-
G
C
A
ML
a
b
RD
0h
E J Port Gastrenterol. 2013;20(6):266---271
www.elsevier.pt/ge
ASO CLÍNICO
miloidose gastrointestinal
aria João Pereiraa,∗, Joana Raposob, Joana Carvalheiroa, Zita
Romãoa,ígia Pradob, Luís Toméa e Carlos Sofiaa
Serviço de Gastrenterologia, Centro Hospitalar e Universitário
de Coimbra, Coimbra, PortugalServiço de Anatomia Patológica,
Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
ecebido a 9 de abril de 2013; aceite a 5 de setembro de
2013isponível na Internet a 22 de novembro de 2013
PALAVRAS-CHAVEHemorragia digestivabaixa;Amiloidose
primária;Mieloma múltiplo
Resumo A amiloidose primária (AL) é uma gamapatia monoclonal de
envolvimento sistémico.O envolvimento do trato gastrointestinal
manifesta-se com sinais e sintomas variados e ines-
pecíficos, podendo apresentar-se de forma distinta consoante a
sua localização e mimetizarclínica e endoscopicamente outras
doenças do foro digestivo, sendo o diagnóstico final estabe-lecido
pelo exame histológico.
Os autores apresentam o caso clínico de um doente com hemorragia
digestiva baixa, queapresentava várias sufusões hemorrágicas
subepiteliais dispersas pela mucosa do cólon, comomanifestação
inicial de AL e mieloma múltiplo. Salienta-se a relevância deste
caso pela suararidade e pela iconografia endoscópica e histológica
recolhida.© 2013 Sociedade Portuguesa de Gastrenterologia.
Publicado por Elsevier España, S.L. Todos osdireitos
reservados.
KEYWORDSLowergastrointestinalbleeding;Primary
amyloidosis;Multiple myeloma
Gastrointestinal amyloidosis
Abstract Primary (AL) amyloidosis is a monoclonal gammopathy of
systemic involvement.The involvement of the gastrointestinal tract
is manifested by varied and nonspecific signs
and symptoms, may present itself differently depending on their
location, and clinically andendoscopically mimic other diseases of
the digestive tract. The final diagnosis is established
byhistological examination.
The authors present the case of a patient with lower
gastrointestinal bleeding who presented
several subepithelial hemorrhagic suffusions distributed across
the colonic mucosa, as the initial
manifestation of primary AL amof this case for its rarity and
the© 2013 Sociedade Portuguesa dereserved.
∗ Autor para correspondência.Correio eletrónico:
[email protected] (M.J. Pereira).
872-8178/$ – see front matter © 2013 Sociedade Portuguesa de
Gastrenterottp://dx.doi.org/10.1016/j.jpg.2013.09.005
yloidosis and Multiple myeloma. We emphasize the relevance
endoscopic and histological iconography collected.
Gastrenterologia. Published by Elsevier España, S.L. All
rights
logia. Publicado por Elsevier España, S.L. Todos os direitos
reservados.
dx.doi.org/10.1016/j.jpg.2013.09.005http://www.elsevier.pt/gehttp://crossmark.crossref.org/dialog/?doi=10.1016/j.jpg.2013.09.005&domain=pdfmailto:[email protected]/10.1016/j.jpg.2013.09.005
-
�1ps6cbTtíad
chsaf
dpt
ptc
ep
aldmns(s2eImlLn(rmdndatiadp
Amiloidose gastrointestinal
Introdução
A amiloidose é uma entidade rara caracterizada peladeposição
extracelular de proteínas fibrilares anormais inso-lúveis em vários
tecidos ou órgãos e que caracteristicamentecoram com o Vermelho do
Congo. A classificação dos tipos deamiloidose baseia-se na
identificação da proteína precursoraque forma os respetivos
depósitos1---3.
