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6052309 – RX REV. ARQUIVOS GASTRO ED. 02/2011

Arquivos de Gastroenterologia • Volume 48 • Número 2 • 2011 • p.89-166

Publication of the Brazilian Institute for Studies and Research in Gastroenterology and others Specialities - IBEPEGE

2

número

abril/junho 2011 volume 48

Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia e outras Especialidades - IBEPEGE Brazilian Institute for Studies and Research in Gastroenterology and others Specialities Colégio Brasileiro de Cirurgia Digestiva - CBCD Brazilian College of Digestive Surgery Sociedade Brasileira de Motilidade Digestiva - SBMD Brazilian Digestive Motility Society Federação Brasileira de Gastroenterologia - FBG Brazilian Federation of Gastroenterology Sociedade Brasileira de Hepatologia Brazilian Hepatology Society Sociedade Brasileira de Endoscopia Digestiva Brazilian Digestive Endoscopy Society

GASTROv48n2_capa.indd 1

31/05/11 18:03


No Tratamento da Sii

Preço é um fator importante para adesão ao tratamento 1

0 6 IS s o d i m i compr

O nosso tratamento para o alívio da dor abdominal do seu paciente.3,4

A o M c i é m ô n o c e

*

ado com s2 r a p m o c o quando 30 comprimid o d i m i r e p d por com 100mg *Custo ção de Siilif* enta a apres

Contraindicações: hipersensibilidade conhecida aos componentes da fórmula. Interaçõesmedicamentosas:osestudosrealizadosnãodemonstraraminterações medicamentosas com nenhum dos seguintes tratamentos concomitantemente prescritos: hipoglicemiantes orais, anticoagulantes e digitálicos. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. Este material é destinado aos profissionais de saúde habilitados a prescrever ou dispensar tais produtos. Fevereiro/2011.

comprimidos

Também nas apresentações: • 50mg com 30 comprimidos • 100mg com 30 comprimidos

Referências bibliográficas: 1) Sabaté E (org.) Adherencia a los tratamientos a largo plazo: pruebas para la acción. [online]. Organización Mundial de la Salud. 2004 [acesso em 23 nov. 2010]. Disponível em: http://www.paho.org/Spanish/ad/dpc/nc/adherencia-largo-plazo.pdf. 2) Revista Kairos, nov. 2010. 3) Guslandi M. Profilo farmacologico clinico del pinaverio bromuro. Minerva Med. 1994;85:179-85. 4) Siilif*[Bula]. São Paulo: Nycomed Pharma. SIILIF* - brometo de pinavério - USO ADULTO - Apresentações e composição: Comprimido revestido de 50 mg em embalagens com 30 unidades. Comprimido revestido de 100 mg em embalagens com 10, 30 e 60 unidades. Indicações: Tratamento sintomático da dor ou desconforto abdominal, dos distúrbios da frequência ou consistência das evacuações (constipação ou diarréia) e da distensão abdominal, decorrentes dos transtornos funcionais do intestino (SII). Tratamento sintomático das dores decorrentes dos transtornos funcionais das vias biliares. Preparação de enemas opacos. Contraindicações: hipersensibilidade conhecida aos componentes da fórmula. Precauções e advertências: É desaconselhável a utilização do brometo de pinavério durante a gravidez. Além disso, deve-se observar a presença de bromo, cuja administração no final da gravidez pode causar alterações neurológicas no recém-nascido (hipotonia, sedação). Em função da falta de estudos, recomenda-se não utilizar o brometo de pinavério durante a lactação. Interações medicamentosas: os estudos realizados não demonstraram interações medicamentosas com nenhum dos seguintes tratamentos concomitantemente prescritos: hipoglicemiantes orais, anticoagulantes e digitálicos. Reações adversas: foram relatados, raramente, alguns casos de alterações digestivas leves e casos isolados de reações cutâneas, algumas do tipo alérgico. Raramente pode haver agravamento da constipação e epigastralgia. Em casos de erupção cutânea, é conveniente interromper a administração do medicamento. Posologia: recomenda-se a administração de 1 comprimido de 50 mg, 3 ou 4 vezes ao dia, ou 1 comprimido de 100 mg, 2 vezes ao dia (manhã e noite). Excepcionalmente, a posologia pode ser aumentada para 6 comprimidos de 50 mg ou 3 comprimidos de 100 mg ao dia. Os comprimidos devem ser deglutidos inteiros, sem mastigar, com um pouco de água, imediatamente antes ou durante as refeições. Na preparação de enemas opacos, a posologia é de 2 comprimidos diários de 100 mg ou 4 comprimidos diários de 50 mg, nos 3 dias anteriores ao exame. MEDICAMENTO SOB PRESCRIÇÃO. MS - Registro MS – 1.0639.0254. SICO_NSPC_1209 Material de distribuição exclusiva à classe médica. Nycomed Pharma Ltda. Rua do Estilo Barroco, 721 - 04709-011 - São Paulo - SP. Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes. * Marca Depositada.

O brometo de pinavério da Nycomed anuncio.indd 1 1971-SI-anuncio duplo-OK.indd 1 GASTROv48n2_capa.indd 2

28/07/10 25/02/11 14:43 17:58

31/05/11 18:03


Certos momentos pedem que você fique sentado. E sem nenhum desconforto. Alívio rápido da dor e CICATRIZAÇÃO das lesões anorretais.1,2

Referências: 1. Espinosa DJ. Revisión analítica de estudios multicentricos con policresuleno en patologia hemorroidal. Acta Gastroentestinal Latinoamericana. 2000; 30(3): 177− 186. 2. Arnold K, Abele I, Auel H. Multicenter clinical study of a new non−steroid preparation in proctology. Arzneimittel−Forschung Drug Res.1976;26(1):95−9. 3. Seppaner J, Mattinen P. Salo H. Experience of the topical use of Faktu ointment in the treatment of various conditions and postoperative wounds in the anorectal region. Diagnosis. 1979; 4: 449−452. 4. Proctyl® [Bula]. São Paulo: Nycomed Pharma. PR00_0807_0808

Indicações: hemorroidas, fissuras anais, pruridos e eczemas anais. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO PROCTYL® É UM MEDICAMENTO. SEU USO PODE TRAZER RISCOS. PROCURE O MÉDICO E O FARMACÊUTICO. LEIA A BULA. EM CASO DE DÚVIDAS LIGUE GRATUITAMENTE

SAC:0800-77100345

www.nycomed.com.br

Nycomed Pharma Ltda. Rua do Estilo Barroco, 721 - CEP 04709-011 - São Paulo - SP Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes. Material exclusivo para a classe médica.

Março/2011

Registro MS − 1.0639.0111


Lançamento

INOVANDO E AMPLIANDO HORIZONTES

adesão adesão é um fator importante para o sucesso do tratamento da retocolite

Preferência dos pacientes quanto à meses. posologia Não adesão e risco de recidiva em 24 da mesalazina no tratamento da rcUi 100

% Pacientes

80

82%

n: 380

60 40

14%

20 0

Preferem 1x ao dia

2%

2%

Sem preferência Preferem 3x ao dia Nenhum Comentário

1


Lançamento Uma Dose Diária2-4

No tratamento da RETOCOLITE ULCERATIVA2,5

O que é a TECNOLOGIA MMX?

Comprimidos gastrorresistentes (Eudragit-S®)

1

Componentes hidrofílicos

2 3

Componentes lipofílicos

o exclusivo revestimento garante a liberação prolongada de 5-asa por todo o cólon com uma dose diária. 5-8


INOVANDO E AMPLIANDO HORIZONTES

MaNHã

Manutenção indução à remissão

9-11

1,5,12

MESACOL® MMX 2400 mg/dia 1x ao dia MESACOL® MMX 4800 mg/dia 1x ao dia

tarde

Noite

liberação prolongada MMX, gastrorresistente


Lançamento

INOVANDO E AMPLIANDO HORIZONTES Uma Dose Diária2-4

No tratamento da RETOCOLITE ULCERATIVA2,5

Nã op gen o éricssui o 13

Manutenção 9-11 Mesacol® MMX 2400mg/dia 1x ao dia

indução à remissão 1,5,12 Exclusiva Tec no lo

14

g i a M MX

Mesacol® MMX 4800mg/dia 1x ao dia

Mesacol® MMX* não é recomendado em casos de hipersensibilidade  a salicilatos. A administração da mesalazina pode potencializar a toxicidade do metotrexato. Referências bibliográficas: 1) Kruis W, et al. Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomized, non-inferiority trial. Gut. 2009;58(2):233-40. 2) Mesacol® MMX* [Bula]. São Paulo: Nycomed Pharma. 3) Lakatos PL. Use of new once-daily 5-aminosalicylic acid preparations in the treatment of ulcerative colitis: Is there anything new under the sun? World J Gastroenterol 2009; 15(15):1799-1804. 4) D’Haens GD, et al. Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study. Aliment Pharmacol Ther. 2006;24:1087-97. 5) Kamm MA, et al. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology. 2007;132:66-75. 6) Tenjarla S, et al. Release of 5-aminosalicylate from na MMX meslaminr tablet during transit throught a simulated gastrointestinal tract system. Adv Ther. 2007;24(4):826-40. 7) Brunner M, et al. Gastrointestinal transit and 5-ASA release from a new mesalazine extended-release formulation. Aliment Pharmacol Ther 2003;17:395-402. 8) Prantera C, et al. A new oral delivery system for 5-ASA: preliminary clinical findings for MMx. Inflamm Bowel Dis 2005;11:421-7. 9) Kamm MA, et al. Randomised trial of once- or twice-daily MMX mesalazine for maintenance of remission in ulcerative colitis. Gut. 2008;57(7):893-902. 10) Kamm MA, et al. MMX meslazine is well tolerated during 12 month’s maintenance treatment of mild to moderate ulcerative colitis. 11) C. Prantera, et al. Clinical trial: ulcerative colitis maintenance treatment with 5-ASA: a 1-year, randomized multicentre study comparing MMX with Asacol. Aliment Pharmacol Ther. 2009; 30: 908-918. 12) Lichtenstein GR, et al. Effect of once or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol. 2007;5:95-102. 13) Lista de genéricos. Guia da Farmácia. 2011 marc;18(220 Supl):2-32. 14) Hu MY, Peppercorn MA. MMX mesalamine: a novel high-dose, once-daily 5-aminosalicylate formulation for the treatment of ulcerative colitis. Expert Opin Pharmacother. 2008;9(6):1049-58. Mesacol® MMX* - mesalazina - Uso adulto - Apresentações e composição: Comprimidos revestidos de liberação prolongada, com 1,2 g de mesalazina cada. Embalagens com 10 e 30 unidades. Indicações: antiinflamatório de ação local no tratamento da colite ulcerativa ativa leve a moderada, na fase aguda (indução da remissão) e na manutenção da remissão. Contra-indicações: Este medicamento não deve ser usado por pacientes com história de hipersensibilidade aos salicilatos (que inclui o ácido acetilsalicílico), à mesalazina, à sulfassalazina ou a qualquer dos componentes da fórmula; pacientes com insuficiência hepática e/ou renal graves; pacientes com úlcera gástrica e duodenal ativa; pacientes com tendência elevada a sangramento. Este medicamento é contra-indicado para menores de 18 anos. Precauções e advertências: As mesmas precauções e advertências relacionadas com o uso de preparações contendo mesalazina ou pró-drogas de mesalazina devem ser consideradas para Mesacol® MMX*. Assim como todos os salicilatos, a mesalazina deve ser utilizada com cautela em pacientes com história de úlcera gástrica ou duodenal, por pacientes asmáticos (em função das reações de hipersensibilidade), com disfunção renal ou hepática (leve a moderada), ou com história de miocardite ou pericardite. Mesalazina não é recomendada para pacientes com disfunção renal grave e deve-se ter cautela com pacientes com níveis sangüíneos aumentados de uréia ou com proteinúria. A mesalazina é rapidamente excretada pelos rins, principalmente o seu metabólito ácido N-acetil-5-aminossalicílico. Em ratos, altas doses da mesalazina, administradas por via intravenosa, causaram toxicidade tubular e glomerular. Em caso de aparecimento de disfunção renal durante o tratamento deve-se suspeitar de nefrotoxicidade induzida pela mesalazina. Nestes casos é recomendado monitorar a função renal, especialmente no início do tratamento. Durante tratamento prolongado, é também necessário monitorar regularmente a função renal (creatinina sérica). Ainda não está estabelecida a segurança do produto em crianças. Gravidez e lactação: Mesacol® MMX* está classificado na Categoria B de risco de fármacos destinados ao uso em grávidas. O produto, a princípio, não deve ser empregado em gestantes e lactantes, exceto quando absolutamente necessário. A segurança de Mesacol® MMX* para uso durante a gravidez ou a amamentação ainda não foi estabelecida, mas sabe-se que a mesalazina atravessa a placenta e é excretada pelo leite materno em pequenas quantidades. Estudos pré-clínicos não revelaram evidência de efeitos teratogênicos ou de toxicidade fetal oriundos da mesalazina, nem na evolução da gestação ou no desenvolvimento perinatal e pós-natal. A pequena experiência de uso da mesalazina em outras formulações durante a gravidez não mostrou efeito prejudicial ao feto; entretanto, a mesalazina deve ser usada com cautela durante a gravidez e somente quando os benefícios para a mãe forem superiores aos riscos potenciais ao feto. Baixas concentrações de mesalazina e de seu metabólito N-acetilado foram detectadas no leite materno, mas o significado clínico desta evidência ainda não foi determinado. Portanto, deve-se ter cautela na administração da mesalazina a lactantes. Categoria B de risco na gravidez – Este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do cirurgião-dentista. Pacientes pediátricos: Devido à falta de dados sobre a administração da mesalazina em altas doses na população pediátrica, Mesacol® MMX* não é recomendado para pacientes menores de 18 anos. Pacientes idosos: Não existe experiência suficiente sobre o uso de Mesacol® MMX* em pacientes com idade acima de 65 anos. No entanto, não foram identificadas diferenças entre o uso em pacientes mais jovens e em idosos com outras formulações de mesalazina. Pacientes com insuficiência renal: não são disponíveis informações sobre o uso em pacientes com insuficiência renal leve ou moderada. O medico deverá avaliar a relação risco/benefício para o seu uso. Pacientes com insuficiência hepática: não são disponíveis informações sobre o uso em pacientes com insuficiência hepática leve ou moderada. O medico deverá avaliar a relação risco/benefício para o seu uso. Dirigir e operar máquinas: É improvável que o uso deste medicamento tenha qualquer efeito na capacidade de dirigir veículos ou de usar máquinas. Interações medicamentosas: Nenhum estudo formal de interação foi conduzido. Não são disponíveis informações sobre interações entre Mesacol® MMX* e outros fármacos. Entretanto, existem relatos de interação entre a mesalazina (outras formulações) e outros medicamentos. O uso concomitante da mesalazina com agentes sabidamente nefrotóxicos, inclusive com os anti-inflamatórios não-hormonais (AINHs – como aspirina, ibuprofeno, diclofenaco, etc.) e azatioprina, pode aumentar o risco de reações renais; o potencial para discrasias sangüíneas da azatioprina e da 6-mercaptopurina pode ser aumentado; a ação hipoglicemiante das sulfoniluréias pode ser intensificada; a atividade anticoagulante dos derivados cumarínicos (varfarina) pode ser reduzida; a toxicidade do metotrexato pode ser potencializada; o efeito uricosúrico da probenecida e da sulfimpirazona pode ser diminuído, assim como a ação diurética da furosemida e da espironolactona e a ação tuberculostática da rifampicina. Em tese, a administração concomitante de anticoagulantes orais deve ser feita com cautela. Substâncias como a lactulose, que diminuem o pH do cólon, podem reduzir a liberação da mesalazina dos comprimidos revestidos de Mesacol® MMX*. Reações adversas: A maioria das reações adversas relatadas com Mesacol® MMX* foi transitória, e de intensidade leve a moderada. Foram descritas as seguintes reações adversas, distribuídas em grupos de freqüências: Reação comum (> 1/100 e < 1/10): Gastrintestinal: Flatulência e Náusea. Sistema Nervoso: Cefaléia. Estas reações ocorreram em menos de 3% dos pacientes, independente da dose administrada. Reação incomum (> 1/1.000 e < 1/100): Gastrintestinal: vômito, dor abdominal, distensão abdominal, diarréia, dispepsia, pancreatite, colite e pólipo retal. Hepatobiliar: aumento das transaminases, anormalidades no teste da função hepática. Sistema nervoso: tontura, sonolência, tremores. Cardiovascular: taquicardia, hipertensão e hipotensão arterial. Respiratório: dor faringolaríngea. Ouvido e labirinto: otalgia. Pele e tecido subcutâneo: acne, alopécia, prurigo, urticária, exantema, prurido. Sangue e linfa: Redução do número de plaquetas. Musculosqueléticas: artralgia, lombalgia. Gerais: Astenia, fadiga, pirexia, edema da face. Posologia e modo de usar: Mesacol® MMX* é para uso exclusivo por via oral. Para o tratamentoda colite ulcerativa leve a moderada, a dose usual para adultos acima de 18 anos é de 2.400 mg a 4.800 mg (2 a 4 comprimidos) ao dia, administrada em dose única, de preferência sempre à mesma hora de cada dia, acompanhada de uma refeição. Caso o paciente esteja tomando a dose mais elevada (4.800 mg/dia), deve ser reavaliado após 8 (oito) semanas de tratamento. Não apresentando mais sintomas, pode-se prescrever uma dose diária de 2.400 mg (2 comprimidos) para prevenir a recorrência de novas crises da doença (manutenção da remissão). A duração recomendada é de 8 semanas consecutivas, salvo critério médico diferente. Este medicamento não deve ser partido, mastigado ou dissolvido. A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. MEDICAMENTO SOB PRESCRIÇÃO. Registro MS - 1.0639. 0248 MEMX_0109_1210_VP. Material destinado exclusivamente a profissionais habilitados a prescrever e/ou dispensar medicamentos. MESACOL® é Marca Registrada da Nycomed Pharma Ltda., MMX* é Marca Depositada de Giuliani S.p.A. Nycomed Pharma Ltda. Rua do Estilo Barroco, 721 - 04709-011 - São Paulo - SP Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes.


No Tratamento da Sii

O nosso tratamento para o alívio da dor abdominal do seu paciente

1,2

Reduz em até 93% o principal sintoma da Sii: a 1

DOR.

