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Saiba tudo sobre Doença de Crohn

A doença de Crohn é uma doença inflamatória crônica transmural que normalmente afeta o íleo distal e o cólon, mas pode ocorrer em qualquer parte do trato GI. Os sintomas incluem diarreia e dor abdominal. Abscessos, fístulas internas e externas e obstruções intestinais podem estar presentes. Sintomas extraintestinais, particularmente artrite, podem ocorrer. O diagnóstico é feito por colonoscopia e estudos de imagem. O tratamento é feito com 5-AAS, corticoides, imunomoduladores, anticitocinas, antibióticos e, com frequência, cirurgia.

Fisiopatologia

A doença começa com inflamação das criptas e dos abscessos, que progridem para pequenas úlceras aftoides. Essas lesões da mucosa podem evoluir para úlceras profundas transversais e longitudinais com edema mucoso entre as úlceras, criando, no intestino, aspecto característico de pedra de calçamento.

Visão geral da doença de Crohn
Visão geral da doença de Crohn

A disseminação transmural da inflamação causa linfedema e espessamento da parede intestinal e do mesentério. A gordura mesentérica tipicamente se estende à superfície serosa do intestino. Linfonodos mesentéricos com frequência aumentam de tamanho. Inflamação extensa pode resultar em hipertrofia muscular, fibrose e estenose, que podem causar obstrução intestinal.

Abscessos são comuns e fístulas frequentemente penetram estruturas vizinhas, incluindo outras alças intestinais, bexiga ou o músculo psoas. As fístulas podem mesmo se estender para a pele do abdome anterior ou flancos. Independentemente da atividade da doença intra-abdominal, abscessos e fístulas perianais ocorrem em 25 a 33% dos casos; essas complicações são frequentemente o aspecto mais preocupante da doença de Crohn.

Granulomas não caseosos podem ocorrer em linfonodos, peritônio, fígado e todas as camadas da parede intestinal. Embora patognomônicos quando presentes, os granulomas não são detectados em aproximadamente metade dos pacientes com doença de Crohn. Sua presença parece não ter relação com o curso clínico.

Os segmentos afetados do intestino são precisamente diferenciados das áreas adjacentes normais (chamadas áreas poupadas), daí o nome enterite regional.

Cerca de 35% dos casos de doença de Crohn envolvem apenas o íleo (ileíte).

Cerca de 45% envolvem o íleo e colo (ileocolite), com uma predileção pelo lado direito do colo.

Cerca de 20% envolvem somente o colo (colite granulomatosa), a maioria dos quais, ao contrário da colite ulcerativa, poupam o reto.

Ocasionalmente, todo o intestino delgado está envolvido (jejunoileíte). Raramente, o estômago, o duodeno e o esôfago são clinicamente envolvidos, embora evidências microscópicas de doenças muitas vezes sejam detectáveis no antro gástrico, especialmente em pacientes jovens. Na ausência de intervenção cirúrgica, a doença não se estende para áreas do intestino delgado que não estavam inicialmente envolvidas na ocasião do diagnóstico inicial.

Ileíte de Crohn
Ileíte de Crohn
IMAGEM FORNECIDA POR DAVID M. MARTIN, MD.
Úlcera do íleo na doença de Crohn
Úlcera do íleo na doença de Crohn
IMAGEM CEDIDA POR DRS. AARON E. WALFISH E RAFAEL A. CHING COMPANIONI.

Classificação

A doença de Crohn é classificada em 3 padrões principais: (1) primariamente inflamatória, que depois de vários anos costuma evoluir para (2) primariamente estenótica ou obstrutiva ou (3) primariamente penetrante ou fistulizante.

Esses diferentes padrões clínicos ditam as diferentes estratégias terapêuticas. Alguns estudos genéticos sugerem uma base molecular para essa classificação.

Complicações

Existe risco aumentado de câncer nos segmentos de intestino delgado afetados. Pacientes com acometimento colônico têm, a longo prazo, risco de câncer colorretal semelhante ao da colite ulcerativa, quando apresentam a mesma extensão e duração da doença. A má absorção crônica pode causar deficiências nutricionais, particularmente das vitaminas D e B12.

