM:G>NKHE_@B<H:L>LM:MB
G:L?HK:F:LLH<B:=:L:NF:=BFBGNBZYH=H
KBL<H => =>L>GOHEOBF>GMH => =H>GZ: =>
ESA>BF>K
*:O>K=:=>G^O>BL:NF>GM:=HL
=><HE>LM>KHEE>O:F:NF:NF>GMH=HCDA=>
E4A =HL>LM>K_B=>LGH<[K>;KH<HFBG<K>F>G
MHG:M:Q:=>IKH=NZYH=>:FBE_B=>B >=HL
G^O>BL => :IHEBIHIKHM>^G: <HF ?HKF:ZYH
=:L IE:<:L G>NK^MB<:L <:K:<M>K^LMB<:L =>LM:
I:MHEH@B:
LLBF:L>LM:MBG:L>LMYH:LLH<B:
=:L : NF: IK>O:E]G<B: => =H>GZ: =>
ESA>BF>K BG?>KBHK >F <HFI:K:ZYH
<HF I:<B>GM>L JN> NL:F HNMK:L M>K:I]NMB
<:L I:K: =H>GZ:L <:K=BHO:L<NE:K>L =>OB=H
:HL L>NL >?>BMHL G: FH=NE:ZYH =: ?NGZYH
>G=HM>EB:E > :GMBBG?E:F:M_KBH I:K: :E[F
=H<HGMKHEHEBI^=B<H
1F:M>FVMB<:K><>GM><HGLBLM>GHNLH=>
>LM:MBG:L > H KBL<H => =>L>GOHEOBF>GMH =>
=B:;>M>L <4;;8CDB MBIH : EHG@H IK:SH
0:;>E:%
1F>LMN=HK><>GM>F>GM>IN;EB<:
=H =>FHGLMKHN NF KBL<H EB@>BK:F>GM>
F:BHK F:L LB@GB?B<:MBOH => :I:K><BF>GMH
=>=B:;>M>LF>EEBMNLMBIH>F=H>GM>LF>=B
<:=HL <HF >LM:MBG:L IH=>G=H L>K <HGL>
JN]G<B: =: F:BHK EHG@>OB=:=> <HGL>@NB=:
G>LM>L=H>GM>L
HGMN=H:M[:HFHF>GMH[
?A75<@23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
E>@BMBFH :<>BM:K JN> H ;>G>?^<BH =:L >LM:MB
G:LLH;K>:L=H>GZ:L<:K=BHO:L<NE:K>LLNI>
K:HBFI:<MHG>@:MBOH=H>O>GMN:E:NF>G
MH=HKBL<H=>=B:;>M>L<4;;8CDB MBIH
!F K>E:ZYH :H F>M:;HEBLFH _LL>H
0:;>E: %% ?HK:F :MKB;N^=:L IKHIKB>=:=>L
:GMBHLM>HIHK_MB<:L WL >LM:MBG:L <HF =BFB
GNBZYH =H KBL<H => ?K:<MNK: IHK BGM>GLB?B<:
ZYH=:?HKF:ZYH=>HLLH>BGB;BZYH=:K>:;
LHKZYH _LL>: M><B=NE:K
*NF >LMN=H K>:EB
S:=H>FI:<B>GM>L<HFHLM>HIHKHL>F>=B<:
=HL<HF>LM:MBG:?HBH;L>KO:=:NF:=BFB
GNBZYH=>=HKBL<H=>?K:<MNK:>LM:G=H
:L>LM:MBG:L:LLH<B:=:L::NF>GMH=:=>GLB
=:=> FBG>K:E _LL>: =: <HENG: > =: :G<:
0H=:OB:GYHAV>OB=]G<B:LN?B<B>GM>I:K:H
NLH => >LM:MBG:L >F FHGHM>K:IB: G: IK>
O>GZYHHNMK:M:F>GMH=:HLM>HIHKHL>
HFH EBGA:L ?NMNK:L LNK@BK:F =HBL
>LMN=HL JN> K>E:<BHG:F H NLH => >LM:MBG:L
G: L[ILBL > G: IK>O>GZYH =H <:G<KH =:
F:F:
!F K>E:ZYH :H NLH => >LM:MBG:L >F
=H>GM>L <HF L[ILBL H IK>LLNIHLMH K>E:<BH
G:L> <HF : I:MH?BLBHEH@B: <HFNF > :GM:
@HGBS:GM>=HL>?>BMHLIE>BHMK_IB<HL=:L>LM:
MBG:L > =HL F><:GBLFHL =: L[ILBL <HFH
E>LYHO:L<NE:KHN:<MBO:ZYH=:K>LIHLM:E>N
<H<BMVKB: > MKHF;_MB<:
HGMN=H FNBM:L