Fevereiro / 2011

3

Siilif* diminui a duração da dor de várias horas para alguns minutos. 4

Contraindicações: hipersensibilidade conhecida aos componentes da fórmula. Interações medicamentosas: os estudos realizados não demonstraram interações medicamentosas com nenhum dos seguintes tratamentos concomitantemente prescritos: hipoglicemiantes orais, anticoagulantes e digitálicos. SIILIF* - brometo de pinavério - USO ADULTO - Apresentações e composição: Comprimido revestido de 50 mg em embalagens com 30 unidades. Comprimido revestido de 100 mg em embalagens com 10, 30 e 60 unidades. Indicações: Tratamento sintomático da dor ou desconforto abdominal, dos distúrbios da frequência ou consistência das evacuações (constipação ou diarréia) e da distensão abdominal, decorrentes dos transtornos funcionais do intestino (SII). Tratamento sintomático das dores decorrentes dos transtornos funcionais das vias biliares. Preparação de enemas opacos. Contraindicações: hipersensibilidade conhecida aos componentes da fórmula. Precauções e advertências: É desaconselhável a utilização do brometo de pinavério durante a gravidez. Além disso, deve-se observar a presença de bromo, cuja administração no final da gravidez pode causar alterações neurológicas no recém-nascido (hipotonia, sedação). Em função da falta de estudos, recomendase não utilizar o brometo de pinavério durante a lactação. Interações medicamentosas: os estudos realizados não demonstraram interações medicamentosas com nenhum dos seguintes tratamentos concomitantemente prescritos: hipoglicemiantes orais, anticoagulantes e digitálicos. Reações adversas: foram relatados, raramente, alguns casos de alterações digestivas leves e casos isolados de reações cutâneas, algumas do tipo alérgico. Raramente pode haver agravamento da constipação e epigastralgia. Em casos de erupção cutânea, é conveniente interromper a administração do medicamento. Posologia: recomenda-se a administração de 1 comprimido de 50 mg, 3 ou 4 vezes ao dia, ou 1 comprimido de 100 mg, 2 vezes ao dia (manhã e noite). Excepcionalmente, a posologia pode ser aumentada para 6 comprimidos de 50 mg ou 3 comprimidos de 100 mg ao dia. Os comprimidos devem ser deglutidos inteiros, sem mastigar, com um pouco de água, imediatamente antes ou durante as refeições. Na preparação de enemas opacos, a posologia é de 2 comprimidos diários de 100 mg ou 4 comprimidos diários de 50 mg, nos 3 dias anteriores ao exame. MEDICAMENTO SOB PRESCRIÇÃO. MS - Registro MS – 1.0639.0254. Referências bibliográficas: 1) Guslandi M. Profilo farmacologico clinico del pinaverio bromuro. Minerva Med. 1994;85:179-85. 2) Siilif*®[Bula]. São Paulo: Nycomed Pharma. 3) Cain KC, et al. Abdominal pain impacts quality of life in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101(1):124-32. 4) Awad R, Dibildox M, Ortiz F. Irritable bowel syndrome treatment using pinaverium bromide as a calcium channel blocker. Acta Gastroenterol Latinoam. 1995;25(3):137-44.

SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. Material destinado exclusivamente à classe médica. Material exclusivo à classe médica. Nycomed Pharma Ltda. Rua do Estilo Barroco, 721 - 04709-011 - São Paulo - SP. Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes. * Marca Depositada.

O brometo de pinavério da Nycomed


EX

IV

A

APR E

O

NTAÇÃ SE

C LU

S


CONTENTS EDITORIAL 1541

Usefulness of proximal esophageal pH monitoring Roberto Oliveira DANTAS, 89

ORIGINAL ARTICLES 1542

Interstitial lung disease and gastroesophageal reflux disease: key role of esophageal function tests in the diagnosis and treatment Renato Vianna SOARES, Anne FORSYTHE, Kyle HOGARTH, Nadera J. SWEISS, Imre NOTH, Marco G. PATTI, 91

1543

Gastroesophageal reflux disease and vocal disturbances Maria Aparecida Coelho de Arruda HENRY, Regina Helena Garcia MARTINS, Mauro Masson LERCO, Lídia Raquel CARVALHO, Vânia Cristina LAMÔNICA-GARCIA, 98

1544

Does low dose 13C-urea breath test maintain a satisfactory accuracy in diagnosing Helicobacter pylori infection? Luiz Gonzaga Vaz COELHO, Arilto Eleutério da SILVA Jr, Maria Clara de Freitas COELHO, Francisco Guilherme Cancela e PENNA, Rafael Otto Antunes FERREIRA, Elisa Viana SANTA-CECÍLIA, 104

1545

Helicobacter pylori has no influence on distal gastric cancer survival Renata S. SANTOS, José E. V. LOURENÇO, Fernando Augusto Mardiros HERBELLA, Jose Carlos Del GRANDE, Marco G. PATTI, 109

1546

Nutritional profile of asymptomatic alcoholic patients Maria Beatriz SOBRAL-OLIVEIRA, Joel FAINTUCH, Dulce Reis GUARITA, Claudia P. OLIVEIRA, Flair J. CARRILHO, 112

1547

Prospective study of ultrasound with perflutrene contrast compared to magnetic resonance imaging in the diagnosis of hepatic hemangiomas Joel SCHMILLEVITCH, Luiz Arnaldo SZUTAN, Fábio Gonçalves FERREIRA, Maria de Fátima SANTOS, Ricardo MINCIS, Ana GORSKI, 119

1548

HBV and HCV serological markers in patients with the hepatosplenic form of mansonic schistosomiasis Jéfferson Luis de Almeida SILVA, Veridiana Sales Barbosa de SOUZA, Tatiana Aguiar Santos VILELLA, Ana Lúcia C. DOMINGUES, Maria Rosângela Cunha Duarte COÊLHO, 124

1549

Prevalence of celiac disease in siblings of Iranian patients with celiac disease Bashir CHOMEILI, Majid AMINZADEH, Amir Kamal HARDANI, Payam FATHIZADEH, Pooya CHOMEILI, Azarakhsh AZARAN, 131

1550

The value of high-resolution anoscopy in the diagnosis of anal cancer precursor lesions in HIV-positive patients Felicidad GIMENEZ, Ivan Tramujas da COSTA-e-SILVA, Adriana DAUMAS, José de ARAÚJO, Sara Grigna MEDEIROS Luiz FERREIRA, 136

ARCHIVES OF GASTROENTEROLOGY

ISSN 0004-2803 ISSN 1678-4219 – on-line Coden ARQGA

v. 48 – no.2 – Abr./Jun. 2011


EXPERIMENTAL GASTROENTEROLOGY 1551

Islet transplantation in rodents. Do encapsulated islets really work? Yngrid Ellyn Dias Maciel de SOUZA, Eleazar CHAIB, Patricia Graça de LACERDA, Alessandra CRESCENZI, Arnaldo BERNAL-FILHO, Luiz Augusto Carneiro D’ALBUQUERQUE, 146

1552

Hepatic and biochemical repercussions of a polyunsaturated fat-rich hypercaloric and hyperlipidic diet in Wistar rats Idália M. B. BURLAMAQUI, Conceição A. DORNELAS, José Telmo VALENÇA Jr., Francisco J. C. MESQUITA, Lara B. VERAS, Lusmar Veras RODRIGUES, 153

1553

Endoscopic treatment for gastric perforation using T-Tag and a plastic protection chamber: a short-term survival study Kiyoshi HASHIBA, Pablo R. SIQUEIRA, Horus A. BRASIL, Marco A. D’ASSUNÇÃO, Daniel MORIBE, Jorge Carim CASSAB, 159

BRIEF COMMUNICATION 1554

Celiac disease screening in patients with scleroderma Renato NISIHARA, Shirley Rosa UTIYAMA, Pedro Ming AZEVEDO, Thelma Larocca SKARE, 163

ARCHIVES OF GASTROENTEROLOGY

ISSN 0004-2803 ISSN 1678-4219 – on-line Coden ARQGA

v. 48 – no.2 – Abr./Jun. 2011


ISSN 0004-2803 ISSN 1678-4219 – on-line Coden ARQGA

CONTEÚDO EDITORIAL 1541

Utilidade do registro do pH em parte proximal do esôfago Roberto Oliveira DANTAS, 89

ARTIGOS ORIGINAIS 1542

Papel-chave dos testes de fisiologia do esôfago no diagnóstico e tratamento da doença do refluxo gastroesofagiano em pacientes com doença intersticial pulmonar Renato Vianna SOARES, Anne FORSYTHE, Kyle HOGARTH, Nadera J. SWEISS, Imre NOTH, Marco G. PATTI, 91

1543

Doença do refluxo gastroesofágico e distúrbios da voz Maria Aparecida Coelho de Arruda HENRY, Regina Helena Garcia MARTINS, Mauro Masson LERCO, Lídia Raquel CARVALHO, Vânia Cristina LAMÔNICA-GARCIA, 98

1544

Precisão do teste respiratório com pequenas doses de ureia marcada com carbono-13 no diagnóstico da infecção por Helicobacter pylori Luiz Gonzaga Vaz COELHO, Arilto Eleutério da SILVA Jr, Maria Clara de Freitas COELHO, Francisco Guilherme Cancela e PENNA, Rafael Otto Antunes FERREIRA, Elisa Viana SANTA-CECÍLIA, 104

1545

A infecção por Helicobacter pylori não influencia a sobrevida no câncer gástrico distal Renata S. SANTOS, José E. V. LOURENÇO, Fernando Augusto Mardiros HERBELLA, Jose Carlos Del GRANDE, Marco G. PATTI, 109

1546

Perfil nutricional de pacientes alcoólatras assintomáticoss Maria Beatriz SOBRAL-OLIVEIRA, Joel FAINTUCH, Dulce Reis GUARITA, Claudia P. OLIVEIRA, Flair J. CARRILHO, 112

1547

Estudo prospectivo comparando a ultrassonografia com o contraste perflutreno e a ressonância magnética no diagnóstico de hemangiomas hepáticos Joel SCHMILLEVITCH, Luiz Arnaldo SZUTAN, Fábio Gonçalves FERREIRA, Maria de Fátima SANTOS, Ricardo MINCIS, Ana GORSKI, 119

1548

Marcadores sorológicos do VHB e VHC em pacientes com esquistossomose mansônica na forma hepatoesplênica Jéfferson Luis de Almeida SILVA, Veridiana Sales Barbosa de SOUZA, Tatiana Aguiar Santos VILELLA, Ana Lúcia C. DOMINGUES, Maria Rosângela Cunha Duarte COÊLHO, 124

1549

Prevalência de doença celíaca em filhos de pais iranianos com doença celíaca Bashir CHOMEILI, Majid AMINZADEH, Amir Kamal HARDANI, Payam FATHIZADEH, Pooya CHOMEILI, Azarakhsh AZARAN, 131

1550

Anuscopia de alta resolução: valor diagnóstico em lesões precursoras de câncer anal em pacientes soropositivos Felicidad GIMENEZ, Ivan Tramujas da COSTA-e-SILVA, Adriana DAUMAS, José de ARAÚJO, Sara Grigna MEDEIROS Luiz FERREIRA, 136

ARQUIVOS DE GASTROENTEROLOGIA

v. 48 – no.2 – Abr./Jun. 2011


GASTROENTEROLOGIA EXPERIMENTAL 1551

Transplante de ilhotas de Langerhans em modelos experimentais em roedores. Ilhotas encapsuladas realmente funcionam? Yngrid Ellyn Dias Maciel de SOUZA, Eleazar CHAIB, Patricia Graça de LACERDA, Alessandra CRESCENZI, Arnaldo BERNAL-FILHO, Luiz Augusto Carneiro D’ALBUQUERQUE, 146

1552

Repercussões hepáticas e bioquímicas da dieta hipercalórica e hiperlipídica rica em gordura poliinsaturada em ratos Wistar Idália M. B. BURLAMAQUI, Conceição A. DORNELAS, José Telmo VALENÇA Jr., Francisco J. C. MESQUITA, Lara B. VERAS, Lusmar Veras RODRIGUES, 153

1553

Tratamento endoscópico para perfuração gástrica por sutura utilizando dispositivos em T associados à câmara plástica protetora: estudo com curto tempo de sobrevida Kiyoshi HASHIBA, Pablo R. SIQUEIRA, Horus A. BRASIL, Marco A. D’ASSUNÇÃO, Daniel MORIBE, Jorge Carim CASSAB, 159

COMUNICAÇÃO BREVE 1554

Triagem para doença celíaca em pacientes com esclerodermia Renato NISIHARA, Shirley Rosa UTIYAMA, Pedro Ming AZEVEDO, Thelma Larocca SKARE, 163

ARQUIVOS DE GASTROENTEROLOGIA

ISSN 0004-2803 ISSN 1678-4219 – on-line Coden ARQGA

v. 48 – no.2 – Abr./Jun. 2011


EDITOR FUNDADOR/FOUNDING EDITOR EDITOR CIENTÍFICO/SCIENTIFIC EDITOR EDITOR EXECUTIVO / EDITOR-IN-CHIEF EDITORES ASSISTENTES / ASSISTANT

José Fernandes Pontes (IBEPEGE, São Paulo) Mounib Tacla (IBEPEGE, São Paulo) Ricardo Guilherme Viebig (IBEPEGE, São Paulo) Fernando Pardini (IBEPEGE) Ivan Cecconello (CBCD) Alberto Queiroz Farias (SBH) Flávio A. Quilici (FBG) Paulo Roberto Arruda Alves (SOBED) Maria do Carmo Friche Passos (SBMD)

EDITORES ASSOCIADOS/ASSOCIATE EDITORS Adávio de Oliveira e Silva (USP, São Paulo) Adérson Omar C.A. Damião (USP, São Paulo) Ary Nasi (USP, São Paulo) Ben-Hur Ferraz Neto (PUC, Sorocaba, SP) Carlos Walter Sobrado (USP, São Paulo) Claudemiro Quireze Jr. (UFGO, Goiânia, GO) Claudia P. Marques de Oliveira (USP, São Paulo) Dan L. Waitzberg (USP, São Paulo) Dulce Reis Guarita (USP, São Paulo) Dulciene M. M. Queiroz (UFMG, Belo Horizonte, MG) Edna Frasson de Souza Montero (UNIFESP, São Paulo) Edna Strauss (USP, São Paulo) Fabio Guilherme Campos (USP, São Paulo) Fabio P. Lopasso (USP, São Paulo) Fauze Maluf Filho (USP, São Paulo) Flair José Carrilho (USP, São Paulo) Gaspar de Jesus Lopes Filho (UNIFESP, São Paulo) Heitor Rosa (UFGO, Goiânia, GO) Jacques Waisberg (FMABC, Santo André, SP) João Gomes Netinho (FM São José do Rio Preto, SP) Joel Faintuch (USP, São Paulo) José Celso Ardengh (USP, Ribeirão Preto, SP) José Eduardo Monteiro da Cunha (USP, São Paulo) José Marcio Neves Jorge (USP, São Paulo) Julio Cezar Uili Coelho (UFPR, Curitiba, PR)

Luiz Augusto Carneiro D’Albuquerque (USP, São Paulo) Luiz Fernando Corrêa Zantut (USP, São Paulo) Marcel Autran C. Machado (USP, São Paulo) Marcelo Averbach (Hospital Sírio Libanês, São Paulo, SP) Marcelo Gil Cliquet (PUC, Sorocaba, SP) Marcelo Eidi Nita (USP, São Paulo) Marco Aurelio Santo (USP, São Paulo) Mario Guimarães Pessoa (USP, São Paulo) Mauro Batista de Morais (UNIFESP, São Paulo) Milton M. Barbosa Costa (UFRJ, Rio de Janeiro) Nora Manoukian Forones (UNIFESP, São Paulo) Osvaldo Malafaia (UFPR, Curitiba, PR.) Paulo Lisboa Bittencourt (Hospital Português, Salvador, BA) Paulo Sakai (USP, São Paulo) Roberto Carlos Burini (UNESP, Botucatu, SP.) Roberto Oliveira Dantas (USP, Ribeirão Preto, SP.) Sender Jankiel Miszputen (UNIFESP, São Paulo) Sergio Carlos Nahas (USP, São Paulo) Sonia Penteado (USP, São Paulo) Suzane Kioko Ono-Nita (USP, São Paulo) Ulysses Fagundes Neto (UNIFESP, São Paulo) Ulysses Ribeiro Jr. (USP, São Paulo) Valter Nilton Felix (USP, São Paulo) Venâncio Avancini Ferreira Alves (USP, São Paulo) Yu Kar Ling Koda (Inst. da Criança – USP, São Paulo)

CONSULTORES - BRASIL Arthur B. Garrido Jr. (USP, São Paulo), Cervantes Caporossi (UFMT, Cuiabá, MT), Desidério Roberto Kiss (USP, São Paulo), Edmundo Machado Ferraz (UFPE, Recife, PE), Helio Moreira (UFGO, Goiânia, GO.), João Batista Marchesini (UFPR, Curitiba, PR.), Joaquim Gama Rodrigues (USP, São Paulo), Luiz Rohde (UFRS, Porto Alegre, RS.), Marcel Cerqueira César Machado (USP, São Paulo), Maria Aparecida C. A. Henry (UNESP, Botucatu, SP.), Paulo Roberto Ott Fontes (FFFCMPA, Porto Alegre, RS.), Renato Bonardi (UFPR, Curitiba, PR.), Samir Rasslam (USP, São Paulo), Sérgio Brenner (UFPR, Curitiba, PR.), William Abrão Saad (USP, São Paulo), William Saad Hossne (UNESP, Botucatu, SP.)