Megacólon tóxico é uma complicação rara da doença de Crohn colônica. É uma síndrome clínica do íleo acompanhada por evidência radiográfica de dilatação colônica; muitos casos devem ser tratados agressivamente com intervenção cirúrgica.

Sinais e sintomas

As manifestações iniciais mais comuns da doença de Crohn são:

Diarreia crônica com dor abdominal, febre, anorexia e perda ponderal

O abdome é sensível e uma massa ou distensão pode ser palpável.

Sangramento retal abundante não é usual, excetuando-se casos de doença colônica isolada, que pode se apresentar de maneira similar à colite ulcerativa. Alguns pacientes se apresentam com abdome agudo que simula apendicite aguda ou obstrução intestinal. Cerca de 33% dos pacientes têm doenças perianais (em especial, fissuras e fístulas), que são algumas vezes as queixas mais proeminentes ou mesmo iniciais.

Em crianças, as manifestações extra intestinais frequentemente predominam em relação aos sintomas gastrointestinais; artrite, FOD, anemia ou retardamento do crescimento podem ser o sintoma de apresentação, enquanto a dor abdominal ou diarreia podem estar ausentes.

Com a recorrência da doença, os sintomas variam. A dor é o mais comum e ocorre como recorrência simples ou mesmo com formação de abscessos. Os pacientes com graves apresentações ou abscessos são mais propensos a apresentarem desconforto, descompressão brusca e aparência geral de toxemia. Segmentos estenosados podem causar obstrução colônica, com dor em cólica, distensão, obstipação e vômitos. Aderências de cirurgias anteriores também podem causar obstrução intestinal, que começa rapidamente, sem pródromos de febre, dor e indisposição típicos da obstrução por causa da doença de Crohn. Fístula enterovesical pode provocar bolhas de ar na urina (pneumatúria). Fístulas cutâneas podem estar presentes. A perfuração livre para a cavidade peritoneal é rara.

Doença crônica causa uma variedade de sintomas sistêmicos, incluindo febre, perda ponderal, má nutrição e manifestações extraintestinais.

Diagnóstico

Radiografias com bário do intestino delgado

TC do abdome (convencional ou enterografia por TC)

Algumas vezes, enema baritado, enterografia por ressonância magnética, endoscopia alta, colonoscopia e/ou endoscopia por vídeo-cápsula

A doença de Crohn deve ser considerada suspeita em pacientes com sintomas inflamatórios ou obstrutivos ou em pacientes sem sintomas gastrointestinais proeminentes, mas com abscessos ou fístulas perianais ou, do contrário, com artrite inexplicada, eritema nodoso, febre, anemia ou (em crianças) crescimento retardado. História familiar da doença de Crohn também aumenta a suspeita.

Sinais e sintomas similares (p. ex., dor abdominal, diarreia) podem ser causados por outras doenças gastrointestinais, especialmente colite ulcerativa. A diferenciação da colite ulcerativa pode ser difícil em 20% dos casos em que a doença de Crohn está confinada ao cólon. Entretanto, em razão de o tratamento ser similar, essa distinção é crítica somente quando cirurgia ou terapia experimental for contemplada.

Pacientes com quadro de abdome agudo (seja inicialmente ou durante uma recaída) devem ser submetidos à radiografia abdominal em pé e deitado e à TC do abdome. Esses estudos demonstram obstrução, abscessos ou fístulas e outras possíveis causas de abdome agudo (p. ex., apendicite). A ultrassonografia pode delinear melhor a patologia ginecológica em mulheres com dor abdominal ou pélvica inferior.

Se a apresentação inicial for menos aguda, preferem-se séries de trânsito intestinal com incidências específicas para íleo terminal à tomografia computadorizada convencional. No entanto, novas técnicas de enterografia por TC ou ressonância magnética, que combinam TC ou RNM de alta resolução com ingestão de grandes volumes de contraste, estão se tornando os procedimentos de escolha em alguns centros. Esses exames são praticamente diagnósticos caso mostrem presença de estenoses ou fístulas com a concomitante separação das alças intestinais.