A amiloidose primária (imunoglobulinas monoclonaisde cadeias
leves, AL) constitui o tipo mais comum deamiloidose e está
associada a discrasia de células plas-máticas e à presença de
cadeias leves monoclonais nosoro e/ou na urina4. Os órgãos mais
comumente afe-tados são o coração e os rins5. Cerca de 15%
destesdoentes apresentam mieloma múltiplo, sendo este o tipode
amiloidose que mais frequentemente envolve o tratogastrointestinal,
podendo afetar qualquer parte do tubodigestivo e apresentar-se de
forma distinta consoante a sualocalização2,4. As manifestações
clínicas e endoscópicas sãoinespecíficas, podendo mimetizar outras
doenças do forodigestivo2---4,6.
A amiloidose primária (AL) raramente se apresentacom hemorragia
gastrointestinal aguda, especialmentena ausência de doença noutra
parte do organismo5.O diagnóstico definitivo é estabelecido pelo
examehistológico2,3.
Caso clínico
Doente do sexo masculino, de 76 anos de idade,
caucasoide,internado com um quadro de hematoquézias e vómitos,
comum dia de evolução. Concomitantemente apresentava quei-xas de
dorso-lombalgias, astenia, fraqueza muscular global etonturas, com
cerca de 4 meses de evolução. Negava febre,alterações dos hábitos
intestinais, dores abdominais, anore-xia ou emagrecimento.
Internamento recente (há um mês) no serviço de medi-cina para
estudo de lesões ósseas da coluna de provávelnatureza lítica,
mialgias das cinturas escapular e pélvica eparestesias dos membros,
tendo alta com o diagnóstico depolimialgia reumática e medicado com
prednisolona. Nesteúltimo internamento constatou-se também a
elevação dafosfatase alcalina, transaminases e LDH, e
hipogamaglobu-linemia.
Ao exame objetivo destacava-se a presença de sinaisde
desidratação e edemas periféricos ligeiros. Hemodina-micamente
estável, sem febre, alterações à auscultaçãocardiopulmonar,
adenopatias ou organomegalias. Ao toqueretal constatou-se a
presença de sangue vivo no dedo deluva.
Antecedentes de insuficiência cardíaca, hipertensãoarterial
(HTA), bloqueio completo de ramo direito (BCRD),bloqueio
auriculoventricular (BAV) de 1.◦ grau, cirurgia àcoluna lombar em
2010 (laminectomia de L3 e L4 e artrodeselaterotransversa por
estenose da coluna vertebral), doençado refluxo gastroesofágico,
dislipidemia e adenomas docólon. Medicado com lansoprazol,
valsartan e hidrocloroti-
azida, pregabalina, diazepam, sinvastatina,
bioflavonoides,ranelato de estrôncio e prednisolona.
Analiticamente, apresentava hemoglobina 16 g/dL, leu-cocitose de
25.000 cél/�L, com neutrofília de 22.250 cél/
tpel
267
L, plaquetas 243.000 cél/�L, tempo de protrombina1,5 (controlo
10) segundos, tempo de trombloplastinaarcial ativado 27 (controlo
30) segundos, velocidade deedimentação 4 mm/1.a hora, ureia 11,7
mmol/L, creatinina4,4 �mol/L, sódio 139 mmol/L, potássio 4,14 mm/L,
cál-io 2,21 mmol/L, proteínas totais 60,5 g/L, albumina 40
g/L,ilirrubina total 23,1 �mol/L, fosfatase alcalina 211 U/L,GO 67
U/L, TGP 71 U/L, LDH 916 U/L e proteína C rea-iva 7,7 mg/dL. A
radiografia do tórax revelou aumento dondice cardiotorácico. A
ecografia abdominal não mostroulterações do fígado nem dos
restantes órgãos avalia-os.
Realizou colonoscopia que revelou presença de sangue eoágulos
no lúmen em todo o trajeto a jusante do ânguloepático, áreas de
mucosa congestiva e friável, com sufu-ões subepiteliais de
coloração arroxeada pericentimétricas
nível do ângulo hepático, transverso e sigmoide, ondeoram
realizadas biopsias.
Pela hipótese diagnóstica inicial de colite isquémica, ooente
realizou fluidoterapia endovenosa e restante tera-êutica médica de
suporte, contudo, sem necessidadesransfusionais de concentrado
eritrocitário.
A endoscopia digestiva alta mostrou, similarmente, aresença de
sufusões subepiteliais no antro. O estudo his-ológico identificou
depósitos de amiloide nas mucosas doólon e gástrica.