CONSULTANT - INTERNATIONAL Prof. Dr. med. Peter Malfertheiner (OTTO-von-Guericke-Universität, Magdeburg, Germany); Prof. Francis Megraud (INSERM - U853, Bordeaux, France). Daniel Sifrim, MD, PhD (Barts and The London School of Medicine and Dentistry, London, UK); Steven Wexner MD, PhD (Cleveland Clinic Florida, Weston, FL, USA); Mark Scott, MD, PhD (Royal London Hospital, London, UK); Etsuro Yazaki (Barts and The London School of Medicine and Dentistry, London, UK). A revista ARQUIVOS de GASTROENTEROLOGIA é indexada nas seguintes Bases de Dados / The journal ARCHIVES of GASTROENTEROLOGY is abstracted and/or indexed in: EMBASE/Excerpta Medica, Hygiene and Communicable Diseases (CAB Abstracts), LILACS, PUBMED/MEDLINE, Periódica: Índice de Revistas Latinoamericana en Ciencias, Tropical Diseases Bulletin (CAB Abstracts). On-line texto completo/Full texts: http://www.scielo.br/ag.htm

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INSTRUCTIONS TO AUTHORS The journal ARQUIVOS de GASTROENTEROLOGIA (Archives of Gastroenterology) a quarterly journal is the Official Publication of the Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia – IBEPEGE (Brazilian Institute for Studies and Research in Gastroenterology), Colégio Brasileiro de Cirurgia Digestiva – CBCD (Brazilian College of Digestive Surgery), Sociedade Brasileira de Motilidade Digestiva – SBMD (Brazilian Digestive Motility Society) and of the Federação Brasileira de Gastroenterologia – FBG (Brazilian Federation of Gastroenterology), is dedicated to the publishing of scientific papers by national and foreign researchers who are in agreement with the aim of the journal as well as with its editorial polices. Scientific papers sent for publication should be unpublished and intended exclusively for ARQUIVOS de GASTROENTEROLOGIA. Papers for publication should be submitted in triplicate typed double-spaced (authors are advised to keep a copy for their own files) on the white bond paper ISO A4 (210 x 297 mm) with margins of at least 2.5 cm (1 in) and all pages numbered consecutively, beginning with the tittle page. Each manuscript submitted to ARQUIVOS de GAS­TRO­ ENTEROLOGIA should be arraged as follows: 1) title; 2) author(s) name(s); 3) the departament and institution where the work was performed; 4) the name, telephone number, FAX number, electronic address and postal correspondence address of author to whom galley proofs and requests for reprints should be sent; 5) acknowledgement of grants and other financial support; 6) structured abstract – the papers should be sent with abstract in English (200 words at least); abbreviations, footnotes and references should be avoided; 7) key words (3 to 10). Whenever possible, use terms of Medical Subject Headings (MESH) list from MEDLINE; 8) introduction; 9) literature; 10) material; 11) method; 12) results; 13) discussion; 14) conclusions; 15) references – arranged in alphabetical order of author’s last name (or the name of the first author, in case of more than one). Abbreviations of journals should conform to those used in INDEX MEDICUS. The references are identified in the text by arabical numerals in parenthesis. The style of the references follow the format of the ‘Vancouver style”: Uniform requirements for manuscripts submitted to biomedical journals of the International Committee of Medical Journal Editors (ICMJE), complete text in: Ann Intern Med. 1997;126:36-47; N Eng J Med. 1991;324:424-8 or

in Canadian Medical Association site: http://www.cma.ca/mwc/ uniform.htm. The references are identified in the text by arabical numerals in parenthesis. Exemples: Journal article (list all authors and do not use “et al.”): Ribeiro Jr U, Cecconello 1, Safatle-Ribeiro AV, Zilberstein B, Pinotti HW. Squamous cell carcinoma of the esophagus and multiple primary tumors of the upper aerodigestive tract. Arq Gastroenterol. 1999;36:195-200. Books and other monographs (list all authors/editors and do not use “et al.”): Castell DO, Richter JE, editors. The esophagus. 3. ed. Philadelphia: Lippincott Williams & Wilkins; 1999. Chapter in a book (list all authors and do not use “et al.”): Cohen RV, Roll S, Schaffa TD. Hernioplastia incisional videolaparoscópica. Rio de Janeiro: Reichmann & Affonso; 1999. p. 127-31. Dissertations and thesis: Cecconello 1. Contribuição ao conhecimento e histopatologia do colédoco. [Dissertação de mestrado]. São Paulo: Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia – IBEPEGE; 1979, Published proceedings paper (list all authors and do not use “et al.”): Nasi A, Cenatti A, Falcão A, Cecconello 1, Sallum RAA, Pinotti HW. Evaluation of lower esophageal sphincter pressure by two variant techniques in patents with endoscopic reflux esophagitis [abstract]. In: Meeting abstracts of the Esophagus ’98: 7th World Congress of the International Society for Diseases of the Esophagus; 1998; Montreal, Canada. Can J Gastroenterol. 1998;12Suppl.B:93B.[Abstract 278]. TABLES - Number tables in arabic numbers and supply a legend for each. Explanatory matter should be placed in footnotes as well as nonstandard abbreviation that are used. Do not use internal horizontal or vertical rules. ILLUSTRATIONS – Photographs, graphics and drawings should be sent sharp, glossy, black-and-white photographic prints, usually 127 mm x 178 mm. Each illustration should have a label pasted on its back indicating its number, the first author’s name and the article’s title. Ilustrations in colour only if the author pays for the extra cost.

MANUSCRIPT SUBMISSION Manuscripts must be submitted using the Online Submission system available at: http://submission.scielo.br/index.php/ag/index accessing the link Online Submission. The author responsible for the submission must be a system user prior the submission. All steps of the editorial process will occur using the system. When submitting a manuscript the author must digitally assign that the article is no being considered for publication at the same time in no other journal. This procedure avoids the need of sending the letters of Authorship Agreement and Copyright Transferral.


INSTRUÇÕES AOS AUTORES A revista trimestral, ARQUIVOS de GASTROENTEROLOGIA, é órgão

ordem alfabética em relação ao sobrenome do autor (ou do primeiro,

oficial do Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia

no caso de vários), de acordo com o “estilo Vancouver”: Uniform

– IBEPEGE, do Colégio Brasileiro de Cirurgia Digestiva - CBCD, da

requirements for manuscripts submitted to biomedical journals of the

Sociedade Brasileira de Motilidade Digestiva – SBMD e da Federação

International Committee of Medical Journal Editors (ICMJE), cujo

Brasileira de Gastroenterologia - FBG. Destina-se a publicar trabalhos

texto completo pode ser consultado em: Ann Intern Med. 1997;126:36-

científicos de pesquisadores nacionais ou estrangeiros que se enquadrem

47; N Engl J Med. 1997;336:309-15 ou no site da Canadian Medical

no objetivo da Revista e em suas exigências redatoriais. Os textos devem ser

Association: http://www.cma.ca/mwc/uniform.htm. Os títulos dos

redigidos em inglês.

periódicos devem ser referidos de forma abreviada de acordo com

Os trabalhos científicos enviados para publicação devem ser inéditos e destinar-se exclusivamente a ARQUIVOS de GAS­TROENTEROLOGIA. Toda matéria relacionada à investigação humana e à pesquisa animal deve

a List of Journals Indexed in INDEX MEDICUS. As citações no texto devem ser por números índices, correspondendo às respectivas referências bibliográficas.

ter aprovação prévia da Comissão de Ética da instituição onde o trabalho foi

Exemplos:

realizado, de acordo com as recomendações da Declaração de Helsinque (1964

Artigos de periódicos (cite todos os autores; não use “et al.”):

e suas versões posteriores de 1975, 1983 e 1989), as Normas Internacionais de

Ribeiro Jr U, Cecconello I, Safatle-Ribeiro AV, Zilberstein B, Pinotti HW.

Proteção aos Animais e a Resolução no 196/96 do Conselho Nacional de Saúde

Squamous cell carcinoma of the esophagus and multiple primary tumors of

sobre pesquisa envolvendo seres humanos. São aceitos estudos de natureza

the upper aerodigestive tract. Arq Gastroenterol. 1999;36:195-200.

original, clínicos ou cirúrgicos, técnicas e estudos de epidemiologia. Artigos de revisão e atualização só são aceitos à convite do Conselho Editorial. Não se publicam Relatos de caso. Os estudos submetidos a publicação nos ARQUIVOS de GASTROENTEROLOGIA são enviados a três pareceristas de reconhecida competência no tema abordado. O anonimato é garantido durante todo o processo de julgamento. A decisão sobre aceitação é tomada pela Comissão Editorial. Os originais (manuscritos) para publicação devem ser enviados em triplicata (recomenda-se ao autor guardar consigo uma quarta via

Livros e outras monografias (cite todos os autores/editores; não use “et al.”): Castell DO, Richter JE, editors. The esophagus. 3.ed. Philadelphia: Lippincott Williams & Wilkins; 1999. Capítulo de livro (cite todos os autores e não use “et al.”): Cohen RV, Roll S, Schaffa TD. Hernioplastia incisional videolaparoscópica. In: Goldenberg S, editor. Avanços em cirurgia laparoscópica. Rio de Janeiro: Reichmann & Affonso; 1999. p.127-31.

para seu arquivo), digitados em uma só face, com espaço duplo, em

Dissertação e tese:

fonte Times New Roman ou Arial, tamanho 12, em papel branco

Cecconello I. Contribuição ao conhecimento e histopatologia do colédoco.

tamanho ISO A4 (210 × 297 mm), com margens de, pelo menos,

[Dissertation]. São Paulo: Instituto Brasileiro de Estudos e Pesquisas de

2,5 cm, numerando-se as páginas consecutivamente, iniciando na

Gastroenterologia – IBEPEGE; 1979.

página de identificação. Todo artigo para publicação deverá constar de: 1) Página de identificação, que deve conter: título do artigo (com tradução em inglês); nome(s) completo(s) do(s) autor(es) com sua principal filiação acadêmica ou profissional. Para estudos originais admite-se até um máximo de seis autores, nos demais apenas três; nome do departamento e instituição onde o trabalho foi realizado; nome, endereço completo, telefone, número do Fax e e-mail do autor para quem deverão ser enviadas as provas tipográficas e pedidos de separatas; agradecimentos (quando pertinentes); 2) Página de resumos e descritores, contendo resumos estruturados – um em português, outro

Trabalho de evento (publicado) (cite todos os autores e não use “et al.”): Nasi A, Cenatti A, Falcão A, Cecconello I, Sallum RAA, Pinotti HW. Evaluation of lower esophageal sphincter pressure by two variant techniques in patients with endoscopic reflux esophagitis [abstract]. In: Meeting abstracts of the Esophagus ’98: 7th World Congress of the International Society for Diseases of the Esophagus; 1998; Montreal, Canada. Can J Gastroenterol. 1998;12 Suppl.B:93B. [Abstract 278]. TABELAS – Devem ser apresentadas em folhas separadas do texto numeradas com algarismos arábicos na ordem em que forem citadas, contendo legendas;

em inglês (com pelo menos 200 palavras cada um); descritores (de 3

explicações dos símbolos devem figurar no rodapé.

a 10), sempre que possível, extraídos do Medical Subject Headings

ILUSTRAÇÕES – Fotos, gráficos e desenhos devem ser enviados em preto

(MESH) da National Library of Medicine ou do vocabulário Descritores

e branco, com dimensões 127 mm × 178 mm, limitados a quantidade de seis.

em Ciências da Saúde, que pode ser consultado no site www.bireme.

Devem conter identificação no verso, com a orientação, o número de ordem

br; 3) introdução; 4) literatura; 5) material; 6) método; 7) resultados; 8)

no texto, o nome do autor e o título do artigo. O custo da reprodução de

discussão; 9) conclusões; 10) referências bibliográficas – relacionadas na

ilustrações coloridas correrão por conta do autor do artigo.

SUBMISSÃO DE ARTIGOS Os artigos deverão ser submetidos pelo Sistema de Submissão Online disponível no site: http://submission.scielo.br/index.php/ag/index acessando o link submissão online. O autor responsável pela submissão deverá cadastrar-se previamente no sistema. Toda a tramitação das etapas do processo editorial será realizada por meio deste sistema. Ao submeter o manuscrito, o autor deverá firmar eletronicamente que o artigo não está sendo submetido paralelamente a outro periódico. Este procedimento elimina a necessidade do envio de cartas de responsabilidade de Autoria e Transferência de Direitos Autorais.


EDITORIAL

ARQGA/1541

USEFULNESS OF PROXIMAL ESOPHAGEAL pH MONITORING Dantas RO. Usefulness of proximal esophageal pH monitoring. Arq Gastroenterol. 2011;48(2):89-90. HEADINGS – Gastroesophageal reflux. Esophageal pH monitoring.

Monitoring esophageal acid exposure in both the distal and proximal esophagus is considered to be the best way to identify gastroesophageal acid reflux as the cause of atypical and/or extra esophageal symptoms of gastroesophageal reflux disease(1). The traditional dual-sensor pH catheter used to measure simultaneously proximal and distal reflux has the sensors located 15 cm apart. During the measurement the distal sensor is located 5 cm from the lower esophageal sphincter (LES) and the proximal sensor 20 cm from the LES. In this position the proximal sensor will be located near the upper esophageal sphincter (UES), at the proximal esophagus in 55% of the examinations, in the pharynx in 9% and within the UES in 36%(7). Other publication reported that with this design (15 cm apart) the proximal sensor will be located in the proximal esophagus in 69% of the examinations, in the pharynx in 7%, and within the UES in 24% (1). These studies concluded that the proximal pH data are often inaccurate with 15 cm spacing between the dual sensors for esophageal pH monitoring. The other problem with dual-probe pH monitoring is the lack of clearly defined normal values, which may be the consequence of the different position of the proximal sensor in each individual. Normal values have been described many years ago for the distal sensor and are references for the interpretation of the results(6). A recent study conducted on 59 normal volunteers reported that the upper limit of normality for the proximal sensor is 0.9% of the total time with pH < 4, number of reflux episodes of 24, no episode with duration above 5 minutes and 5 minutes as the duration of the longest episode(1). It has been reported that the proximal esophagus of normal subjects has a pH < 4 less than 1% of the total time, with no acid exposure in the proximal esophagus in the supine position(2). In another study, with the proximal sensor located 20 cm from LES, the pH was under 4 in 0.5% of the total time, 0.8% in the upright position and 0% in the supine position(8). The Grupo Español para el Studio de la Motilidade Digestiva (GEMD) performed a multicentric study on

v. 48 – no.2 – abr./jun. 2011

a large number of healthy volunteers (118), excluding the meal periods and the pseudo-reflux events, defined as a drop in pH to less than 4.0 on the proximal sensor in the absence of reflux in the distal esophagus simultaneously or during the previous 8 seconds, and found (in subjects without abnormal reflux in the distal sensor) 18 as the number of reflux episodes, no episodes with a duration longer than 5 minutes, 4 minutes for the duration of the longest episode, and 0.95% of the time with pH below 4(3). A study conducted in China reported 0.70% of the time with pH below 4 in the proximal esophagus, no episodes with duration longer than 5 minutes, 3 minutes duration of the longest episode and 12 reflux episodes(5). With the pH sensor in the pharynx the normal limit was described as 7 reflux episodes, 0.10% of time with pH < 4.0, 1 minute duration of the longest episode, with no episode with duration longer than 5 minutes(11). The study of the reproducibility of proximal sensor pH parameters concluded that the proximal pH values recorded during 24 hours has excellent specificity (91%), but poorer sensitivity and reproducibility (55%) for identifying abnormal amounts of proximal esophageal acid reflux. The authors stated that a negative test result does not exclude proximal reflux with microaspiration as a cause of atypical and/or extra esophageal reflux symptoms(10). From these publications we may conclude that the pH of the proximal esophagus of normal subjects is below 4 less than 1% of the time, the duration of the longest drop in pH is less than 5 minutes and the number of 24 hour reflux episodes is about 20, with descriptions of 24, 18, 12 and 7 episodes. The number of reflux episodes should be the most important factor because it increases the possibility of the acid to cross the UES and cause pharyngeal and respiratory symptoms. The time the pH stays below 4 is short in normal subjects. In the interpretation of the 24 hour pH recording it is important to understand its limitation. First of all it measures only acid reflux, when the pH drops

Arq Gastroenterol

89


Dantas RO. Usefulness of proximal esophageal pH monitoring.

below 4. Non-acid reflux, or acid reflux with pH between 4 and 5, may be the cause of atypical symptoms. Second, the position of the pH sensor is not the same for all subjects, when the distance between the proximal and distal sensors of the catheter does not take into consideration the distance between the UES and LES(1, 7). Finally, the examination has poorer sensitivity and reproducibility(10). In this number of Arquivos de Gastroenterologia two papers use pH monitoring with proximal and distal sensors in their methods. In one paper, which evaluated gastroesophageal acid reflux in patients with interstitial lung disease, 20% of the patients had pH < 4 at the proximal sensor more than 1% of the total time of pH recording(9), and in the other, which evaluated patients with gastroesophageal reflux and vocal disturbances, the proximal acid exposure did not differ

between patients with and without dysphonia, with similar values for the number of reflux episodes and percentage of time with pH below 4(4). The reflux of small amounts of gastric content into the larynx may cause lesions. Other factors are associated in the mechanism of lesion and symptoms, such as sensitivity. The measurement of proximal esophageal acid exposure most of the time is not enough to determine a cause-effect relationship between gastroesophageal reflux and pharyngeal, laryngeal or pulmonary symptoms. Nowadays, the importance of the recording of proximal pH for the diagnosis of atypical and/ or extra esophageal symptoms is being questioned, although it may be an important tool in research. Roberto Oliveira DANTAS*

Dantas RO. Utilidade do registro do pH em parte proximal do esôfago. Arq Gastroenterol. 2011;48(2):89-90. DESCRITORES – Refluxo gastroesofágico. Monitoramento do pH esofágico.

REFERENCES

6.

1.

Ayazi S, Hagen JA, Zehetner J, Oezcelik A, Abate E, Kohn GP, Sohn HJ, Lipham JC, Demeester SR, Demeester TR. Proximal esophageal pH monitoring: improved definition of normal values and determination of a composite pH score. J Am Coll Surg. 2010;210:345-50. 2. Dobhan R, Castell DO. Normal and abnormal proximal esophageal acid exposure: results of ambulatory dual-probe pH monitoring. Am J Gastroenterol. 1993;88:25-9. 3. Grupo Español para el Estudio de la Motilidade Digestiva (GEMD). Normal values in ambulatory oesophageal pH monitoring at two levels in Spain. Rev Esp Enferm Dig. 2010;102:406-12. 4. Henry MACA, Martins RHG, Leico MM, Carvalho LR. Gastroesophageal reflux disease and vocal disturbances. Arq Gastroenterol. 2011;48:98-103. 5. Hu WHC, Wong NYH, Lai KC, Hui WM, Lam KF, Wong BCY, Xia HHX, Chan CK, Chan AOO, Wong WM, Tsang KWT, Lam SK. Normal 24-hour ambulatory proximal and distal gastroesophageal reflux parameters in Chinese. Hong Kong Med J. 2002;8:168-71.

Johnson LF, DeMeester TR. Twenty-four hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol. 1974;62:325-32. 7. McCollough M, Jabbar A, Cacchione R, Allen JW, Harrell S, Wo JM. Proximal sensor data from routine dual-sensor esophageal pH monitoring is often inaccurate. Dig Dis Sci. 2004;49:1607-11. 8. Ruiz de León A, Sevilla-Mantilla MC, Pérez de La Serna J, Taxonera C, GarcíaCabezas J, Díaz-Rubio M. [Physiological reflux in proximal esophagus (assessment with simultaneous pH monitoring in proximal and distal esophagus in healthy subjects)]. Rev Esp Enferm Dig. 1994;86: 874-8. 9. Soares RV, Forsythe A, Hogarth K, Sweis NJ, Noth I, Patti MG. Interstitial lung disease and gastoesophageal reflux disease: key role of esophageal function tests in the diagnosis and treatment. Arq Gastroenterol. 2011;48:91-7. 10. Vaezi MF, Schroeder PL, Richter JE. Reproducibility of proximal probe pH parameters in 24-hour ambulatory pH monitoring. Am J Gastroenterol. 1997;92:825-9. 11. Vicent DA Jr, Garrett JD, Radionoff SL, Reussner LA, Stasney CR. The proximal probe in esophageal pH monitoring: development of a normative database. J Voice. 2000;14:247-54.