Se os achados forem questionáveis, enteróclise por TC ou videocápsula endoscópica podem revelar úlceras aftoides e lineares. Radiografia com bário contrastado do enema pode ser usada se os sintomas parecerem predominantemente colônicos (p. ex., diarreia) e pode mostrar refluxo do bário no íleo terminal com irregularidade, nodularidade, rigidez, espessamento de parede e lúmen estreitado. Achados radiológicos semelhantes ocorrem em câncer de ceco, carcinoide ileal, linfossarcoma, vasculite sistêmica, enterite actínica, tuberculose ileocecal e ameboma.

Em casos atípicos (p. ex., diarreia predominante, com mínima dor), a avaliação é similar à suspeita de colite ulcerativa, com colonoscopia (incluindo biópsias, amostras para patógenos entéricos e, quando possível, visualização do íleo terminal). Endoscopia digestiva alta pode identificar envolvimento gastrointestinal mesmo na ausência de sintomas gastrointestinais.

Exames laboratoriais

Exames laboratoriais devem ser feitos para pesquisa de anemia, hipoalbuminemia e anormalidades de eletrólitos. Testes de função hepática devem ser feitos; fosfatase alcalina e gamaglutamil transpeptidase elevadas em pacientes com grande envolvimento colônico sugerem possível colangite esclerosante primária. Leucocitose ou níveis elevados de reagentes de fase aguda (p. ex., velocidade de hemossedimentação, proteína C-reativa) são inespecíficos, mas podem ser usados de maneira seriada para monitorar a atividade da doença.

Para detectar deficiências nutricionais, os níveis de vitamina D e B12 devem ser verificados a cada 1 a 2 anos. Pode-se realizar exames laboratoriais adicionais, como a determinação dos níveis de vitaminas hidrossolúveis (ácido fólico e niacina), vitaminas lipossolúveis (A, D, E e K) e minerais (zinco, selênio e cobre), quando houver suspeita de deficiências.

A densidade mineral óssea de todos os pacientes com doença inflamatória intestinal (DII), homens ou mulheres, jovens ou idosos, deve ser monitorada, geralmente por densitometria óssea (DXA).

Anticorpos citoplásmicos antineutrofílicos perinucleares estão presentes em 60 a 70% dos pacientes com colite ulcerativa e em somente 5 a 20% dos pacientes com doença de Crohn. Anticorpos anti-Saccharomyces cerevisiae são relativamente específicos para a doença de Crohn. Entretanto, esses testes não separam de maneira segura as 2 doenças, mas eles são recomendados para diagnóstico de rotina. Anticorpos adicionais como anti-OmpC e anti-CBir1 estão agora disponíveis, mas a importância clínicas desses testes complementares é incerta; alguns estudos sugerem que títulos elevados desses anticorpos têm implicações prognósticas adversas.

Prognóstico

Uma vez confirmada, a doença de Crohn raramente é curada e é caracterizada por episódios intermitentes de exacerbações e remissões. Alguns pacientes apresentam doença grave com períodos frequentes de dor debilitante. Entretanto, com terapia clínica e cirúrgica judiciosa, muitos pacientes evoluem bem e se adaptam com sucesso. A mortalidade relacionada à doença é bem baixa. Câncer gastrointestinal, incluindo câncer de cólon e intestino delgado, é a principal causa de mortalidade associada à doença de Crohn. Complicações tromboembólicas (especialmente durante a colite de Crohn ativa) também podem causar morte. Cerca de 10% das pessoas tornam-se incapacitadas pela doença de Crohn e complicações que ela causa.

Tratamento

Loperamida ou antiespasmódicos para alívio sintomático

Ácido 5-aminosalicílico (5-AAS) ou antibióticos

Outros fármacos, dependendo dos sintomas e gravidade

Algumas vezes, cirurgia

Detalhes sobre medicações específicas e posologia são discutidos em Fármacos para doença intestinal inflamatória.