Constatou-se evolução clínica favorável, com remissãospontânea
da hemorragia digestiva e sem recorrência daserdas hemáticas.
Com o intuito de identificar uma etiologia subjacente àmiloidose
realizou estudo complementar. Efetuou medu-ograma que revelou a
presença de 20% de plasmócitose origem monoclonal, compatível com
o diagnóstico deieloma múltiplo, confirmado posteriormente pela
imu-
ofenotipagem medular. Diminuição das imunoglobulinaséricas,
nomeadamente G 2,5 g/L (7,0-15,0), A < 0,24 g/L0,6-4,0), M <
0,16 g/L (0,6-3,0). Cadeias leves livres nooro Kappa 0,18 g/L
(0,33-1,90), Lambda 0,62 g/L (0,57-,63). Eletroforese das proteínas
séricas sem alterações
urinárias com vestígios de proteinúria tipo tubular.munofixação
sérica com acentuada hipogamaglobuliné-ia. Sem alterações na
imunofixação urinária. Cadeias
eves livres na urina Kappa 2,6 mg/dL (0,135-2,42) eambda 0,8
mg/dL (0,024-0,666). Clearance da creati-ina 46,3 ml/min e
proteinúria das 24 horas de 103 mg42,0-255,0). Realizou ressonância
magnética à coluna queevelou vários focos hipointensos sugestivos
de infiltraçãoielomatosa a nível cervical, torácico e lombar.
Alémas alterações referidas, identificaram-se alterações
dege-erativas da coluna com unco-discartroses e
protusõesisco-osteofitárias, motivando ligeira compressão da
medula
nível cervical. A TAC do tórax, abdómen e pélvis não mos-rou
alterações de relevo. O ecocardiograma transtorácicodentificou
hipertrofia moderada do septo basal anterior ecentuada do septo
interventricular, com ligeiro aumentoa refringência e padrão de
disfunção diastólica do tiposeudonormal.
Pelo diagnóstico de mieloma múltiplo, não secre-or, sintomático,
iniciou quimioterapia com melfalan e
rednisolona. Foi orientado para reabilitação e pelolevado risco
de fraturas ósseas colocado colete dorso-ombostato.
-
2
4trc
tpp
D
Add
ado
lnd
dAfAordmpfi
ear
gedvot
prctfott
nppso
iu
mtctnpd
mdcuevccdmsfmdf
pd
pacnd
ddourdmdccpa
tddpmcdso
68
A reavaliação por colonoscopia esquerda, realizada meses depois
de diagnóstico de amiloidose gastrointes-inal, e ainda durante o
tratamento com quimioterapia,evelou a nível do sigmoide a
persistência das lesões des-ritas previamente.
O doente não apresentou recidiva da hemorragia diges-iva.
Contudo, registaram-se 2 internamentos posterioresor
intercorrências infeciosas, nomeadamente infeções
res-iratórias.
iscussão
amiloidose não é uma doença única, mas sim um grupo deoenças
que partilham a característica comum de depósitoe proteínas na
matriz extracelular1.
Pode ser adquirida ou hereditária, sistémica ou localizada um
único órgão, como o trato gastrointestinal3,6. A verda-eira
incidência da amiloidose é desconhecida pois apenass doentes
sintomáticos são investigados8.
A nomenclatura atual da doença consiste na primeiraetra --- A
(de amiloide) --- seguida pela descrição daatureza da proteína
precursora que forma os respetivosepósitos1,2.
Existem 6 tipos diferentes de amiloidose. A AL, comeposição de
cadeias leves, é a forma mais comum.
amiloidose secundária (AA) é causada pela deposição deragmentos
de proteína de fase aguda, a proteína amiloide
sérica (SAA), causada por distúrbios inflamatórios crónicosu
infeções3,6,7. Outros tipos de amiloidose são: a
amiloidoseelacionada com a diálise (A�2MG), causada pela
deposiçãoe �2-microglobulina; a amiloidose hereditária,
nomeada-ente a polineuropatia amiloidótica familiar (FAP),
causadaela deposição de transtirretina; a amiloidose senil; e
asormas localizadas de amiloidose no esófago, estômago,ntestino
delgado e/ou no cólon2,6---8.