* Departamento de Clínica Médica da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.

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ARTIGO ORIGINAL / ORIGINAL ARTICLE

ARQGA/1542

INTERSTITIAL LUNG DISEASE AND GASTROESOPHAGEAL REFLUX DISEASE: key role of esophageal function tests in the diagnosis and treatment Renato Vianna SOARES1, Anne FORSYTHE1, Kyle HOGARTH2, Nadera J. SWEISS2, Imre NOTH2 and Marco G. PATTI1 ABSTRACT – Context - Gastroesophageal reflux disease (GERD) is common in patients with respiratory disorders and interstitial lung fibrosis from diverse disease processes. However, a cause-effect relationship has not been well demonstrated. It is hypothesized that there might be more than a coincidental association between GERD and interstitial lung damage. There is still confusion about the diagnostic steps necessary to confirm the presence of GERD, and about the role of effective control of GERD in the natural history of these respiratory disorders. Objectives - To determine the prevalence of GERD in patients with respiratory disorders and lung involvement; the sensitivity of symptoms in the diagnosis of GERD; and the role of esophageal function tests (manometry and 24hour pH monitoring) in the diagnosis and treatment of these patients. Methods - Prospective study based on a database of 44 patients (29 females) with respiratory disorders: 16 patients had idiopathic pulmonary fibrosis, 11 patients had systemic sclerosis associated interstitial lung disease, 2 patients had polymyositis associated interstitial lung disease, 2 patients had Sjögren associated interstitial lung disease, 2 patients had rheumatoid artrithis associated interstitial lung disease, 1 patient had undifferentiated connective tissue diseases associated interstitial lung disease and 10 patients had sarcoidosis. The average forced vital capacity (% predicted) was 64.3%. All patients had esophageal function tests. Results - Thirty patients (68%) had pathologic reflux (average DeMeester score: 45, normal <14.7). The average number of reflux episodes recorded 20 cm above the lower esophageal sphincter was 24. Sensitivity and specificity of heartburn were 70% and 57%, of regurgitation 43% and 57%, and of dysphagia 33% and 64%. Twelve patients with GERD underwent a laparoscopic fundoplication which was tailored to the manometric profile: three patients in which peristalsis was normal had a total fundoplication (360°) and nine patients in which the peristalsis was absent had a partial anterior fundoplication (180°). Conclusions - The results of our study show that: (a) abnormal reflux was present in about 2/3 of patients with respiratory disorders (idiophatic pulmonary fibrosis, connective tissue disorders and sarcoidosis), and it extended to the upper esophagus in most patients; (b) the sensitivity and specificity of reflux symptoms was very low; and (c) esophageal function tests were essential to establish the diagnosis of abnormal reflux, to characterize the esophageal function and guide therapy. Long term follow-up will be necessary to determine if control of reflux alters the natural history of these respiratory disorders. HEADINGS – Gastroesophageal reflux. Lung diseases, interstitial. Esophageal pH monitoring. Manometry.

INTRODUCTION

Idiopathic pulmonary fibrosis (IPF), connective tissue disorders (CTD) associated lung diseases and pulmonary sarcoidosis are a heterogeneous group of restrictive respiratory disorders that have in common inflammation and/or fibrosis of the pulmonary interstitium, with consequent dyspnea on exertion(2). Idiopathic interstitial pneumonias – IPF and idiopathic non-specific fibrotic interstitial pneumonias are diseases of unknown association. These diseases cause progressive dyspnea with eventual oxygen dependence. In both disorders the lung seems to be the only organ

affected. A high prevalence of gastroesophageal reflux disease (GERD) in patients with IPF has been documented in a number of studies(9, 16, 19, 22, 29). CTD (systemic sclerosis, polymyositis, Sjögren syndrome and rheumatoid arthritis) are multi-organ disorders with auto-immune basis in which the lung interstitium may be involved with variable frequency and severity. In these patients, abnormal motility of the esophagus has been associated with worsened pulmonary function and more severe GERD. Sarcoidosis affects the lung in 85%-90% of patients. The diagnosis is made by clinical and radiological characteristic findings and supported by a surgical

Departments of 1Surgery and 2 Medicine of University of Chicago Pritzker School of Medicine – Chicago, USA. Correspondence: Dr. Renato Vianna Soares - Centro de Medicina Pélvica Hospital Santa Cruz – Avenida Batel, 1889 – 20 andar – 80420-090 – Curitiba, PR, Brasil. E-mail: renatovsoares@hotmail.com

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biopsy demonstrating non-caseous granulomas in an affected organ. No studies to date have been done in the prevalence of GERD in sarcoidosis. In this study, we hypothesized that: (a) abnormal gastroesophageal reflux is highly prevalent in patients with interstitial lung diseases related to CTD, sarcoidosis and IPF; (b) presence of gastroesophageal reflux symptoms cannot reliably predict abnormal gastroesophageal reflux; and (c) esophageal function tests are essential for the diagnosis of abnormal reflux and for management. METHODS

Patients with interstitial lung disease (ILD) from diverse causes were prospectively collected from the referrals for esophageal function tests in the Swallowing Center of the University of Chicago, Ill, USA from October 1, 2008 to September 30, 2009. Forty-four patients were included. They were evaluated by the rheumatology and pulmonary clinic for IPF, CTD and sarcoidosis and referred for esophageal function tests at the attending physician discretion. All patients had esophageal function tests (esophageal manometry and 24-hour pH monitoring). Fortythree patients had pulmonary function tests (PFT). Sixteen patients had IPF, 18 patients had CTD and ILD (scleroderma ILD- 11, polymyositis ILD- 1, dermatopolymiositis 1, Sjögren syndrome -ILD- 2, reumathoid artrithis ILD-2, undetermined CTD ILD- 1), 10 patients had sarcoidosis. Consecutive patients with a confirmed diagnosis of IPF, CTD or sarcoidosis with lung involvement according previously published American Thoracic Society/ European Respiratory Society criteria(2) for ILD, who also had a successful completion of esophageal function testing comprised the study cohort. Symptomatic evaluation All patients referred for esophageal function tests answered a standardized questionnaire that included presence or absence of symptoms (heartburn, regurgitation, difficulty swallowing, chest pain, hoarseness and cough). Each patient was discussed with the referring physicians (pulmonologist and rheumatologist) regarding the presence of a respiratory condition and/or rheumatologic condition. Current use of acid reducing medications was also documented. Esophageal manometry Patients stopped medications that interfere with esophageal motility at least 48 hours before the procedure. After an overnight fast, esophageal manometry was performed using a solid state catheter with 5 circumferential pressure sensors (Sandhill Scientific, Highlands Ranch, CO, USA). Lower esophageal sphincter (LES) pressure and length were determined using the station pull-through technique, with 0.5 cm increments between stations. Esophageal peristalsis was measured then with 10 swallows of 5 mL of water given at 30-s intervals. Peristaltic wave amplitude, duration and velocity were recorded at 3, 8, 13, 18 cm above the manometrically determined LES. Peristaltic wave amplitude was then independently calculated for the distal esophagus (3 cm and 8 cm above the LES, distal esophageal amplitude) and for the proximal esophagus (13 cm 92

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and 18 cm above the LES, proximal esophageal amplitude). Final manometric reporting was done using the Spechler and Castell criteria(26). Ambulatory pH monitoring Acid reducing medications were stopped 3 days for histamine H2-receptors antagonists and 10 days for proton pump inhibitors before the test. A dual sensor pH probe in which the lower sensor was placed 5 cm above the superior border of the manometrically determined LES and the proximal sensor was placed 15 cm above the distal sensor was used. Four patients had a pH with impedance (for these patients, only calculations on the pH probe located 5 cm above the LES were performed). Patients were instructed to eat an unrestricted diet and avoid acid suppressing medications during the study. Patients were given a diary to describe symptoms and events. Based on the collected data, a composite reflux score (DeMeester score) was calculated for the distal esophagus. The data were analyzed using a commercial software program (BioView, Sandhill Scientific, Highlands Ranch, CO, USA). Meal periods were excluded from analysis. A DeMeester score above 14.7 was considered abnormal(11). These patients were referred as GERD+ group (pathologic gastroesophageal reflux). Patients with DeMeester score less than 14.7 were called GERD- (normal esophageal acid exposure). Patients were considered to have abnormal proximal reflux if the acid exposure was above 1%(5) 20 cm above the LES. In the proximal channel, pseudoreflux (gradual decrease in pH to less than 4 in the proximal channel without an accompanying drop in the distal channel, with rapid recovery, usually occurring in the recumbent position), and artifacts due to acidic foods or drinks (an abrupt drop in the pH identical in the two electrode sites) were excluded from analysis(14). For the patients that had pH with impedance testing, the threshold for abnormal reflux was 73 episodes (both acid and non-acid)(25). Pulmonary function tests Spirometry, diffusion capacity for carbon monoxide, and lung volumes by plethysmography were obtained per American Thoracic Society guidelines(12, 17, 30). Surgical technique A total fundoplication (360°) was the preferred technique for patients with normal esophageal peristalsis. In patients with absent peristalsis, a partial anterior (180°) fundoplication was performed. The initial steps were similar for both operations. They included: (1) mobilization of the esophagus in the posterior mediastinum; (2) transection of the short gastric vessels; (3) approximation of the right and left pillars of the crus behind the esophagus; and (4) creation of a wrap. The total fundoplication was constructed over a 56 F bougie. RESULTS

Forty-four patients were included. The average age was 54 years (range 28-76). Twenty-nine patients were female and 15 were male. Twelve patients were in the lung transplant list. Demographic characteristics in each group of patients and the results of the PFT are outlined in Table 1. v. 48 – no.2 – abr./jun. 2011


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Symptom evaluation The prevalence of symptoms of GERD, sensitivity, specificity, positive predictive value and negative predictive value of each symptom for the diagnosis of GERD were determined (Table  2). Table 3 shows the difference in prevalence of the typical reflux symptoms in patients with (GERD+) and without abnormal esophageal acid exposure (GERD-). Manometric profile Esophageal peristalsis was abnormal in 28 patients (64%). In 14 patients (32%), peristalsis in response to wet swallows was absent (Table 4). In patients with absent peristalsis, the median DeMeester score was 37.3, compared to 19.9 in patients with normal peristalsis (P = 0.024) TABLE 1. Demographic characteristics and pulmonary function tests IPF/NISP (n = 16) Age (average) 61 Female sex 5 29 BMI (kg/m2, average) DLCO (average, % predicted) 49 FEV1 (average, % predicted) 75 FVC (average, % predicted) 63 15 C Race 1AA

Ambulatory 24h pH monitoring Abnormal DeMeester score was diagnosed in 30 of the 44 patients (68%). The mean score in this population was 45.2 (normal <14.7). In 8 patients (20%), the acid exposure in the proximal channel (20 cm above the LES) was abnormal. In 7 of these, the acid exposure in both proximal and distal channels were abnormal. Four patients had pH with impedance testing. The DeMeester score was abnormal in two (average 22.5), and normal in two (average 3.6). In all four patients, the number of reflux episodes detected by impedance was within normal limits. Surgical treatment Twelve patients with abnormal reflux score DeMeester (score >14.72) had a laparoscopic fundoplication. There

CTD (n = 18) 51 15 27 51 71 63 11C 7 AA

Sarcoidosis (n=10) 50 9 33 72 73 68 2C 8 AA

Total 54 29 28 55 73 64 28 C 16AA

IPF – idiopathic pulmonary fibrosis; NISP – idiopathic non-specific fibrotic interstitial pneumonias; CTD – connective disorders; BMI – body mass index; DLCO- diffusion capacity of carbon monoxide; FEV1- forced expiratory volume in 1 second; FVC- forced vital capacity; C - Caucasian race; AA - African-American race.

TABLE 2. Prevalence of reflux symptoms in 44 patients with ILD, sensitivity, specificity, positive predictive value, negative predictive value Prevalence Sensitivity Specificity PPV NPV Symptom (%) (%) (%) (%) (%) Heartburn 61 70 57 77 47.5 Regurgitation 43 43 57 68 31 Dysphagia 34 33 64 67 31 Any typical reflux 77 83 29 71 40 symptom PPV: positive predictive value. NPV: negative predictive value

TABLE 3. Prevalence of symptoms in patients with and without GERD GERD+ (%) Heartburn 70 Regurgitation 43.3 Dysphagia 30 TABLE 4. Esophageal manometry Aperistalsis CTD 10 (55.6%) IPF/NISP 3 (18.8%) Sarcoid 1(10%) Total

14 (32%)

GERD- (%) 42.8 42.8

P-value 0.53 0.89

35.7

0.83

IEM 2 (11.8%) 4 (25%) 2 (20%)

NEMD 3 (11.8) 1 (6.25%) 1(10%)

NE 0 1(6.25%) 0

Normal 3 (17.6%) 7(43.45%) 6 (60%)

8 (19%)

5 (11%)

1(2%)

16 (36%)

IEM- ineffective esophageal motility disorder; NEMD - non-specific esophageal dismotility; NE - Nutcracker esophagus. IPF- Idiopathic pulmonary fibrosis; NISP- idiopathic non-specific fibrotic interstitial pneumonias

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were no intra-operative complications. Of these, nine had a partial fundoplication (six scleroderma, two IPF, one sarcoidosis) and three had a total fundoplication (three sarcoidosis). At a mean follow-up of 10 months, two patients who had preoperative dysphagia (both with scleroderma and diffuse gastrointestinal involvement) had worsening of this symptom. Because the dysphagia persisted despite dilation, they both required total parenteral nutrition while taking only liquids by mouth. One patient with sarcoidosis developed post-operative dysphagia that improved after one dilation done 6 months after the operation. DISCUSSION

The results of our study show that: (a) pathologic distal gastroesophageal reflux is present in more than two-thirds of patients with ILD, and abnormal proximal gastroesophageal reflux is present in 20%; (b) typical reflux symptoms are a poor predictor of pathological reflux; and (c) esophageal function tests are essential for establishing the correct diagnosis and for the treatment of these patients. Prevalence of GERD in ILD Idiopathic pulmonary fibrosis A link between abnormal reflux and pulmonary fibrosis have been suggested since Pearson et al.(21) and latter Mays et al.(16) reported that a hiatal hernia seen in a barium swallow was more common IPF patients when compared with controls. In a large Veteran’s study, patients with erosive esophagitis had a 1.36 odds ratio for IPF(7). Abnormal 24-hour pH-monitoring in patients with IPF have been reported to be as high as 94%(29). In other articles, the prevalence of abnormal reflux varied from 87% to 67%(19, 22, 23) , but in a recent report only 35% of an IPF cohort had pathological reflux(3). In our study, 56% of patients with IPF had abnormal distal reflux and 23% had abnormal proximal reflux. The reasons for this relatively low prevalence of GERD in this IPF cohort are unclear. Abnormal motor function of the esophagus was seen in 56% of the patients, similar of that of a previous report by our group(19). The most prevalent abnormal finding on esophageal manometry was ineffective esophageal motility disorder. Connective tissue disorders The prevalence of ILD in patients with connective tissue disorders is high(1, 4). In a study with high-resolution computed tomography, 81% of CTD patients had signs of ILD(1). GERD is also frequent in patients with CTD. Studies with 24-hour pH with and without impedance monitoring demonstrated abnormal reflux in 83% to 50%(8, 9, 24) of patients. A negative impact of abnormal reflux in the pulmonary function has been demonstrated.

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For example, Johnson et al.(10) studied 13 patients with systemic sclerosis with 24-hour pH monitoring and PFT. This author did a multiple regression analysis and the impairment in the diffusion capacity of carbon monoxide (DLCO) correlated with proximal and distal reflux. The fact that ILD and GERD frequently coexist in patients with CTD, and that CTD patients with lung involvement may have a higher incidence of pathologic reflux reinforce the hypothesis that GERD may play a role in the natural history of the interstitial lung fibrosis in patients with connective tissue disorders. In our study, 78% of patients with CTD had abnormal reflux score. In the scleroderma group, abnormal reflux was found in 91%. Nevertheless, the 57% of patients with CTD other than scleroderma had also abnormal reflux. Esophageal dismotility was present in 15 out of 18 patients (82%). In 10 patients (55.6%) peristalsis was absent. Sarcoidosis Little is known about the prevalence of reflux in patients with sarcoidosis and if GERD plays a role in the natural history of this disease. In our study, 70% of patients with sarcoidosis had an abnormal DeMeester score. While this percentage seems very high, one must acknowledge that the reason for referring patient for EFT in this population was a little different compared to the other patients of the study. While patients with IPF and patient with CTD are systematically send to be screened for reflux, in patient with sarcoidosis, only when clinical suspicion of GERD arises the patient are screened for reflux by EFT (8/10 patients had typical reflux symptoms and 1/10 patient had EFT as part of lung transplant protocol). The majority of the patients in this group had preserved peristalsis. Does impairment in the esophageal motility have influence on prevalence and severity of ILD? In the present study, abnormal motility was diagnosed in 64% of our patients. Approximately one third of the patients had complete absence of peristalsis. Impairment of the motor function of the esophagus has been linked to more severe reflux and possible recurrent episodes of micro aspiration and lung damage. For example, Marie et al.(15) studied 43 patients with scleroderma. These authors divided the patients in three groups according to the degree of esophageal dismotility. Patients with absent peristalsis had significant lower DLCO compared with patients that had preserved peristalsis. The degree of mucosal damage diagnosed by endoscopy was also worse in patients with aperistalsis. In our study, absence of peristalsis was also linked to more severe reflux. Fagundes et al.(8) studied 50 patients with mixed connective tissue disease and correlated esophageal dilation seen on high resolution CT scan with the presence of ILD. The prevalence of ILD in patients with esophageal dilation was 92%, compared with 45% in patients without esophageal dilation. Patti et al. (20) compared