JN>LMa>L L> <HEH<:F K>E:MBO:F>GM> :H NLH
=>>LM:MBG:LG>LM>L<:LHL?:<>WL<HFHK;BEB
=:=>L>QBLM>GM>L>:HLL>NL>?>BMHLE:M>K:BL
*:IK>O>GZYH=H<:G<KH=:F:F: ?HB
H;L>KO:=: 8= E8CA> NF: :<MBOB=:=> :GMB<:G
<>K^@>G:=:L>LM:MBG:LEBIH?^EB<:LG:JN:E:L
<[ENE:L G>HIEVLB<:L <HF :<MBO:ZYH =: OB:
.:LHN!K;FHLMK:K:FF:BHKL>GLB;BEB=:
=> >F K>E:ZYH WL <[ENE:L <HF >QIK>LLYH
:NF>GM:=:=>K><>IMHK>L>LMKH@[GB<HL
HF
>LM: ;:L> I>KLI><MBO:FL> GHOHL >LMN=HL
LH;K> HL >?>BMHL :GMBIKHEB?>K:MBOHL > IK_
:IHIM_MB<HL=:L>LM:MBG:LGHLOVKBHLMBIHL=>
G>HIE:LB:LANF:G:L
G:;:L>=HL;>G>?^<BHL<E^GB<HL=:M>K:I]NMB
<:<HF>LM:MBG:L=>O>G=HF:GM>KL><HFH
H;C><MBOHG:L>LMK:M[@B:L=>K>=NZYH=HKBL<H
<:K=BHO:L<NE:K
L >LM:MBG:L :IK>L>GM:F >?>BMHL I:K:
:E[F =: HIMBFBS:ZYH =H I>K?BE EBI^=B<H
=>GHFBG:=HL>?>BMHLIE>BHMK_IB<HLL><NG=V
KBHL G: LN: F:BHKB: W BGB;BZYH =: L^GM>L>
=HLBLHIK>G_B=>L
n)>EAHKB:=:?NGZYH>G=HM>EB:E>=BFBGNB
ZYH=:BG?E:F:ZYHO:L<NE:Kn/+.0
n !?>BMHL IHLBMBOHL G: ABI>KM>GLYH :KM>
KB:E K>LIHLM: MKHF;H@[GB<: > >LM:;BEB
=:=>=:IE:<::M>KHL<E>K_MB<:n/+.0
n,KHIKB>=:=>LBFNGHFH=NE:=HK:L:GMB
=>F>G<B:BL :GMBHLM>HIHK_MB<:L > :GMB
G>HIEVLB<:Ln/+.0
HGMN=H LYH G><>LLVKBHL F:BL >LMN=HL
<HFOBLM:W=>M>KFBG:ZYH=::FIEBMN=>=HL
>?>BMHL IE>BHMK_IB<HL G: IKVMB<: <E^GB<:
+L
>LMN=HL>QBLM>GM>LLYH=B?^<>BL=>BGM>KIK>M:K
>F @K:G=> F>=B=: I>E: =B?B<NE=:=> >F
L>I:K:K HL >?>BMHL IE>BHMK_IB<HL @>GN^GHL
=:JN>E>L =>I>G=>GM>L =: =BFBGNBZYH =HL
G^O>BL=><HE>LM>KHENF:O>SJN>H4=3?>8=C
IKBFVKBH>K:G:F:BHKB::HIMBFBS:ZYH=H
I>K?BEEBI^=B<H
!F<HG<ENLYH=>OB=H:HL;>G>?^<BHL<E^
GB<HL CV <HGA><B=HL :LLH<B:=HL :HL >?>BMHL
IE>BHMK_IB<HLJN>L>I>KLI><MBO:F>WK>=N
SB=:BG<B=]G<B:=>>?>BMHL<HE:M>K:BL[E>@BMB
FH <HGLB=>K:K L> L> >LM:KV I>K:GM> : GHO:
o:LIBKBG:p =HL[<NEH44%
"#(#')(#&'
+L :NMHK>L =><E:K:F : BG>QBLM]G<B: =>
<HG?EBMH=>BGM>K>LL>L
')''W##" )'W#
*::<MN:EB=:=>:K>=NZYH=H<HE>LM>KHE
( ( <HGMBGN: : L>K H F><:GBLFH IKBFVKBH
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
?A75<@23&3C7@N<
.!2%/0,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+H
H
&&]"' #&^'
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Linarelli MC et al, Statins: a review about vascular aspects, Rev. Ciênc. Méd. 2008;17(1):43-52.