O envolvimento gastrointestinal na AL é comum, sendostimado em
98% em algumas series de autópsias5. Contudo,
apresentação inicial da AL como hemorragia digestiva éaramente
reportada na literatura5,9.
Os sinais e sintomas dependem da localização do
tratoastrointestinal que está envolvida2. O envolvimento dostômago
e do duodeno é incomum, sendo a maioria dosoentes assintomáticos.
Os sintomas podem incluir náuseas,ómitos, epigastralgias e
hematemeses2. No presente caso
doente apresentou um episódio de vómitos coincidenteemporalmente
com a hemorragia digestiva baixa.
A hepatomegália é comum nos doentes com AL1. Naresença de
insuficiência cardíaca pode ser difícil dife-enciar a congestão
hepática da infiltração por amiloide,ontudo, a presença de
hepatomegália dura e irregular, par-icularmente se associada a
elevação da fosfatase alcalina,ortemente sugere esta última
entidade1. No presente caso,
doente apresentava elevação da fosfatase alcalina e
dasransaminases, mas sem alterações da imagiologia hepá-ica.
A deposição de amiloide, quando presente, é maior aível do
intestino delgado. Clinicamente pode traduzir-se
or diarreia, esteatorreia, enteropatia perdedora deroteínas,
isquemia mesentérica, hemorragia, intus-usceção, pneumatose
intestinal, obstrução ou pseudo-bstrução4,6,9---11. Os achados
endoscópicos mais frequentes
ectm
M.J. Pereira et al.
ncluem aparência granular fina, pólipos, erosões,lcerações ou
friabilidade da mucosa10,12---14.
As manifestações clínicas da amiloidose do cólon podemimetizar
outras doenças, tais como doença inflama-
ória intestinal, neoplasias, colite isquémica ou
coliteolagenosa. Endoscopicamente podemos encontrar pro-usões
polipoides, úlceras, hematomas da submucosa,ódulos, colite bolhosa
hemorrágica, estreitamento luminal,erda das haustrações e
espessamento das pregas mucosaso cólon3,4,15---17.
A hemorragia digestiva baixa, que pode ser aanifestação inicial
da amiloidose do cólon em cercae 25-45% dos doentes, tal como
aconteceu no presenteaso clínico, pode ser causada por isquemia,
enfarte,lceração, lesão infiltrativa ou secundária a hemorragiam
babamento generalizada sem uma fonte identificá-el. Geralmente
ocorre na ausência de distúrbios daoagulação4,9. Contudo, as
doenças hemostáticas sãoomuns na AL, estando descritas na história
de 28% destesoentes. Equimoses cutâneas e púrpura são as
alteraçõesais frequentemente registadas. Hemorragias
significativas
ão mais comuns a partir do trato digestivo e renal. Arequência
da deficiência de fator X nestes doentes foi esti-ada em 14%18. No
presente caso, perante a normalidadeos tempos de coagulação não se
efetuou doseamento deatores de coagulação.
Perante esta diversidade de aspetos clínicos e endoscó-icos, o
diagnóstico da amiloidose requer um elevado nívele suspeita por
parte dos endoscopistas.
O diagnóstico requer a confirmação histológica daresença de
amiloide. No presente caso clínico e atendendoos achados clínicos e
endoscópicos, a hipótese diagnósticaolocada inicialmente foi a de
uma colite isquémica, quandoa realidade, e de forma surpreendente,
se tratavam deepósitos de amiloide na mucosa.
O órgão classicamente a ser biopsado com o intuitoe se
diagnosticar amiloidose tem sido o reto e a gor-ura submucosa,
contudo, o restante trato gastrointestinal,
fígado, a medula óssea e os rins também podem sertilizados para
esse fim2. Os depósitos de amiloide apa-ecem homogéneos e amorfos à
microscopia ótica. Corame rosa pela hematoxilina e eosina e exibem
metacro-asia com o metil violeta. A coloração pelo Vermelhoo Congo
é a mais específica, produzindo a característicaoloração
avermelhada à microscopia ótica e birrefringên-ia verde-maçã à luz
polarizada2,7. A imunohistoquímica,or sua vez, permite a
determinação do tipo específico demiloide2,4,6.