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the esophageal motility pattern in patients with connective tissue disorders with or without pulmonary involvement. Forty-six percent of the patients with CTD and pulmonary involvement had no peristalsis. Peristalsis was present in all patients who had CTD but no pulmonary involvement. Can the presence of GERD symptoms reliably predict GERD? This study confirms that the clinical history, even using a standardized questionnaire, cannot distinguish between patients with and without abnormal reflux. Neither the presence nor the severity of symptoms predicted the presence of abnormal reflux, which is consistent with other reports (6, 27). For example, among 822 patients with a clinical diagnosis of GERD, manometry and pH monitoring showed that only 575 patients (70%) actually had abnormal reflux(18). Others have documented low sensitivity and specificity between reflux symptoms and a positive DeMeester score in patients with IPF as well as in patients with ILD associated with CTD. For instance, Raghu et al. (22) reported 87% of abnormal reflux in 65 patients with IPF. However, only 47% had heartburn more than once a month. Patti et al.(19) reported the symptom profile in 16 patients with IPF. No difference was demonstrated in the prevalence of heartburn and regurgitation between the 10 patients in whom the 24 hour pH was abnormal and the remaining 6 patients that had a normal reflux score. Gasper et al. (9) studied 26 patients with CTD and ILD listed for lung transplant. In this study, the sensitivity of having one or more typical reflux symptoms was 74%, and specificity was 75%. Is surgical treatment effective and does it alter the natural history of these diseases? Our study shows that in patients with CTD and lung disease a pan esophageal motility disorder are often present, characterized by a hypotensive LES and weak or absent esophageal peristalsis. In addition, reflux often extends all the way to the pharynx. It is reasonable to suggest that the esophageal dysmotility can cause or contribute to the development of pulmonary complications through repeated episodes of micro aspiration. For instance, in a prospective study of patients with systemic sclerosis, Marie et al.(15) identified a correlation between the degree of esophageal dysmotility (as shown by manometry) and evidence of ILD both by pulmonary function tests and high resolution computed tomography. In addition, at 2 year follow-up, patients with severe esophageal dysmotility had a faster deterioration of lung function and a higher frequency of ILD on high resolution computed tomography scans, suggesting that GERD may be one of the contributing factors of ILD in patients with systemic sclerosis. Proton pump inhibitors do not stop reflux but they only change

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the pH of the gastric refluxate(28), while a fundoplication restores the competence of the gastroesophageal junction, blocking acid and nonacid reflux. This observation is very important because aspiration of nonacid reflux can also cause respiratory symptoms. For instance, Mainie et al.(13) were able to identify by pH impedance monitoring patients with cough due to nonacid reflux while treated by proton pump inhibitors. A laparoscopic Nissen fundoplication improved or resolved the symptoms in 13 of 14 such patients (93%). In our study, symptoms were improved suggesting control of abnormal reflux, although we do not have post operative pH testing. Some patients with absent esophageal peristalsis and dysphagia had worsening of this symptom requiring total parenteral nutrition. Even a partial fundoplication aggravated the emptying of food from the esophagus into the stomach. For this reason it would be important to treat patients with CTD and GERD at an early stage, when peristalsis is still preserved. Long term follow-up will determine if control of reflux improves the respiratory status and prognosis of these patients. Our study has deficiencies. A referral bias may have occurred, since the patients were send to the Swallowing Center of the University of Chicago at the referring physician discretion. Even with that, we were able to demonstrate that typical reflux symptoms are not reliable for the diagnosis of abnormal reflux. Besides, the small number of patients limited the statistical power of the study. Increased severity of reflux did not correlate with worsened pulmonary function (DLCO or FVC). Also, changes in trans-diaphragmatic pressures and respiratory mechanics may predispose patients with pulmonary diseases to abnormal reflux, without a cause-effect relationship. Our study cannot contribute to answer this question. Finally, the study is not able to prove if adequate control of reflux changes the natural history of ILD. However, we do have the merit to demonstrate that it is important to screen patients with interstitial damage for reflux, even if asymptomatic. Furthermore, our study has shown that in several different pulmonary disease processes, abnormal motility of the esophagus is often present and linked to more severe reflux. CONCLUSION

In summary, correct diagnosis and adequate control of reflux are particularly challenging in this group of patients. Pathological distal and proximal abnormal reflux are highly prevalent. Spillage of gastric juice into the lungs may play a role in this heterogeneous group of pulmonary diseases. While typical reflux symptoms are not enough to reliably predict abnormal reflux, importance of the 24-hour pH monitoring cannot be overemphasized. Furthermore, esophageal manometry is crucial to tailor surgical therapy in these patients, since a considerable proportion will have absent peristalsis.

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Soares RV, Forsythe A, Hogarth K, Sweiss NJ, Noth I, Patti MG. Papel-chave dos testes de fisiologia do esôfago no diagnóstico e tratamento da doença do refluxo gastroesofagiano em pacientes com doença intersticial pulmonar. Arq Gastroenterol. 2011;48(2):91-7. RESUMO – Contexto - A doença do refluxo gastroesofagiano (DRGE) é comum em pacientes com lesões intersticiais pulmonares. Todavia, a relação de causa e efeito não foi claramente demonstrada. Tem sido formulada a hipótese de que a frequente coexistência de DRGE e dano pulmonar intersticial não seja meramente uma coincidência. Ainda existe controvérsia em relação a melhor forma de se confirmar o diagnóstico de DRGE e se o controle efetivo do refluxo tem influência na história natural destas enfermidades respiratórias. Objetivo - Determinar: (a) a prevalência da DRGE em pacientes com doenças respiratórias e envolvimento pulmonar intersticial; (b) a sensibilidade dos sintomas típicos de DRGE para o diagnóstico; (c) o papel dos exames de fisiologia do esôfago (manometria esofágica e pHmetria de 24 horas) no diagnóstico e manejo destes pacientes. Métodos - Estudo prospectivo de 44 pacientes (29 sexo feminino) com doenças respiratórias: 16 pacientes com fibrose pulmonar idiopática, 11 com doença intersticial pulmonar associada à esclerose sistêmica, 2 com doença intersticial pulmonar associada à polimiosite, 2 com doença intersticial pulmonar relacionada à síndrome de Sjögren, 2 com doença intersticial pulmonar associada à artrite reumatóide, 1 com doença intersticial pulmonar associada à doença indiferenciada do tecido conjuntivo e 10 pacientes com sarcoidose e acometimento pulmonar. A capacidade vital forçada média (% predito) foi de 64,3%. Todos os pacientes fizeram manometria esofágica e pHmetria de 24 horas. Resultados - Trinta pacientes (68%) tiveram refluxo patológico (média do escore de DeMeester de 45; normal <14.7). A média de episódios de refluxo detectados 20 cm acima do esfíncter inferior do esôfago foi de 24. A sensibilidade e especificidade de queimação retroesternal foi de 70% e 57%, de regurgitação de 43% e 57% e de disfagia de 33% e 64%. Doze pacientes com DRGE foram levados à fundoplicatura videolaparoscópica guiada pelo perfil manométrico: em três pacientes com peristalse normal foi realizada uma fundoplicatura à Nissen e em nove pacientes com peristalse ausente foi realizada fundoplicatura à Dor. Conclusões - Os resultados do estudo demonstraram que: (a) refluxo anormal esteve presente em 2/3 dos pacientes com doenças respiratórias e comprometimento intersticial; (b) a sensibilidade e especificidade dos sintomas de refluxo foi baixa; (c) provas de fisiologia do esôfago foram essenciais para o diagnóstico de refluxo anormal, para caracterizar a função esofagiana e guiar o manejo. Seguimento de longo prazo vai ser importante para determinar se o controle do refluxo tem influência na história natural destas doenças respiratórias. DESCRITORES – Refluxo gastroesofágico. Doenças pulmonares intersticiais. Monitoramento do pH esofágico. Manometria.

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7. 8. 9. 10.

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R, McKay R, Miller MR, Navajas D, Pedersen OF, Pellegrino R, Wanger J. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26:720-35. Mainie I, Tutuian R, Agrawal A Admas D, Castell DO. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastroesophageal reflux for laparoscopic Nissen fundoplication. Br J Surg. 2006;93:1483-7. Maldonado A, Diederich L, Castell DO, Gideon RM, Katz PO. Laryngopharyngeal reflux identified using a new catheter design: defining normal values and excluding artifacts. Laryngoscope. 2003;113:349-55. Marie I, Dominique S, Levesque H, Ducrotté P, Denis P, Hellot MF, Courtois H. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum. 2001;45:346-54. Mays EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobronchial aspiration. A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology. Chest. 1976;69:512–5. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, Maclntyre N, Mckay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J. Standardisation of spirometry. Eur Respir J. 2005;26:319-38. Patti MG, Diener U, Tamburini A, Molena D, Way LW. Role of esophageal function tests in diagnosis of gastroesophageal reflux disease. Dig Dis Sci. 2001;46:597-602. Patti MG, Tedesco P, Golden J, Hays S, Hoopes C, Meneghetti A, Damani T, Way LW. Idiopathic pulmonary fibrosis: how often is it really idiopathic? J Gastrointest Surg. 2005;9:1053-6. Patti MG, Gasper WJ, Fisichella PM, Nipomnick I, Palazzo F. Gastroesophageal reflux disease and connective tissue disorders: pathophysiology and implications for treatment. J Gastrointest Surg. 2008;12:1900-6. Pearson JE, Wilson RS. Diffuse pulmonary fibrosis and hiatus hernia. Thorax. 1971;26:300–5. Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, Sillery JK, Pope CE 2nd, Pellegrini CA. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27:136-42. Salvioli B, Belmonte G, Stanghellini V, Baldi E, Fasano L, Pacilli AM, De Giorgio R, Barbara G, Bini L, Cogliandro R, Fabbri M, Corinaldesi R. Gastro-oesophageal reflux and interstitial lung disease. Dig Liver Dis. 2006;38:879-84. Savarino E, Bazzica M, Zentilin P, Pohl D, Parodi A, Cittadini G, Negrini S, Indiveri F, Tutuian R, Savarino V, Ghio M. Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring. Am J Respir Crit Care Med. 2009;179:408-13.

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25. Shay S, Tutuian R, Sifrim D, Vela M, Balaji N, Zhang X, Adhami T, Murray J, Peters J, Castell D. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol. 2004;99:1037-43. 26. Spechler SJ, Castell DO. Classification of esophageal motility abnormalities. Gut. 2001;49:145-51. 27. Sweet MP, Patti MG, Leard LE, Golden JA, Hays SR, Hoopes C, Theodore PR. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg. 2007;133:1078-84. 28. Tamhankar AP, Peters JH, Portale G, Hsieh CC, Hagen JA, Bremner CG, DeMeester TR. Omeprazole does not reduce gastroesophageal reflux: new insights using multichannel intraluminal impedance technology. J Gastrointest Surg. 2004;8:890-7.

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29. Tobin RW, Pope CE 2nd, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;158:1804–8. 30. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, Casaburi R, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson D, Macintyre N, Mckay R, Miller MR, Navajas D, Pellegrino R, Viegi G. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26:511-22.

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Received 25/10/2010. Accepted 13/1/2011.

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ARTIGO ORIGINAL / ORIGINAL ARTICLE

ARQGA/1543

GASTROESOPHAGEAL REFLUX DISEASE AND VOCAL DISTURBANCES Maria Aparecida Coelho de Arruda HENRY1, Regina Helena Garcia MARTINS2, Mauro Masson LERCO1, Lídia Raquel CARVALHO3 and Vânia Cristina LAMÔNICA-GARCIA4 ABSTRACT – Context - Gastroesophageal reflux disease is a chronic disease in which gastroduodenal contents reflux into the esophagus. The clinical picture of gastroesophageal reflux disease is usually composed by heartburn and regurgitation (typical manifestations). Atypical manifestations (vocal disturbances and asthma) may also be complaint. Objective – To analyse the clinical, endoscopic, manometric and pHmetric aspects of patients suffering from gastroesophageal reflux disease associated with vocal disturbances. Methods - Fifty patients with gastroesophageal reflux disease were studied, including 25 with vocal disturbances (group 1 – G1) and 25 without these symptoms (group 2 – G2). All patients were submitted to endoscopy, manometry and esophageal pHmetry (2 probes). The group 1 patients were submitted to videolaryngoscopy. Results - Endoscopic findings: non-erosive reflux disease was observed in 95% of G1 patients and 88% of G2. Videolaryngoscopy: vocal fold congestion, asymmetry, nodules and polyps were observed in G1 patients. Manometric findings: pressure in the lower esophageal sphincter (mm Hg): 11.6 ± 5.2 in G1 and 14.0 ± 6.2 in G2 (P = 0.14); pressure in the upper esophageal sphincter (mm Hg): 58.4 ± 15.9 in G1 and 69.5 ± 30.7 in the controls. pHmetric findings: De Meester index: 34.0 ± 20.9 in G1 and 15.4 ± 9.4 in G2 (P<0.001); number of reflux episodes in distal probe: 43.0 ± 20.4 in G1 and 26.4 ± 17.2 in G2 (P = 0.003); percentage of time with esophageal pH value lower than 4 units (distal sensor): 9.0% ± 6.4% in G1 and 3.4% ± 2.1% in G2 (P<0.001); number of reflux episodes in proximal probe: 7.5 ± 10.9 in G1 and 5.3 ± 5.7 in G2 (P = 0.38); percentage of time with esophageal pH values lower than 4 units (proximal probe): 1.2 ± 2.7 in G1 and 0.5 ± 0.7 in G2 (P = 0.21). Conclusions - 1) The clinical, endoscopic, and manometric findings observed in patients with vocal disturbance do not differ from those without these symptoms; 2) gastroesophageal reflux intensity is higher in patients with vocal disturbance; 3) patients without vocal disturbance can also present reflux episodes in the proximal probe. HEADINGS - Gastroesophageal reflux. Voice disorders.

INTRODUCTION

In gastroesophageal reflux disease (GERD), a high prevalence digestive affliction, the gastroduodenal contents leak back into the esophagus and can reach beyond it, go through the upper esophageal sphincter (UES) and reach the aero-digestive airways(4, 20, 28). Such an episode is called laryngopharyngeal reflux(9, 22). The larynx, an important organ responsible for phonation, can be injured in this situation, resulting in a process called acid laryngitis, described by Cherry and Margulies(3) in 1968. The clinical manifestation is voice disorder(24) that affect life quality as they reduce the speaker’s communicative effectiveness. Besides GERD, other factors affect the voice considerably, with the most important being smoking, drinking, voice abuse, allergy, asthma, air conditioning and addiction to drugs, especially marijuana(18, 28, 32). Two mechanisms have been mentioned in the etiopathogenesis of injured organs in the aero-digestive

airways, most importantly the direct contact of refluxed material with the larynx(32). According to Koufmann(13), laryngeal epithelium is 100 times more sensitive than the esophagus. Therefore, the reflux of small amounts of gastric secretion containing hydrochloric acid, pepsin and other digestive enzymes is sufficient to cause serious lesions in the larynx(23). Another aspect to be considered is the fact that the larynx is practically defenseless given that its only defense mechanism is the UES. On the other hand, the esophagus has several defense mechanisms including peristalsis, the mucous barrier, bicarbonate production, and the LES(13). The second mechanism that produces larynx inflammatory process is chemoreceptor stimulation resulting from refluxed material from the stomach, with vagal reflexes followed by coughing and throat clearing. The prevalence of extra esophageal manifestations related to GERD is unknown. It is estimated that 4%

1 Department of Surgery and Orthopedics, Botucatu Medical School, São Paulo State University (UNESP);2 Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, UNESP; 3 Department of Statistics – Institute of Biosciences, UNESP; 4 Post-Graduation in Basic Surgery Program, Botucatu School of Medicine – UNESP, Botucatu, SP, Brasil. Correspondence: Prof. Maria Aparecida Coelho de Arruda Henry – Rua Miguel Ciofi, 200 – Vila dos Médicos – 18607-790 – Botucatu, SP, Brasil. E-mail: rhenry@ibb.unesp.br

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Henry MACA, Martins RHG, Lerco MM, Carvalho LR, Lamônica-Garcia VC. Gastroesophageal reflux disease and vocal disturbances

to 10% of the patients that seek otorhinolaryngologic service show symptoms of this disease(12). This paper aimed to analyze the clinical, endoscopic, manometric and pHmetric aspects of patients with GERD and vocal disturbances and to compare them with chronic refluxers without these symptoms. METHODS

In this retrospective survey, 50 patients with GERD divided into groups of 25 each were studied. They had the following characteristics: Group 1 (G1): patients with typical symptoms of GERD and vocal disturbance (hoarseness, voice failure), being 3 men and 22 women, age varying from 24 to 68 years (average 46.8 ± 12.1 years). Group 2 (G2): 9 men and 16 women with GERD symptoms but without dysphonia (controls), mean age 39.1 ± 10.7 (extremes of 15 and 54 years). Inclusion criteria: females or males, ranging in age from 15 to 70 years, suffering from GERD with or without dysphonia (G1 and G2, respectively). Exclusion criteria: patients under 15 and above 70 years, pregnant women, alcoholics, smokers, and individuals with systemic diseases that affect esophageal motor activity. After the agreement of the research project by the Ethical Committee on Research from our hospital (Of. no 020/2010), the patients from both groups were submitted to endoscopic, manometric, and pHmetric esophagus exams to confirm GERD diagnostic. Individuals with dysphonia were submitted to pharyngolaryngoscopy, carried out by an othorhinolaryngologist, responsible of the Voice Disturbances Ambulatory. Patients from G2 (controls) did not undergo this exam based on an instruction from the Ethics Committee. • Endoscopy After a clinical evaluation, 10-hour fast, and oropharyngeal topical anesthetic with 10% xylocaine spray, the patients were submitted to high digestive endoscopy using Olympus flexible endoscopic video. The exam was performed with the patient in left lateral decubitus. Esophageal mucosa lesions were evaluated using Savary and Miller(25) classification. • Esophageal manometry Esophageal manometry was performed using the usual technique of our laboratory(7) which included an 8-channel probe, physiographic process and continuous infusion device. Through the analysis of the graphic records the following parameters were evaluated: lower and upper sphincter resting pressure of the esophagus (LES, UES) and its peristalsis. • Esophageal 24-hour pH study A pH catheter of two probes was passed transnasally into the previously anesthetized (xylocaine gel) patients after 24–hour fast and 1-week suspension of proton pump inhibitors. The patients were guided to avoid acid food and juices ingestion during the investigation. The distal probe was positioned 5 cm above LES, and

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the proximal probe near the UES. The patient was examined at home for 24 hours (6, 12). The following parameters were evaluated: number of reflux episodes and percentage of time in which the esophageal pH showed values below 4 units in the two probes and the De Meester index. • Videolaryngoscopy The flexible device (Olympus) was introduced nasally into the patients after 12-hour fast and topic anesthesia with 10% xylocaine spray. The patient was seated. This exam permitted evaluation of vocal folds, pharynx, larynx and arytenoids (Figures 1, 2 and 3, Table 1). • Statistical analysis

FIGURE 1. Edema, packydermia and mucosal thickening of vocal folds and posterior glottis