Tratamento geral

Cólicas e diarreia podem ser aliviadas pela administração oral de loperamida (de preferência antes das refeições), 2 a 4 mg, até 4 vezes/dia. Esse tratamento sintomático é seguro, exceto em casos de colite de Crohn aguda e grave, que pode evoluir para megacólon tóxico, assim como na colite ulcerativa. Muciloides hidrofílicos (p. ex., metilcelulose ou preparações com psílio) às vezes ajudam a prevenir irritação anal pelo aumento da consistência fecal. Dietas ricas em fibras devem ser evitadas nos casos de doença estenosante ou de inflamação colônica ativa.

Deve-se enfatizar medidas para a manutenção de rotina da saúde (p. ex., imunizações, triagem para câncer).

Doença leve a moderada

Esta categoria é de pacientes ambulatoriais que toleram a ingestão oral e não apresentam sinais de toxemia, desconforto abdominal, massa ou obstrução. O 5-AAS (mesalamina) é comumente usado como terapia de primeira linha. O Pentasa® é preferido para doença do intestino delgado, e o Asacol® HD é preferido para a doença íleo distal e colônica. Contudo, os benefícios de qualquer fármaco 5-AAS para a doença de Crohn do intestino delgado são modestos, e muitos especialistas não defendem usá-lo na doença de Crohn do intestino delgado.

Os antibióticos são considerados agentes de primeira linha por alguns médicos, ou podem ser reservados a pacientes que não respondam a 4 semanas de 5-AAS; seu uso é estritamente empírico. Com qualquer desses fármacos há necessidade de 8 a 16 semanas de tratamento.

Os pacientes responsivos devem passar para a terapia de manutenção.

Doença moderada a grave

Os pacientes sem fístulas ou abscessos, mas com dor significativa, desconforto, febre ou vômitos ou aqueles que não responderam ao tratamento para doença leve, frequentemente têm alívio rápido dos sintomas quando recebem corticoides, orais ou parenterais. Prednisona ou prednisolona oral pode agir mais rapidamente e de maneira mais confiável que a budesonida oral; mas budesonida têm relativamente menos efeitos adversos e é considerada o corticosteroide de escolha em muitos centros, especialmente na Europa.

Pacientes que não respondem rapidamente aos corticoides, ou nos quais não é possível diminuir a dose em poucas semanas, não devem ser mantidos nesses fármacos e exigem terapia diferente.

Um antimetabólito (azatioprina, 6-mercaptopurina ou metotrexato), um agente anti-FNT (infliximabe, adalimumabe ou certolizumabe pegol), ou uma combinação de ambos, podem ser utilizados como terapia de 2ª linha depois dos corticoides, e mesmo como tratamento de primeira linha em vez de corticoides. Esses fármacos, orientados por medições dos níveis de fármacos e anticorpos, são clinicamente bem-sucedidos na maior parte dos casos. Quando essas linhas de tratamento falham em pacientes para os quais a cirurgia não é viável ou adequada, pode-se usar fármacos biológicos mais recentes, incluindo anti-integrinas (p. ex., natalizumabe e vedolizumabe) ou um anticorpo anti-IL-12/23 (p. ex., ustecinumabe). Além disso, outros agentes biológicos estão surgindo rapidamente.

A obstrução é manuseada inicialmente com colocação de sonda nasogástrica e líquidos intravenosos. Obstrução por causa de doença de Crohn não complicada deve desaparecer em poucos dias e, portanto, não requer terapia anti-inflamatória nem nutrição parenteral; mas a ausência de uma resposta imediata indica uma complicação ou outra etiologia e exige cirurgia imediata.

Doença fulminante ou abscessos

Os pacientes com toxemia, febre alta, vômitos persistentes, descompressão brusca positiva ou massa palpável devem ser hospitalizados para administração de líquidos IV e antibióticos. Os abscessos devem ser drenados, seja por via percutânea ou cirurgicamente. Os corticoides IV ou agentes biológicos só devem ser administrados quando a infecção foi descartada ou controlada. Caso não haja resposta à corticoterapia em 5 a 7 dias, indica-se a cirurgia, geralmente.