Liao JK, Isoprenoids as mediators of the biological effects of statins, J Clin Invest
2002;110:285-88.
Corsini A et al, Are pleiotropic effects of statins
real?,
Vasc
Health
Risk
Manag.
2007;3(5):611–613.
Kastelein J et al, Simvastatin with or without
Ezetimibe in Familial Hypercholesterolemia, N
Engl J Med 2008;358:1431-43.
Dias P et al, Estatinas e microalbuminúria
Medicina Interna 10(2):101-109, 2003.
McFarlane et al,Pleiotropic Effects of Statins:
Lipid Reduction and Beyond, J Clin Endocrinol
Metab 2002;87:1451–1458.
Kwang K K et al, Are statins effective for simultaneously treating dyslipidemias and hypertension?, Atherosclerosis 2008;196:1-8.
Mathur N et al, Spectrum of Pleiotropic Effects
of Statins in Heart Failure, Heart Fail Clin
2008;4:153-161.
Wang CY, Pleiotropic effects os statin therapy:
molecular mechanisms and clinical results,
Trends Mol Med. 2008;14(1):37-44.
Futterman L G et al, Statin Pleiotropy: Fact Or
Fiction? Am J Crit Care. 2004;13:244-249
Sattar N et al, Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials, Lancet Early publication
online, 17 de Fevereiro de 2010.
Rajpathak S et al, Statin Therapy and Risk of
Developing Type 2 Diabetes: A Meta-Analysis
Diabetes Care October 2009;32(10):1924-1929.
Bone HG et al, Effects of atorvastatin on bone
in postmenopausal women with dyslipidemia:
a double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab.
2007;92(12):4671-7.
Moura L M et al, O Papel das Estatinas na
EstenoseValvular Aórtica Calcificada. Mito ou
Realidade?, Rev Port Cardiol 2007;26(1):51-62
Hadi AR et al, Pleiotropic effects of statins in
atrial fibrillation patients: the evidence,
Vascular Health and Risk Management
2009;5:533–551.
Bielinska A et al, Statins – are they potentially
useful in rheumatology?, Pol Arch Med Wewn.
2007;117(9):420-425.
fn/+%! !,+.01#1!/ !!* +.%*+(+#% %!0!/!)!0+(%/)+
17. Weber M S et al, Spotlight on statins, Int MS J.
2007;14(3):93-7.
18. Sugawara T et al, Role of statins in cerebral
vasospasm,
Acta
Neurochir
Suppl
(2008)104:287–290.
19. Feldman L S, Perioperative statins: More than
lipid-lowering?, Clev cl j med, 2008(75)9.
20. Schwartz et al, Myocardial Ischemia Reduction
with Aggressive Cholesterol Lowering
(MIRACL) Jama 2001; 285:1711-1718.
21. Albert et al, Pravastatin Inflammation CRP
Evaluation
(PRINCE)
Am
Heart
J.
2001;141:893–898.
22. Van Wissen et al, Atorvastatin vs. Simvastatin
on Atherosclerosis Progression (ASAP) Clin
Drug Invest 2000;20:67-79.
23. Van de Ree et al, The Diabetes Atorvastatin
Lipid Intervention Study Group. The Effect of
Aggressive Versus Standard Lipid Lowering by
Atorvastatin on Diabetic Dyslipidemia: The
DALI Study: a double-blind, randomized, placebo-controlled trial in patients with type 2
diabetes and diabetic dyslipidemia. Diab Care
2001;24:1335-41.
24. Cortellaro et al, Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque (ATROCAP), Thromb Haemost. 2002;88(1):41-7.
25. Nissen, Reversing Atherosclerosis with
Aggressive Lipid Lowering (REVERSAL), Am J
Card 2005;96(5):61-68.
26. Vasa M et al, Increase in circulating endothelial progenitor cells by statin therapy in
patients with stable coronary artery disease,
Circulation. 2001;103(24):2885-90.
27. Sathyapalan T et al, The Effect os Atorvastatin in
Patients with Polycystic Ovary Syndrome: A
Randomized Double Blind Placebo Controlled
Study, J Clin Endocrinol Metab 2009;94:103-108.
28. Gao F et al, Statins and sepsis, Br J Anaesth
2008 100(3):288-298.
29. Campbell M J et al, Breast Cancer Growth
Prevention by Statins, Cancer Res 2006;66(17):
8707-13.
30. Veillard NR, Mach F, Statins: the new aspirin?
Cell Mol Life Sci. 2002;59:1771-86.