FIGURE 2. Edema in vocal fold, pachydermia inter-aritenoid

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To study the association between qualitative variables, the Chisquare test was used. Student t test was used for comparison of the quantitative variables. The significance level was 5%. RESULTS

FIGURE 3. Polyp in right vocal fold; Reinke’s edema in left vocal fold edema and pachydermia in posterior glottis TABLE 1. Findings observed during pharyngolaryngoscopy Findings n Edema / VF congestion

10

Pachydermia - arytenoid

6

Node in VF

5

Edema in arytenoids

4

Cyst in VF

2

Atrophy in VF

2

Polyp in VF

1

Asymmetry in VF

1

Hoarseness was the most frequently observed vocal disturbance among G1 patients and lasted between 6 months and 20 years (average 3.3 ± 1.6 years) followed by voice failure, referenced by 14 patients (average 1.6 ± 3.3 years). All G1 patients also reported pyrosis, with a mean duration of 9.1 ± 8.5 years. In the control group pyrosis lasted an average of 7.6 ± 6.8 years. The two groups did not differ significantly as to pyrosis duration (P = 0.51) (Table 2). In relation to gender, there was a greater number of females in G1 than in G2 (P = 0.047) (Table 2). High digestive endoscopy revealed similar findings in both groups. Non-erosive reflux (normal mucous relief) was observed in 95% of G1 patients and in 88% of G2 patients (P = 0.53%). Hiatal hernia was diagnosed in 65% of the patients with vocal disturbance and in 60% of controls (P = 0.77). The hiatal hernia diagnostic was validated when epithelial transition (the Z line) was found 2 cm above the diaphragmatic crura(25). The gastric retroversion maneuver showed cardiac orifice incompetence in 70% of G1 and in 60% of G2 patients, with no significant difference (P = 0.54). The esophageal motor activity was studied in all the patients. The average pressure in the LES in individuals with dysphonia was of 11.6 ± 5.2 mm Hg, with no significant difference in relation to controls (14.0 ± 6.2 mm Hg; P = 0.14). A similar result was observed for UES with mean values of 58.4 ± 15.9 mm Hg for G1 and 69.5 ± 30.7 mm Hg for the controls. The esophageal body showed no motor

VF: vocal fold

TABLE 2. Mean and standard deviation of the studied parameters in the two groups, for clinical, manometric and pHmetric findings Groups Parameter Female Age

1

2

88%

64%

P Value 0.047

46.8 ± 12.1

39.1 ± 10.7

0.02

Heartburn

9.1 ± 8.5

7.6 ± 6.8

0.51 NS

LES

11.6 ± 5.2

14.0 ± 6.2

0.14 NS

UES

58.4 ± 15.9

69.5 ± 30.7

0.11 NS

De Meester index

34.0 ± 20.9

15.4 ± 9.4

<0.001

43.0 ± 20.4

26.4 ± 17.2

<0.003

9.0 ± 6.4

3.4 ± 2.1

<0.001

Number reflux

7.5 ± 10.9

5.3 ± 5.7

0.38 NS

% time pH<4

1.2 ± 2.7

0.5 ± 0.7

0.21 NS

Distal probe Number of reflux % time pH<4 Proximal probe

LES = lower esophageal sphincter UES = upper esophageal sphincter

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disturbance in either group. The contraction amplitude in the distal third of the esophagus was 69.5 ± 25.7 mm Hg in voice disturbance patients and 70.0 ± 29.2 mm Hg (P = 0.94) in the controls (Table 2). The prolonged esophageal pHmetry revealed that the De Meester index among dysphonia patients (34.0 ± 20.9) was higher than among controls (15.4 ± 9.4; P<0.001). A similar result was found concerning the number of acid reflux episodes in the distal probe, being 43.0 ± 20.4 in the individuals with dysphonia and 26.4 ± 17.2 in the controls (P < 0.003). The distal probe also showed that the percentage of time in which the esophageal pH values were lower than 4 units was greater among patients with dysphonia (9.0% ± 6.4%) than among controls (3.4% ± 2.1%), with significant difference (P<0.001). The proximal probe did not show significant differences. The number of reflux episodes in G1 patients was 7.5 ± 10.9 versus 5.3 ± 5.7 in the controls (P = 0.38). Time percentage with esophageal pH below 4 units was 1.2 ± 2.7 in G1 and 0.5 ± 0.7 in the controls (P = 0.21) (Table 2). Videolaryngoscopy revealed alterations in the vocal folds in the majority of patients. The most common modifications were: congestion, atrophy, asymmetry, nodules, cysts, and polyps. Pachydermia and edema in arytenoids were other disturbances evaluated by this exam (Table 1; Figures 1, 2 and 3). DISCUSSION

In this retrospective study the clinical, manometric and pHmetric aspects of the esophagus were evaluated in patients with GERD and dysphonia (G1) examined from January 2007 to December 2009. The findings were compared with the same parameters evaluated in chronic refluxers without voice disturbance (G2 – controls). Group 1 patients were, at first, attended in the voice disturbance ward and then sent, as a routine practice, for gastroenterologic evaluation as they complained of pyrosis associated with hoarseness and voice failure. Larynx direct exam showed lesions in the vocal folds (congestion, nodules, polyps) besides pakidermia and edema interarytenoideus, typical of reflux laryngitis(1, 21, 29). Hicks et al.(8) carried out larynx endoscopic investigations of 105 normal volunteers and observed alterations on larynx in 86% of the casuistic. But, these authors did not exclude of the study, individuals using alcohol and tobacco, both factors that can cause lesions on larynx(18, 22, 32). Female patients were more numerous among refluxers with dysphonia than in the control group (P = 0.047), as found by several authors(2, 14, 18, 30). Patients with dysphonia were older (46.8 ± 12.1 years) than the controls (39.1 ± 10.7 years; P = 0.02), suggesting a longer time of aggression to larynx epithelium. However, statistical analysis showed no difference (P = 0.51) in relation to pyrosis duration between the two groups (9.1 ± 8.5 years and 7.6 ± 6.8 years). Digestive endoscopy revealed that most of the patients with dysphonia (95%) did not present lesions in the esophageal epithelium (non-erosive reflux disease), corroborating other

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authors(13, 31). Hiatal hernia, an important GERD pathogenic factor, was diagnosed in 65% of G1 patients and in 60% of G2 (P = 0.77), as also observed by Loffeld and Putten(16). According to Koufman et al.(13), endoscopy is an excellent method to evaluate the esophagus. However, it is not the exam of choice for diagnosing laryngopharyngeal reflux. Our results are similar to findings of some other authors(14, 16). Esophageal motor activity revealed that LES average pressure did not differ between patients with dysphonia and controls. These values were similar to the ones observed by Montenovo et al.(19) and Fouad et al.(5). Somani et al.(27) reported a negative correlation between LES amplitude pressure and the esophagitis degree. According to these authors, non-erosive reflux disease individuals did not present hypotensive LES, as observed in the present study. Knight et al.(11) studied 112 GERD patients with extraesophageal manifestations. Hoarseness was the most prevalent as in the present casuistic. These authors reported esophageal dysmotility in 48% of patients with hoarseness. This finding differed from our casuistic in which the pressure amplitude in the distal third of the esophagus was 58.4 ± 15.9 mm Hg in dysphonic patients and none of them presented amplitude below 30 mm Hg in this esophageal segment (inefficient esophageal motility). This disagreement among findings might be related to exam methodology since the previous authors used a solid state pressure transducer, whereas we used a catheter with continuous infusion for the manometric study. In G2 patients, pressure amplitude in the esophageal distal third was of 70 + 29.2 mm Hg, which does not differ from that of G1 (P = 0.94). Pressure measurement in the UES did not differ from the one observed in the control group, with values similar to those published by Lemme et al.(15), who measured normal individuals. Given our expectation of finding lower indexes, it was surprising to find normal pressure values in individuals with hoarseness. In this situation, the refluxed content from the stomach would reach the larynx more easily, although no research shows this fact. The results concerning the esophageal motor activity in the present study were similar to those of Shaker et al.(26) and Katz(10). Pathologic gastroesophageal reflux was demonstrated by prolonged esophageal pHmetry in 88% of GERD patients with dysphonia, similar to levels found by other researchers(17, 31) . In the control group (without dysphonia), the exam positivity was 56%. In G1 patients, the De Meester index was higher than that observed in the control group (P<0.001). The number of reflux episodes and percentage of time with pH lower than four units in the distal probe, was higher in the group of dysphonic patients than among the chronic refluxers without voice disturbance (P<0.003 and P<0.001, respectively). The seriousness of the gastroesophageal reflux explains the absence of clinical response when patients with dysphonia were submitted to the classic therapy with proton pump inhibitors. We observe that remission of symptoms occurs only after long-term treatment (8 weeks) administered twice a day.

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No significant difference was observed between the groups as to pHmetric parameters recorded in the proximal probe (P = 0.38 for the number of reflux episodes and P = 0.21 for percentage of time with pH lower than 4 units). This result was not expected and no plausible explanation was found. Of the 25 G1 patients studied, 10 actively use the voice because they are teachers. It is likely that GERD and voice abuse constituted a synergic cause, producing voice disturbance.

The conclusions of the present study are: a) The clinical, endoscopic, and manometric findings observed in the patients with voice disturbance do not differ from those without these symptoms. b) Gastroesophageal reflux is more serious in patients with dysphonia. c) Patients without vocal disturbance can also present reflux episodes in the proximal probe.

Henry MACA, Martins RHG, Lerco MM, Carvalho LR, Lamônica-Garcia VC. Doença do refluxo gastroesofágico e distúrbios da voz. Arq Gastroenterol. 2011;48(2):98-103. RESUMO – Contexto – A doença do refluxo gastroesofágico (DRGE) é uma doença crônica na qual o conteúdo gastroduodenal reflui para o esôfago. O quadro clínico da DRGE é usualmente referido como pirose e regurgitação (manifestações típicas). Manifestações atípicas (distúrbios da voz e asma) podem também ser referidas. Objetivo – Analisar os aspectos clínicos, endoscópicos, manométricos e pHmétricos de pacientes portadores da DRGE com distúrbios da voz. Método – Foram estudados 50 pacientes com a DRGE, sendo 25 com distúrbios da voz (grupo 1 – G1) e 25 sem estes sintomas (controles, grupo 2 – G2). Todos os pacientes foram submetidos a endoscopia, manometria e pHmetria esofágica (dois sensores). Os pacientes do G1 foram submetidos a videolaringoscopia. Resultados – Achados endoscópicos: DRGE não-erosiva foi observada em 95% dos pacientes de G1 e em 88% de G2. Videolaringoscopia: congestão das pregas vocais, assimetria, nódulos e pólipos foram diagnosticados nos pacientes do G1. Manometria esofágica: pressão no esfíncter inferior do esôfago (mm Hg): 11,6 ± 5,2 em G1 e 14,0 ± 6,2 em G2 (P = 0,14); pressão no esfíncter superior do esôfago (mm Hg): 58,4 ± 15,9 em G1 e 69,5 ± 30,7 nos controles. Achados pHmétricos: índice de DeMeester: 34,0 ± 20,9 em G1 e 15,4 ± 9,4 em G2 (P<0,001); número de episódios de refluxo no sensor distal: 43,0 ± 20,4 em G1 e 26, 4 ± 17,2 em G2 (P<0,003); percentagem do tempo com pH esofágico menor que 4 unidades (sensor distal): 9,0% ± 6,4% em G1 e 3,4% ± 2,1% em G2 (P<0,001); número de episódios de refluxo no sensor proximal: 7,5 ± 10,9 em G1 e 5,3 ± 5,7 em G2 (P = 0,38); percentagem de tempo com pH esofágico menor que quatro unidades (sensor proximal): 1,2% ± 2,7% em G1 e 0,5% ± 0,7% em G2 (P = 0,210). Conclusões – Os aspectos clínicos, endoscópicos e manométricos em pacientes com a DRGE e distúrbios da voz não diferem dos pacientes sem estes sintomas. A intensidade do refluxo gastroesofágico é maior nos pacientes com distúrbios da voz. Os pacientes sem distúrbios da voz podem também apresentar episódios de refluxo gastroesofágico no sensor proximal. DESCRITORES – Refluxo gastroesofágico. Distúrbios da voz.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Carr M, Nguyen A, Poje C, Pizzuto M, Nagy M, Brodsky L. Correlation of findings on direct laryngoscopy and bronchoscopy with presence of extraesophageal reflux disease. Laryngoscope. 2000;110:1560-2. Cervantes O, Abrahão M. O nódulo vocal - conceitos atuais. RBM Rev Bras Med. 1995;11:12-7. Cherry J, Margulies SI. Contact ulcers of larynx. Laryngoscope. 1968;78: 1937-40. Cuenca-Abente F, Faerberg A, Fernández Marty P, Corti R. Sintomas respiratorios asociados a da enfermedad por reflujo gastroesofágico: diagnóstico y tratamiento. Acta Gastroenterol Latinoam. 2006;36:42-50. Fouad YM, Katz PO, Hatlebakk JG, Castell DO. Ineffective esophageal motility: the most common motility abnormality in patients with GERD – associated respiratory symptoms. Am J Gastroenterol. 1999;94:1464-7. Henry MA. [Continuous evaluation of esophageal pH for 24 hours and its use in the diagnosis of gastroesophageal reflux]. Rev. Hosp Clin Fac Med São Paulo. 1984;39:203-7. Henry MA, Habermann MC, Rocha OM. Esophageal motor disturbances in progressive systemic sclerosis. Dis Esophagus. 1999;12:51-3. Hicks DM, Ours TM, Abelson TI, Vaezi MF, Richter JE. The prevalence of hypopharynx findings associated with gastroesophageal reflux in normal volunteers. J Voice. 2002,16:564-79. Jacob P, Kahrilas PJ, Herzon G. Proximal esophageal pHmetry in patients with ‘reflux laryngitis’. Gastroenterology. 1991;100;305-10. Katz PO. Ambulatory esophageal and hypopharyngeal pH monitoring in patients with hoarseness. Am J Gastroenterol. 1990;85:38-40. Knight RE, Wells JR, Parrish RS. Esophageal dysmotility as an important cofactor in extraesophageal manifestations of gastroesophageal reflux. Laryngoscope. 2000;110:1462-6. Koufman JA, Wiener GJ, Wu WC, Castell DO. Reflux laryngitis and its sequela: the diagnostic role of ambulatory 24-hour monitoring. J Voice. 1988;2:78-9.

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13. Koufman JA. Laryngopharyngeal reflux is different from classic gastroesophageal reflux disease. Ear nose Throat J. 2002;81:1-5. 14. Koufman JA, Belafsky PC, Bach KK, Daniel E, Postma GN. Prevalence of esophagitis in patients with pH – documented laryngopharyngeal reflux. Laryngoscope. 2002;112:1606-9. 15. Lemme EMO, Domingues GR, Silva LFD, Firman CG, Pantoja JAS. Esofagomanometria computadorizada: resultados preliminares em voluntários adultos saudáveis. GED Gastroenterol Endoscop Dig. 2001;20:29-35. 16. Loffeld RJ, van der Putten AB. Rising incidence of reflux oesophagitis in patients undergoing upper gastrointestinal endoscopy. Digestion. 2003;68:141-4. 17. Marambaia O, Andrade NA, Varela DG, Juneal MC. Refluxo laringofaríngeo: estudo prospectivo correlacionando achados laringoscópicos precoces com a pHmanometria de 24 horas de 2 canais. Rev Bras Otorrinolaringol. 2002;68:81-5. 18. Martins RHG. Aspectos anatômicos e fisiológicos da laringe. In: A voz e seus distúrbios. Botucatu: Cultura Acadêmica, 2005. p.15-30. 19. Montenovo M, Tatum RP, Figueredo E, Martin AV, Vu H, Quiroga E, Pellegrini CA, Oelschlager BK. Does combined multichannel intraluminal esophageal impedance and manometry predict postoperative dysphagia after laparoscopic Nissen fundoplication? Dis Esophagus. 2009;22:656-63. 20. Moraes-Filho J, Cecconello I, Gama-Rodrigues JJ, Castro L, Henry MA, Meneghelli UG, Quigley E. Brazilian consensus on gastroesophageal reflux disease: proposal for assesment, classification and management. Am J Gastroenterol. 2002;97:241-8. 21. Nishimura K, Fujita H, Tanaka T, Tanaka Y, Matono S, Murata K, Umeno H, Shirouzu K. Endoscopic classification for reflux pharyngolaryngitis. Dis Esophagus. 2010;23:20-6. 22. Ozturk O, Oz F, Karakullukcu B, Oghan F, Guclu E, Ada M. Hoarseness and laryngopharyngeal reflux: a cause and effect relationship or coincidence? Eur Arch Otorhinolaryngol. 2006;263:935-9. 23. Potluri S, Friedenberg F, Parkman HP, Chang A, MacNeal R, Manus C, Bromer MQ, Malik A, Fisher RS, Nugent T, Thangada VK, Kueppers F, Miller LS. Comparison of salivary / sputum pepsin assay with 24-hour esophageal pH monitoring for detection of gastric reflux into the proximal esophagus, oropharynx and lung. Dig Dis Sci. 2003;48: 1813-7.

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24. Richter JE. Ear, nose and throat and respiratory manifestations of gastroesophageal reflux disease: an increasing conundrum. Eur J Gastroenterol Hepatol. 2004;16:837-45. 25. Savary M, Miller G. The esophagus. handbook and atlas of endoscopy. Solothurn: Verlag Gassmann; 1978. 26. Shaker R, Milbrath M, Ren J, Toohill R, Hogan WJ, Li Q, Hofmann CL. Esophagopharyngeal distribution of reflux and gastric acid in patients with reflux laryngitis. Gastroenterology. 1995;109:1575-82. 27. Somani SK, Ghoshal VC, Saraswat VA, Aggarwal R, Misra A, Krishnanai N, Naik SR. Correlation of esophageal pH and motor abnormalities with endoscopic severity of reflux esophagitis. Dis Esophagus. 2004;17:58-62. 28. Vaezi MF, Hicks DM, Abelson TI, Richter JE. Laryngeal signs and symptoms and gastroesophageal reflux disease (GERD): a critical assessment of cause and effect association. Clin Gastroenterol Hepatol. 2003;1:333-44.

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29. Vaezi MF. Are there specific laryngeal sign for gastroesophageal reflux disease? Am J Gastroenterol. 2007;102:723-4. 30. Vashani K, Murugesh M, Hattiangadi G, Gore G, Kerr V, Ranesh VS, Sandur V, Bhatia SJ. Effectiveness of voice therapy in reflux-related voice disorders. Dis Esophagus. 2010;23:27-32. 31. Wiener GJ, Koufman JA, Wu WC, Cooper JB, Richter JE, Castell DO. Chronic hoarseness secondary to gastroesophageal reflux disease: documentation with 24-hour ambulatory pH monitoring. Am J Gastroenterol. 1989;84:1503-8. 32. Wong RKH, Hanson DG, Warring PJ, Shaw G. ENT manifestations of gastroesophageal reflux. Am J Gastroenterol. 2000;95:S15-22.

