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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: mariajoao.80@hotmail.com (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:mariajoao.80@hotmail.comdx.doi.org/10.1016/j.jpg.2013.09.005

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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/

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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.

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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

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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

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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.

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Amiloidose gastrointestinalIntroduçãoCaso clínicoDiscussãoConclusãoResponsabilidades éticasProteção de pessoas e animaisConfidencialidade dos dadosDireito à privacidade e consentimento escrito

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