Fístulas

Fístulas perianais são inicialmente tratadas com metronidazol e ciprofloxacino. Os pacientes que não respondem em 3 a 4 semanas podem receber um imunomodulador (p. ex., azatioprina, 6-mercaptopurina), com ou sem um regime de indução de infliximabe ou adalimumabe para resposta mais rápida. A terapia anti-FNT (infliximabe ou adalimumabe) também pode ser utilizada isoladamente. Ciclosporina ou tacrolimo são alternativas, mas as fístulas geralmente retornam após o tratamento.

A colocação de cola de fibrina guiada por ultrassom endoscópico ou o uso de um dreno seton (um pedaço de material de sutura temporariamente mantido na fístula para permitir a drenagem) pode ajudar alguns pacientes com fístulas perianais mais complexas ou refratárias. Fístulas perianais refratárias podem necessitar de colostomia temporária, mas quase sempre recidivam após a reconexão; portanto, a diversão é considerada, mais apropriadamente, uma preparação para cirurgia definitiva ou, na melhor das hipóteses, um adjuvante ao infliximabe ou adalimumabe em vez de um tratamento primário.

Terapia de manutenção

Pacientes que requerem somente 5-AAS ou um antibiótico para alcançar a remissão podem ser mantidos com esse fármaco. Pacientes que necessitam de tratamento agudo com corticoides ou agentes anti-FNT tipicamente precisam de azatioprina, 6-mercaptopurina, metotrexato, terapia anti-FNT ou uma combinação de terapias para manutenção. Muitos, se não a maioria, dos pacientes que alcançam remissão com um anti-FNT exigirão aumento da dose ou diminuição dos intervalos de tratamento dentro de 1 ou 2 anos. Os corticoides de ação sistêmica ativa não são seguros e nem eficazes para manutenção a longo prazo, embora a budesonida tenha mostrado adiar as recaída com menos efeitos adversos. Pacientes que respondem à terapia anti-FNT contra doença aguda, mas que não se mantêm bem com antimetabólitos, podem permanecer em remissão com doses repetidas de agentes anti-FNT.

O monitoramento durante a remissão pode ser feito acompanhando os sintomas e fazendo exames de sangue e não exige testes radiológicos ou colonoscopia de rotina (além de vigilância regular para displasia depois de 7 a 8 anos da doença).

Cirurgia

Embora cerca de 70% dos pacientes essencialmente exijam, em última análise, uma cirurgia, esta é frequentemente realizada de maneira relutante. Ela é mais indicada para obstruções intestinais recidivantes ou em fístulas e abscessos intratáveis. A ressecção do intestino envolvido pode melhorar os sintomas, mas não cura a doença, já que a doença de Crohn tende a recorrer mesmo depois da ressecção de todo o segmento aparentemente enfermo.

A taxa de recidiva, definida por lesões endoscópicas no local da anastomose, é

> 70% em 1 ano

> 85% em 3 anos

Definida por sintomas clínicos, a taxa de recorrência é de cerca de

25 a 30% em 3 anos

40 a 50% em 5 anos

Em geral, nova cirurgia é necessária em cerca de 50% dos casos. Entretanto, os índices de recorrência parecem ser reduzidos por profilaxia precoce antes da cirurgia com 6-mercaptopurina ou azatioprina, metronidazol ou infliximabe. Quando a cirurgia é realizada com indicações precisas, quase todos os pacientes experimentam melhora da qualidade de vida.

Como o tabagismo aumenta o risco de recorrência, especialmente em mulheres, deve-se incentivar que o paciente pare de fumar.

Fonte: Por Aaron E. Walfish , MD, Mount Sinai Medical Center;

Rafael Antonio Ching Companioni , MD, Icahn School of Medicine, Elmhurst Hospital Center

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Summary

A doença de Crohn é uma doença inflamatória crônica transmural que normalmente afeta o íleo distal e o cólon, mas pode ocorrer em qualquer parte do trato GI. Os sintomas incluem diarreia e dor abdominal.

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