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Received 17/8/2010. Accepted 20/10/2010.

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ARTIGO ORIGINAL/ ORIGINAL ARTICLE

ARQGA/1544

DOES LOW DOSE 13C-UREA BREATH TEST MAINTAIN A SATISFACTORY ACCURACY IN DIAGNOSING Helicobacter pylori INFECTION? Luiz Gonzaga Vaz COELHO1, Arilto Eleutério da SILVA Jr1, Maria Clara de Freitas COELHO2, Francisco Guilherme Cancela e PENNA1, Rafael Otto Antunes FERREIRA1 and Elisa Viana SANTA-CECILIA2

ABSTRACT – Context - The standard doses of 13C-urea in 13C-urea breath test is 75 mg. Objective - To assess the diagnostic accuracy of 13C-urea breath test containing 25 mg of 13C-urea comparing with the standard doses of 75 mg in the diagnosis of Helicobacter pylori infection. Methods – Two hundred seventy adult patients (96 males, 174 females, median age 41 years) performed the standard 13 C-urea breath test (75 mg 13C-urea) and repeated the 13C-urea breath test using only 25 mg of 13C-urea within a 2 week interval. The test was performed using an infrared isotope analyzer. Patients were considered positive if delta over baseline was >4.0‰ at the gold standard test. Results – One hundred sixty-one (59.6%) patients were H. pylori negative and 109 (40.4%) were positive by the gold standard test. Using receiver operating characteristic analysis we established a cut-off value of 3.4% as the best value of 25 mg 13C-urea breath test to discriminate positive and negative patients, considering the H. pylori prevalence (95% CI: 23.9-37.3) at our setting. Therefore, we obtained to 25 mg 13C-urea breath test a diagnostic accuracy of 92.9% (95% CI: 88.1–97.9), sensitivity 83.5% (95% CI: 75.4–89.3), specificity 99.4% (95% CI: 96.6–99.9), positive predictive value 98.3% (95% CI: 92.4-99.4), and negative predictive value 93.0% (95% CI: 88.6-96.1). Conclusions - Low-dose 13C-urea breath test (25 mg 13C-urea) does not reach accuracy sufficient to be recommended in clinical setting where a 30% prevalence of H. pylori infection is observed. Further studies should be done to determine the diagnostic accuracy of low doses of 13C-urea in the urea breath test. HEADINGS - Helicobacter infections. Breath tests.

INTRODUCTION

The diagnosis of the gastric infection by H. pylori is regularly performed by endoscopic examination with the collection of gastric mucosa fragments for histological examination, microbiological tests or even colorimetric methods like the urease test. The diagnosis can also be performed through non-endoscopic techniques like 13C-urea or 14C-urea breath tests. Such tests are based on the organism’s property to produce high quantities of the urea enzyme. The principle of the test is based on the ability of H. pylori (if present in the gastric setting) to break down orally absorbed 13 C or 14C labeled urea. 13CO2 or 14CO2 diffuses into the blood and is excreted via the lung and can therefore be easily measured in the expired air using a mass or an infrared spectrometer(15, 16). The 13C-urea breath test (UBT) is considered the gold standard in the identification of H. pylori as it is a non-invasive, non-radioactive method (13C is a natural

isotope), which is reproducible and secure (able to be performed many times on a single patient, including pregnant women and children), and has a sensitivity and specificity greater than 90% in adults(2, 6, 9, 11). There is no uniform standardization and the great majority of the protocols use a 75 mg dose of urea and two breath samples, one collected before and another collected 10–30 min after urea ingestion. Although the cut-off point must be adapted to different factors, in most studies it is located within the range between 2% and 5%(6). Despite its high level of accuracy, UBT is still fairly unavailable on a global scale, mainly due to its high cost. One recent study suggests the UBT performed with doses that were 2 to 3 times less than that routinely recommended, and therefore of a more accessible cost, was still capable of maintaining high levels of sensitivity and specificity(5). The aim of the present study was to compare the efficacy of the 13C-urea breath test performed with a

1 Instituto Alfa de Gastroenterologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil; 2 Faculdade de Medicina de Barbacena, Barbacena, MG, Brazil. Correspondence: Prof.Luiz Gonzaga Vaz Coelho – Rua dos Otoni, 705/601 – 30150-270 – Belo Horizonte, MG, Brasil. E-mail:lcoelho@gold.com.br

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Coelho LGV, Silva Jr AE, Coelho MCF, Penna FGC, Ferreira ROA, Santa-Cecilia EV. Does low dose 13C-urea breath test maintain a satisfactory accuracy in diagnosing Helicobacter pylori infection?

25 mg dose of labelled urea (25-UBT) with that performed using a standard 75 mg dose (75-UBT), considered the gold standard, in the detection of H. pylori infection. METHODS

The study was conducted at the Breath Tests Laboratory in the Gastroenterology Unit from University Hospital of the Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. This laboratory performs UBT to adult population of Belo Horizonte city (around 2.5 million inhabitants) to initial diagnosis of H. pylori infection and/ or post-treatment control. Patients Initially, aimed at determining the H. pylori prevalence at our setting we analyzed 179 adult patients who were, consecutively, referred to our lababoratory for UBT from February to April 2007. This sample included patients with and without previous treatment to H. pylori infection. Next, from May 2007 to April 2008 we studied 270 patients who were referred to our unit. Patients were excluded from the study if they were taking proton pump inhibitors or H2 receptor antagonists within the last week, or antibiotics and/or bismuth compounds within the 4 weeks preceding the initial visit. All participants included in both cohorts underwent a clinical exam and answered a standardized questionnaire to log clinical and demographic data as well as information about previous treatments for the eradication of H. pylori. C-urea breath test All participants took a 75-UBT and then, within a 2 week interval, took a 25-UBT. No kind of treatment was allowed during this interval. The following methodology was used for the breath tests: after an overnight fast, a sample of exhaled CO2 air was taken, corresponding to time 0 (control), through the inflation of a breath bag. Then, patients ingested 75 mg (or 25 mg) of 13C-urea in 200 mL of pure orange juice, without the addition of water or sugar. Another breath sample was taken 30 min after the administration of the substrate. Samples were analyzed using an infrared analyzer (IRIS, Wagner Analysen-Technik, Bremen, Germany) and the results reported as delta over baseline per thousand (DOB‰), which indicates the change in the 13CO2/12CO2 ratio brought about by the metabolic activity induced by the administration of the labelled urea. A positive 75-UBT was previously validated by our group and were those with DOB values above 4‰(2). 13

Statistics The sample size (number of positive and negative patients needed) was calculated based on the findings from Gatta et al.(5) regarding the estimate of sensitivity, specificity, and amplitudes of the respective confidence intervals. In this light, a sample of 270 patients was set up, including 161 H. pylori-negative and 109 H. pylori-positive patients. Chi-square, t Student,

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and Mann-Whitney tests were used, as appropriate, in the comparison of the two groups (H. pylori-positive and H. pylori-negative). Proportions and 95% confidence intervals (CI) were calculated using the method recommended by Newcombe et al.(12). Sensitivity, specificity, positive predictive value (PV + ve), negative predictive value (PV - ve), and their 95% CI were calculated as compared to the defined gold standard, using methods recommended by Altman(1). The receiver operating characteristic (ROC) analysis was performed using non-parametric methods to define the accuracy of 25-UBT as well as in choosing the best cutoff point, bearing in mind the H. pylori prevalence in our setting. Statistical analysis and graphs were constructed using Minitab 13, Excel, and the confidence interval analysis (CIA). Ethics The present study has been approved by the Ethics Committees of University Federal de Minas Gerais and Faculdade de Medicina de Barbacena, MG, Brazil and written informed consent was obtained from all patients. RESULTS

The present study involved 492 patients, with 179 recruited to determine the prevalence of H. pylori infection in our setting. Likewise, 313 patients were recruited to perform both 25- and 75-UBT: 43 patients were excluded as they either did not show up for the second breath test (35 patients) or presented the need for the use of proton pump inhibitor or antibiotics in the interval between exams (8 patients). Thus, 270 patients were included in the cohort aimed at comparing the 75-UBT to the 25-UBT. H. pylori prevalence in our setting This cohort included 179 patients: 122 women (68.2%), 57 men (31.8%), at a median age of 48.3 years, SD 15.25. One hundred and five patients presented 75-UBT negative (99 patients had previously undergone anti-H. pylori treatment, while 26 patients had never undergone anti-H. pylori treatment), whereas 54 patients presented 75-UBT positive (27 patients had never undergone anti-H. pylori treatment, while 27 patients had undergone previous anti-H. pylori treatment). The prevalence of H. pylori infection found was 30.2% (95% CI: 23.9-37.3). Comparison between 25-UBT and 75-UBT In this cohort, 270 patients underwent 75-UBT and 25UBT within a median interval of 8 days, interquartile range of 7-15 days. One hundred and sixty one patients (59.6%) presented 75-UBT negative (83 patients had previously undergone anti-H. pylori treatment, while 78 patients had never undergone anti-H. pylori treatment), whereas 109 patients (40.4%) presented 75-UBT positive (76 patients had never undergone anti-H. pylori treatment, while 33 had previously undergone anti-H. pylori treatment). Table 1 shows the demographic characteristics of the studied population.

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TABLE 1. Demographic characteristics of the 270 patients included in the study Total 75-UBT negative 75-UBT positive Characteristics (n = 270) (n = 161) (n = 109) Male/female 96/174 58/103 38/71 P-value = 0.845 * Median age 41.0 36.0 46.0 (IQR) (23.0 – 57.0) (22.0 – 54.5) (25.5 – 61.0) P-value = 0.009 ** Median BMI 24.3 24.3 24.2 (IQR) (22.0 – 27.8) (22.1 – 28.3) (21.9 – 27.5) P-value = 0.773 ** UBT = 13C-urea breath test; IQR = interquartill range; BMI = body mass index ; * = chi-squared test; ** = Mann-Whitney test

TABLE 2. Values of descriptive statistics from 25-UBT for 75-UBT positive and negative patients Total 75-UBT negative 75-UBT positive 25-UBT values (n = 270) (n = 161) (n = 109) Mean Median Standard deviation IQR

3.1 0.6 5.8 -0.9 - 5.9

-0.4 -0.5 1.5 -1.3 - 0.4

95% CI for the difference in populations means (-9.8 to -7.5) __ __ __

8.3 7.6 5.9 4.1 - 12.1 P-value = 0.000 #

IQR = Interquartill range; # = t Student test; UBT = 13C-urea breath test

No significant differences between gender and body mass index (BMI) among the H. pylori negative and H. pylori positive patients could be observed in the cohort. The H. pylori negative patients presented median ages which were significantly lower than the H. pylori positive patients (P = 0.009). Table 2 shows the values of descriptive statistics from 25UBT for 75-UBT positive and negative patients. A statistically significant difference was observed among the means obtained in the 25-UBT in H. pylori negative and H. pylori positive patients (P = 0.000). ROC curve The ROC curve (Figure 1) provided a 92.99% (95% CI: 88.07-97-92) diagnostic accuracy. 100%

SENSIVITY(%)

80% 60% 40% 20% 0% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 1 - SPECIFICITY FIGURE 1. ROC curve

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Choice of best cut-off point of 25-UBT for the 270 patients studied The sensitivity and specificity of the test were calculated for each possible cut-off point. The best cut-off point for this study, 3.4‰, was chosen considering the prevalence of H. pylori infection in our setting as 30.2% (95% CI: 23.9–37.3) and the upper positive predictive value (PV+) (or lower false-positive results). Although the sample size of the population studied was not so big, all prevalence values in the 95% CI prevalence (23.9% to 37.3%) confirmed 3.4‰ as the best cut-off of the study. Table 3 shows the values of sensitivity and specificity for some cut-off points, PV+ ve, PV- ve, and the corresponding false-results (positive and negatives) for the prevalence of 30.2%. The results demonstrate that the best cut-off point was 3.4, with lower probabilities of false-positive values, bearing in mind the previous prevalence set for H. pylori infection. Considering the sample of 270 patients and the cutoff point equal to 3.4‰, the present study determined the following values: diagnostic accuracy of 25 mg UBT: 92.9% (95% CI: 88.1–97.9); sensitivity 83.5% (95% CI: 75.4–89.3); specificity 99.4% (95% CI: 96.6–99.9); PV+ ve 98.3% (95% CI: 92.4-99.4), and PV- ve 93.0% (95% CI: 88.6-96.1). DISCUSSION

UBT is currently considered the most accurate noninvasive test in detecting H. pylori infection, especially in the confirmation of its eradication after antimicrobial treatment.

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TABLE 3. Values of sensibility and specificity for some cut-off points, PV+ ve, PV- ve and false-results (positive and negatives) for the prevalence of 30.2% Cut-off Sensitivity Specificity PV+ ve False-positive PV- ve False-negative 2.5 87.16% 95.65% 89.66% 10.34% 94.51% 5.49% 2.7 86.24% 96.89% 92.32% 7.68% 94.21% 5.79% 3.1 85.32% 98.76% 96.74% 3.26% 93.96% 6.04% 3.4 83.49% 99.38% 98.31% 1.69% 93.29% 6.71% 3.8 78.90% 99.38% 98.21% 1.79% 91.59% 8.41%

Nevertheless, its use is still not largely employed worldwide because 13C-urea used to carry out the tests is still costly and makes the widespread use of this test difficult. In this light, different studies have been carried out aimed at reducing the need for serial tests and reducing the dosage of the substrate used in the exams. Although expert groups and regulatory agencies still advocate two UBT after treatment for the confirmation of eradication(8, 19), one study recently demonstrated that a single UBT performed 4 weeks after treatment is as effective as two serial breath tests in confirming H. pylori eradication. Nevertheless, the second breath test doubles the cost with no additional clinical benefit(17). Although the dose 13C-urea described in the pioneer study carried out by Graham et al.(7), in 1987, was of 5 mg/kg (approximately 300 mg), later studies showed that lower doses, between 100 mg and 125 mg, were capable of achieving a sensitivity and specificity of up to 100%(9, 11). More recently, the dose of 75 mg has been recommended and adopted in clinical studies and commercial kits(6, 8, 13). In an attempt to reduce the dose of the substrate used even further, some studies, which employed 50 mg of 13 C-urea released as a liquid solution or in capsules for gastric disintegration, have shown sensitivity and specificity indices greater than 95%(4, 10). In 2006, Gatta et al.(5), using UBT with doses of 10 mg, 15 mg and 25 mg of 13C-urea, suggested that doses of up to 15 mg were accurate in diagnosing H. pylori infection in patients that had not undergone treatment or after the eradication of the bacteria. One limitation of this study was not determining the prevalence of the H. pylori infection in the studied population when determining the sensitivity, specificity, and predictive value in the studied tests. The present study first demonstrated, in a prospective manner, that, in our Unit, 70% of the patients that perform UBT take it to control the eradication of the H. pylori infection, while 30% have never undergone previous treatment for H. pylori. The prevalence of H. pylori infection was therefore 30.2% (95% CI: 23.9-37.3). Having defined the prevalence and its CI, it was determined that the best cut-off point for 25-UBT, with lower possibilities of false-positive values, is that which presents a DOB of equal to 3.4‰. With this cutoff point, the test achieved a sensitivity of 83.49% (95% CI: 75.4-89.3), a specificity of 99.38% (95% CI: 96.6-99.9), and a diagnostic accuracy of 92.99% (IC 95%: 88.07-97.92). Such results, although reasonable, hinder the recommendation of the 25-UBT in daily practice due to the relatively high probability of obtaining false-negative results for the CI of the considered prevalence.

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Some limitations of our study must be addressed: could the female predominance or the significantly (P = 0.009) lower ages in H. pylori negative patients have some influence in our results? Although one study suggests that untreated infected females may have higher UBT values compared to untreated infected males(14), these findings are not considered sufficient to change the cut-off value among sexes(6). Concerning the lower age observed in our H. pylori negative group compared to H. pylori positive group we attributed this finding to an overall decline on H. pylori prevalence observed in the last 2 decades in children and young population in Brazil(3) and, also, to the increasing tendency to perform UBT to screen dyspeptic young people. The similar BMI values in H. pylori-positive and H. pylorinegative subjects of our study give consistency to our sample selection and reduce the possibility that young people, as observed in children under 6 years of age(20), could produce smaller amounts of endogenous 12CO2, changing the ratio 13 CO2/12CO2 with increase in DOB values and consequent false-positive results. And finally, some concern might be raised by the reference test used in the study, consisting of only one UBT performed with orange juice instead of citric acid. Just one UBT is now considered sufficient for initial diagnosis and for the determination of the outcome of H. pylori eradication therapy for most guidelines and studies(17). Although the addition of a test meal, especially citric acid solution incorporated to 13C-urea may improve diagnostic performance of UBT(6), our test confirmed previous studies showing a very good discrimination between infected and non-infected patients when performed in fasting patients, with no test meal and using DOB values lower than 5‰(6, 7, 18). In conclusion, the results of this study demonstrate that UBT that use low doses (25 mg) of 13C-urea were not accurate enough to be recommended in clinical setting where a 30% prevalence of H. pylori infection is observed. Further studies should be done to determine the diagnostic accuracy of low doses of 13C-urea in the urea breath test. ACKNOWLEDGEMENTS

Financial support for the study was furnished by FAPEMIGBrazil. The authors would like to thank Osmar R. Trindade, Maurílio M. Fernandes and Maria de Lourdes M. Fernandes for technical and statistical assistance. The authors also thank Dr. Izabela M. Bomfim, Rafael O.A. Ferreira, Marina R. Moreira, Raphael G. Andrade, Sheila M. Oliveira e Luiza Q. Ottoni for performing the breath tests.

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Coelho LGV, Silva Jr AE, Coelho MCF, Penna FGC, Ferreira ROA, Santa-Cecilia EV. Does low dose 13C-urea breath test maintain a satisfactory accuracy in diagnosing Helicobacter pylori infection?