O tratamento depende do tipo de amiloidose. O obje-ivo do
tratamento da amiloidose AL é suprimir a síntesee cadeias leves de
imunoglobulinas mediante o controloo distúrbio hematológico
subjacente com quimiotera-ia. Recentemente, a quimioterapia em
altas doses comelfalan e prednisolona e o transplante (autólogo)
de
élulas estaminais têm sido realizados neste tipo de amiloi-ose,
com resultados encorajadores, além das medidas deuporte gerais e
nutricionais2. Com a resposta hematológicacorre regressão dos
depósitos de amiloide, resultando emstabilização e melhoria da
função orgânica2,6. No presenteaso, o doente não apresentou
recidiva da hemorragia diges-
iva baixa após iniciar quimioterapia dirigida ao
mielomaúltiplo.
-
Amiloidose gastrointestinal 269
Figura 1 A colonoscopia mostrou áreas de mucosa congestiva e
friável, com sufusões subepiteliais de coloração arroxeada
peri-centimétricas (A, B, C, D) a nível do ângulo hepático,
transverso e sigmoide. O estudo histológico revelou na mucosa
cólica deposiçãode material eosinofílico claro com aspeto amorfo
(Figura 1 E --- hematoxilina e eosina, ampliação 400 x). Este
material cora pelo
birre
it
R
Pps
Vermelho do Congo (Figura 1 F, ampliação 200 x) e apresenta
mucosa cólica (setas).
Conclusão
Em conclusão, a AL com envolvimento gastrointestinal éuma
entidade pouco frequente na prática clínica diária,manifesta-se
clínica e endoscopicamente de forma inespe-cífica, podendo
mimetizar outras doenças do foro digestivo.A deteção endoscópica
de sufusões hemorrágicas subepite-liais ou hematomas petequiais no
contexto de hemorragia
gastrointestinal deve levar à suspeita diagnóstica destadoença,
conferindo à histologia o papel diagnóstico final.Portanto, os
autores pretendem salientar a relevância darealização de biópsias
perante a presença de achados
Csp
fringência verde à luz polarizada --- depósitos de amiloide
na
nespecíficos na endoscopia e sempre que a clínica o jus-ifique
(figs. 1 e 2).
esponsabilidades éticas
roteção de pessoas e animais. Os autores declaram queara esta
investigação não se realizaram experiências emeres humanos e/ou
animais.
onfidencialidade dos dados. Os autores declaram tereguido os
protocolos de seu centro de trabalho acerca daublicação dos dados
de pacientes e que todos os pacientes
-
270 M.J. Pereira et al.
Figura 2 A endoscopia digestiva alta mostrou a presença de
sufusões subepiteliais no antro (G, H). No estudo histológico
observou-se na lâmina própria da mucosa gástrica depósitos de
substância eosinofílica clara, de aspeto amorfo (Figura 2 I ---
hematoxilinae om Vb a m
idt
Ddep
C
O
B
1
1
1
1
eosina, ampliação de 200 x). Os depósitos descritos coram
cirrefringência verde à luz polarizada --- depósitos de amiloide
n
ncluídos no estudo receberam informações suficientes eeram o
seu consentimento informado por escrito para par-icipar nesse
estudo.
ireito à privacidade e consentimento escrito. Os autoreseclaram
ter recebido consentimento escrito dos pacientes/ou sujeitos
mencionados no artigo. O autor para corres-ondência deve estar na
posse deste documento.
onflito de interesses
s autores declaram não haver conflito de interesses.
ibliografia
1. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses.N
Engl J Med. 1997;337:898---909.
2. Ebert EC, Nagar M. Gastrointestinal manifestations of
amyloi-dosis. Am J Gastroenterol. 2008;103:776---87.
3. Hokama A, Kishimoto K, Kobashigawa C, Tetsuo H, KinjoN, Kinjo
F, et al. Endoscopic and histopathological featuresof
gastrointestinal amyloidosis. World J Gastrointest
Endosc.2011;3:157---61.
4. Maza I, Vlodavsky E, Eliakim RA. Rectal Bleeding as a
pre-senting symptom of AL amyloidosis and multiple myeloma.
2010;2:44---6.
5. Spier BJ, Einstein M, Johnson EA, Zuricik 3rd AO, Hu JL, Pfau
PR.Amyloidosis presenting as lower gastrointestinal hemorrhage.WMJ.
2008;107:40---3.
1
ermelho do Congo (Figura 2 J, ampliação 400 x) e
apresentamucosa gástrica (setas).
6. Sattianayagam PT, Hawkins PN, Gillmore JD. Systemic
amy-loidosis and the gastrointestinal tract. Nat Rev
GastroenterolHepatol. 2009;6:608---17.
7. Petre S, Shah IA, Gilani N. Review article:
Gastrointestinalamyloidosis - clinical features, diagnosis and
therapy. AlimentPharmacol Ther. 2008;27:1006---16.
8. Ebert EC. Two Cases of Gastric and Esophageal
Amyloidosis.Gastroenterol Hepatol (N Y). 2009;5(8):575---6.
9. Kim SH, Kang EJ, Park JW, Jo JH, Kim SJ, Cho JH, et
al.Gastrointestinal amyloidosis presenting with multiple episo-des
of gastrointestinal bleeding. Cardiovasc Intervent
Radiol.2009;32:577---80.
0. Tada S, Lida M, Yao T, Kawakubo K, Yao T, Okada M, et
al.Endoscopic features in amyloidosis of the small intestine:
Cli-nical and morphologic differences between chemical types
ofamyloid protein. Gastrointest Endosc. 1994;40:45---50.
1. James DG, Zuckerman GR, Sayuk GS, Wang HL, Prakash C.Clinical
recognition of Al type amyloidosis of the luminalgastrointestinal
tract. Clin Gastroenterol Hepatol. 2007;5:582---8.
2. Bellutti M, Weigt J, Mönkemüller K, Röcken C, Wieners G,
Dom-browski F, et al. Localized primary AL-type amyloidosis of
thejejunum diagnosed by double-balloon enteroscopy.
Endoscopy.2007;39 Suppl 1:E134---5.
3. Mandelli G, Radaelli F, Amato A, Terreni N, Paggi S, Spinzi
G,et al. The spectrum of small-bowel lesions of AL-type
amy-loidosis at capsule endoscopy. Endoscopy. 2009;41 Suppl 2:
E51---2.
4. Pollack MJ, Isenberg GA. Isolated small bowel amyloidosisseen
with capsule endoscopy. Gastrointest Endosc. 2007;66:829---30.
http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0005http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0010http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0015http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0020http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0025http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0030http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0035http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0040http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0045http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0050http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0055http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0060http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0065http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0070
-
1
Amiloidose gastrointestinal
15. Hokama A, Kishimoto K, Azama K, Chinen H, Kinjo F, KatoS, et
al. An unusual cause of haematochezia. Gut. 2010;59:793.
16. Dray X, Treton X, Joly F, Lavergne-Slove A, Uzunhan Y,
ChicheA, et al. Hemorrhagic bullous colitis as a primary
mani-festation of AL amyloidosis. Endoscopy. 2006;38 Suppl
2:E15---6.
1
271
7. Hui YT, Lam TW, Yee Lam PW, Yan Wu WH, Lam WM.
Narrow-bandimaging system with magnifying endoscopy for rectal
amyloido-sis. Gastrointest Endosc. 2008;68:400---1.
8. Munford AD, O′Donnel J, Gillmore JD, Manning RA, HawkinsPN,
Laffan M. Bleeding symptoms and coagulation abnor-malities in 337
patients with AL-amyloidosis. Br J Hematol.2000;110:454---60.
http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0075http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0080http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0085http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090http://refhub.elsevier.com/S0872-8178(13)00111-2/sbref0090
Amiloidose gastrointestinalIntroduçãoCaso
clínicoDiscussãoConclusãoResponsabilidades éticasProteção de
pessoas e animaisConfidencialidade dos dadosDireito à privacidade e
consentimento escrito
Conflito de interessesBibliografia