Coelho LGV, Silva Jr AE, Coelho MCF, Penna FGC, Ferreira ROA, Santa-Cecília EV. Precisão do teste respiratório com pequenas doses de ureia marcada com carbono-13 no diagnóstico da infecção por Helicobacter pylori. Arq Gastroenterol. 2011;48(2):104-8 . RESUMO – Contexto - A dose convencional de 13C-ureia para a realização do teste respiratório com 13C-ureia é 75 mg. Objetivo - Determinar a precisão diagnóstica do teste respiratório contendo 25 mg de 13C-ureia comparada com a dose convencional de 75 mg para o diagnóstico de infecção por H. pylori. Métodos – Duzentos e setenta pacientes adultos (96 homens, 174 mulheres, idade mediana de 41 anos) realizaram o teste respiratório convencional (75 mg 13C-ureia) e repetiram o teste respiratório usando apenas 25 mg de 13C-ureia dentro de 2 semanas de intervalo. O teste respiratório foi realizado empregando-se analisador de isótopos por infravermelho. Os pacientes foram considerados positivos quando apresentavam valor delta acima da linha de base >4.0 no teste respiratório convencional (padrão-ouro). Resultados – Cento e sessenta e um pacientes (59,6%) eram H. pylori negativos e 109 (40,4%) eram positivos aos testes respiratórios convencionais. Para definição do melhor ponto de corte discriminatório entre positivos e negativos pelo teste respiratório com 25 mg, foi utilizado a curva ROC, obtendo-se o valor de 3,4%, considerando–se a prevalência de 30,2% (IC 95%: 23.9-37.3) da infecção por H. pylori no laboratório, onde se realizou este estudo. Desta forma, para o teste respiratório com 25 mg foi obtida uma precisão diagnóstica de 92,9% (IC 95%: 88,1–97,9), sensibilidade de 83,5% (IC 95%: 75,4–89,3) e especificidade de 99,4% (IC 95%: 96,6-99,9). Conclusões – Teste respiratório com dose baixa (25 mg) de 13C-ureia não proporciona precisão suficiente para ser recomendado em ambientes clínicos, onde a prevalência de H. pylori está situada em torno de 30%. DESCRITORES - Infecções por helicobacter. Testes respiratórios.

REFERENCES 1. 2.

3. 4. 5. 6. 7. 8.

9.

Altman DG. Diagnostic tests. In: Altman DG, Machin D, Trevor NB, Gardner MJ, editors. Statistics with confidences. 2nd. ed. Bristol: BMJ Books; 2003. p. 105-19. Coelho LG, Reber M, Passos MC, Aguiar RO, Casaes PE, Bueno ML, Yasaki FR, Castro FJ, Vieira WL, Franco JM, Castro LP. Application of isotope-selective non-dispersive infrared spectrometry for the evaluation of 13C-urea breath test: comparison with three concordant methods. Braz J Med Biol Res. 1999;32:1493-7. Coelho MC, Bonfim IM, Moreira MR, Santa-Cecilia EV, Oliveira SM, Trindade OR, Coelho LG. Helicobacter pylori among medical students in Brazil [abstract]. Helicobacter. 2007;12:454. Gatta L, Vakil N, Ricci C, Osborna JF, Tampieri A, Perna F, Miglioli M, Vaira D. A rapid, low-dose, 13C-urea tablet for the detection of Helicobacter pylori infection before and after treatment. Aliment Pharmacol Ther. 2003;17:793-8. Gatta L, Ricci C, Tampieri A, Osborn J, Perna F, Bernabucci V, Vaira D. Accuracy of breath test using low doses of 13C-urea to diagnose Helicobacter pylori infection: randomized controlled trial. Gut. 2006;55:457-62. Gisbert JP, Pajares JM. 13C-urea breath test in the diagnosis of Helicobacter pylori infection - a critical review. Aliment Pharmacol Ther. 2004;20:1001-17. Graham DY, Klein PD, Evans DJ Jr, Evans DG, Alpert LC, Opekun AR, Boutton TW. Campylobacter pylori detected nonivasively by the 13C-urea breath test. Lancet. 1987;1:1174-7. Health Canada. Guidance When Developing Therapeutic Regimens for the Eradication of Helicobacter pylori in GI diseases. Available at: http://www.hc-sc. gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/helicobacter/hpylor-eng. php (accessed on 19 December 2009). Klein PD, Malaty HM, Martin RF, Graham KS, Genta RM, Graham DY. Noninvasive detection of Helicobacter pylori infection in clinical practice: the 13 C urea breath test. Am J Gastroenterol. 1996;91:690-4.

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10. Liao CC, Lee CL, Chiang TC, Lee SC, Huang SH, Tu TC, Chen TK, Wu CH. The 13C-urea breath test to detect Helicobacter pylori infection: a validated simple methodology with 50 mg 13C-urea. Aliment Pharmacol Ther. 2002;16:787-92. 11. Logan RPH, Dill S, Bauer FE. et al. The European 13C-urea breath test for detection of Helicobacter pylori. Eur J Gastroenterol Hepatol. 1991;3:915-21. 12. Newcombe RG, Altman DG. Proportions and their differences. In: Altman DG, Machin D, Bryant TN, Gardner M, editors. Statistics with confidence. 2nd ed. Bristol: BMJ Books; 2003. p.45-56. 13. Savarino V, Vigneri S, Celle G. The 13C urea breath test in the diagnosis of Helicobacter pylori infection. Gut. 1999;45:18-22. 14. Shmuely H, Yahav J, Samra Z, Chodick G, Ofek I. Elevated 13C-urea breath test values females infected with Helicobacter pylori. Dig Dis Sci. 2007;52:402–4. 15. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:117586. 16. Talley NJ, Li Z. Helicobacter pylori: testing and treatment. Expert Rev Gastroenterol Hepatol. 2007;1:71-9. 17. Vakil N, Zullo A, Ricci C, Hassan C, Vaira D. Duplicate breath testing to confirm eradication of Helicobacter pylori: incremental benefit and cost in 419 patients. Aliment Pharmacol Ther. 2008;28:1304-8. 18. Wong WM, Wong BC, Li TM, Wong KW, Cheung KL, Fung FM, Xia HH, Lam SK. Twenty-minute 50 mg 13C-urea breath test without test meal for the diagnosis of Helicobacter pylori infection in Chinese. Aliment Pharmacol Ther. 2001;15:1499-504. 19. Working Party of the European Helicobacter pylori Study Group. Technical annex: tests used to assess Helicobacter pylori infection. Gut. 1997;41: S10–8. 20. Yang HR, Ko JS, Seo JK. Does the diagnostic accuracy of the 13C-urea breath test vary with age even after the application of urea hydrolysis rate? Helicobacter. 2008;13:239–44. Received 20/7/2010. Accepted 3/11/2010.

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ARTIGO ORIGINAL/ ORIGINAL ARTICLE

ARQGA1545

Helicobacter pylori HAS NO INFLUENCE ON DISTAL GASTRIC CANCER SURVIVAL Renata S. SANTOS1, José E. V. LOURENÇO1, Fernando Augusto Mardiros HERBELLA1, Jose Carlos Del GRANDE1 and Marco G. PATTI2

ABSTRACT – Context - There is some evidence that Helicobacter pylori correlates with distal gastric cancer genesis. However, few studies analyzed the survival related to H. pylori infection. Objective - To correlate gastric cancer survival and H. pylori infection. Methods – Sixty-eight patients with distal gastric cancer that underwent subtotal gastrectomy were studied. Minimal follow-up was 1 month. H. pylori infection was confirmed by biopsy. Results – Thirty-four patients (19 males (55.9%), mean age 60.9 ± 14.03, range 33-82 years) were H. pylori positive. Thirty-four patients (16 males (47.1%), mean age 57.9 ± 13.97, range 27-85 years) were H. pylori negative. Groups were comparable in regards to age (P = 0.4), gender (P = 0.5), stage [T (P = 0.2), N (P = 0.6) and M (P = 0.9)]. Survival was not different when groups were compared [P = 0.1616 (hazard ratio 0.6834, 95% CI 0.4009 to 1.1647)]. Conclusions – H. pylori infection does not affect distal gastric cancer survival. HEADINGS – Stomach neoplasms. Helicobacter infections.

INTRODUCTION

Gastric cancer survival is low, especially in the West, not exceeding 25% at 5 years (2). The prognosis after treatment is linked to classic oncologic factors such as tumor histology, stage, macroscopic characteristics, etc. (2, 3). There is strong evidence that Helicobacter pylori (HP) is associated to gastric adenocarcinoma genesis (2, 7); however, few studies have analyzed survival related to HP infection(4, 5, 6, 8). This study aims to analyze HP infection as a prognostic factor for survival in patients with distal gastric adenocarcinoma.

All patients underwent an open subtotal gastrectomy + DII lymphadenectomy with curative intent (R0 resection). Tumor stage were as follows, T1 – 20 (29%), T2 – 19 (28%), T3 – 27 (40%), T4 – 2 (3%); N0 – 28 (41%), N1 – 29 (43%), N3 – 11 (16%); M0 100%. Patients were followed-up with an upper digestive endoscopy and computerized tomography scan every 6 months until 5 years after the operation and yearly thereafter. Mean time of follow-up was 65.6 ± 53.2 months (range 6.7-207.3 months). Logrank test, Student’s t test, Fisher’s test, and Mann’s Whitney test were used as indicated. P<0.05 was considered significant. RESULTS

METHODS

Sixty-eight patients with stomach adenocarcinoma originated in the gastric antrum submitted to surgical therapy were retrospectively studied. Patients were grouped according to the presence of HP infection detected by endoscopic biopsy and histological analysis prior to the operation. Samples were collected from normal mucosa at the antrum. HP strains were not determined.

HP infection was detected in 34 patients, comprising 19 males (55.9%), with a mean age of 60.9 ± 14.03 years (range 33-82 years). HP infection was not detected in 34 patients, comprising 16 males (47.1%), 16 males (47.1%), with a mean age of 57.9 ± 13.97 years (range 27-85 years). Groups were comparable in regards to age (P = 0.4), gender (P = 0.5), stage [T (P = 0.2), N (P = 0.6) and M (P = 0.9)] and time of follow-up (P = 0.9).

Poster presentation, Digestive Disease Week (DDW), May 1-5, 2010, New Orleans, USA Author’s contribution: RSS: acquisition of data, analysis and interpretation of data, drafting the article, final approval of the version to be published; JEVL: acquisition of data, analysis and interpretation of data, drafting the article, final approval of the version to be published; FAMH: conception and design, acquisition of data, analysis and interpretation of data, drafting the article, final approval of the version to be published; JCDG: review for intellectual content, final approval of the version to be published. 1 Department of Surgery, Escola Paulista de Medicina, Federal University of Sao Paulo, Sao Paulo, Brazil; 2 Department of Surgery, University of Chicago, Chicago, USA. Correspondence: Dr. Fernando A. M. Herbella – Hospital São Paulo – Surgical Gastroenterology – Division of Esophagus and Stomach – Rua Diogo de Faria, 1087, cj. 301 – 04037-003 – São Paulo, SP, Brasil. E-mail: herbella.dcir@epm.br

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Santos RS, Lourenço JEV, Herbella FAM, Del Grande JC, Patti MG. Helicobacter pylori has no influence on distal gastric cancer survival

Survival was not different when groups were compared [P = 0.1616 (hazard ratio 0.6834, 95% CI 0.4009 to 1.1647)] (Figure 1).

mechanisms for different survival, such as micro satellite instability, gene mutations, regulation of matrix proteins, etc.(7, 11). Some authors found more aggressive tumors in HP negative patients(6, 10) while for others(5, 8) and in our study the number of patients with and without HP infection, tumor characteristics and population data were comparable showing a similar behavior. Countries with high incidence of gastric cancer rates have typically a high prevalence of HP infection(2, 7). This study was conducted in an area with high prevalence of HP infection, around 65%(9). Interestingly, other series showed a higher prevalence of HP infection and gastric cancer compared to our patients (Figure 1) and other series of gastric cancer in Brazil(1). Differences in HP strains may explain this finding and the lack of difference in survival found in our series. In fact, some African countries show a low gastric cancer rate but a high HP prevalence, known as the “African enigma”(7). In conclusion, our series did not show differences in survival according to HP infection. Future studies must be conducted with HP strains identification.

DISCUSSION

Our results show that HP infection does not correlate with distal gastric cancer survival. HP is associated to distal gastric cancer genesis(2). The mechanism of action for the carcinogenesis is not yet fully understood. Apparently, HP infection protects against proximal gastric cancer that seems to be more related to gastroesophageal reflux disease(2). Few studies focused on the association between HP and gastric cancer survival, but all of them appointed for better survival in HP positive patients (Figure 2). These studies did not restrict analyzes to distal tumors. Our study was entirely focused on distal tumors and no difference was noted in survival according to HP status. We hypothesized that HP might affect the biological behavior of gastric cancer. Several mechanisms were postulated to explain HP-related carcinogenesis and possible

Author/ year

Study design

Meimarakis et al. 2006(4)

Prospective

n

H. pylori detection

82 HP+ 46 HP-

Marreli et al. 2009(6) Retrospective

256 HP+ 41 HP-

Polymerase chain reaction (PCR) analysis for the vacA gene in gastric mucosa and serological

Retrospective

58 HP+ 27 HP-

Serological

Kurtenkov et al. 2003(7)

Notes

125 HP+ 41 HP- Bacteriological culture, serological Better for HP+ analyses and histological analyses

Retrospective

Lee et al. 1995(5)

Survival

All gastric locations

Better for HP+

All gastric locations. Result not confirmed by multivariated analyses

Better for HP+

All gastric locations

Better for HP+ All gastric locations. Stage 1 only

FIGURE 1. Literature HP+: H. pylori infection detected HP–: H. pylori infection not detected

100 Survival probability (%)

90 80 70 H.pylori

60 50 40 30 20

H.pylori + available to be followed Dead Lost follow-up H.pylori available to be followed Dead Lost follow-up

34 0 0

34 18 5

11 3 1

7 4 3

34 0 0

34 7 3

24 8 1

15 5 0

10 5 5

10 0

50

100 150 Time (months)

200

FIGURE 2. Actuarial distal gastric cancer survival in patients with and without H. pylori infection

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Santos RS, Lourenço JEV, Herbella FAM, Del Grande JC, Patti MG. Helicobacter pylori has no influence on distal gastric cancer survival

Santos RS, Lourenço JEV, Herbella FAM, Del Grande JC, Patti MG. A infecção por Helicobacter pylori não influencia a sobrevida no câncer gástrico distal. Arq

Gastroenterol. 2011;48(2):109-11. RESUMO – Contexto - Há evidência que a infecção por Helicobacter pylori correlacione-se com a etiologia do câncer gástrico distal. Há, entretanto, poucos estudos que analisam a sobrevivência relacionada ao H. pylori. Objetivo - Correlacionar a sobrevida do câncer gástrico distal com a infecção por H. pylori. Métodos – Sessenta e oito pacientes com câncer gástrico distal submetidos a gastrectomia subtotal foram estudados. O tempo mínimo de seguimento foi de 1 mês. A infecção por H. pylori foi confirmada por biopsia. Resultados – Trinta e quatro pacientes (19 homens (55,9%), idade média de 60,9 ± 14,03, variação 33-82 anos) tinham confirmação de infecção por H. pylori. Trinta e quatro pacientes (16 homens (47,1%), idade média de 57,9 ± 13,97, variação 27-85 anos) eram H. pylori negativo. Os grupos eram comparáveis considerando idade (P = 0.4), gênero (P = 0.5) e estágio [T (P = 0.2), N (P = 0.6) e M (P = 0.9)]. Sobrevivência não foi diferente quando os grupos foram comparados (P = 0.1616 (Hazard ratio 0.6834, 95% CI 0.4009-1.1647)). Conclusão - Infecção por Helicobacter pylori não afeta a sobrevida no câncer gástrico distal. DESCRITORES – Neoplasias gástricas. Infecções por helicobacter.

REFERENCES 1.

2. 3.

4.

5.

6.

Araújo-Filho I, Brandão-Neto J, Pinheiro LA, Azevedo IM, Freire FH, Medeiros AC. Prevalence of Helicobacter pylori infection in advanced gastric carcinoma. Arq Gastroenterol. 2006;43:288-92. Catalano V, Labianca R, Beretta GD, Gatta G, de Braud F, Van Cutsem E. Gastric cancer. Crit Rev Oncol Hematol. 2009;71:127-64. Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM. Gastric adenocarcinoma: review and considerations for future directions. Ann Surg. 2005;241: 27-39. Kurtenkov O, Klaamas K, Sergeyev B, Chuzmarov V, Miljukhina L, Shljapnikova L. Better survival of Helicobacter pylori infected patients with early gastric cancer is related to a higher level of Thomsen-Friedenreich antigen-specific antibodies. Immunol Invest. 2003;32:83-93. Lee WJ, Lin JT, Shun CT, Lee WC, Yu SC, Lee PH, Chang KJ, Wei TC, Chen KM. Comparison between resectable gastric adenocarcinomas seropositive and seronegative for Helicobacter pylori. Br J Surg. 1995;82:802-5. Marrelli D, Pedrazzani C, Berardi A, Corso G, Neri A, Garosi L, Vindigni C, Santucci A, Figura N, Roviello F. Negative Helicobacter pylori status is associated with poor prognosis in patients with gastric cancer. Cancer. 2009;115:2071-80

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7. Marshall BJ, Windsor HM. The relation of Helicobacter pylori to gastric adenocarcinoma and lymphoma: pathophysiology, epidemiology, screening, clinical presentation, treatment, and prevention. Med Clin North Am. 2005;89:313-44. 8. Meimarakis G, Winter H, Assmann I, Kopp R, Lehn N, Kist M, Stolte M, Jauch KW, Hatz RA. Helicobacter pylori as a prognostic indicator after curative resection of gastric carcinoma: a prospective study. Lancet Oncol. 2006;7:211-22. 9. Santos IS, Boccio J, Santos AS, Valle NC, Halal CS, Bachilli MC, Lopes RD. Prevalence of Helicobacter pylori infection and associated factors among adults in Southern Brazil: a population-based cross-sectional study. BMC Public Health. 2005;5:118. 10. Wu MS, Hung HW, Wang JT, Tseng CC, Shun CT, Wang HP, Lee WJ, Lin JT. Helicobacter pylori-seronegative gastric carcinoma: a subset of gastric carcinoma with distinct clinicopathologic features. Hepatogastroenterology. 1998;45:2432-6. 11. Yeh YC, Sheu BS, Cheng HC, Wang YL, Yang HB, Wu JJ. Elevated serum matrix metalloproteinase-3 and -7 in H. pylori-related gastric cancer can be biomarkers correlating with a poor survival. Dig Dis Sci. 2009;55:1649-57.

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Received 8/9/2010. Accepted 15/12/2010.

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ARTIGO ORIGINAL/ ORIGINAL ARTICLE

ARQGA/1546

NUTRITIONAL PROFILE OF ASYMPTOMATIC ALCOHOLIC PATIENTS Maria Beatriz SOBRAL-OLIVEIRA1, Joel FAINTUCH1, Dulce Reis GUARITA2, Claudia P. OLIVEIRA3 and Flair J. CARRILHO4

ABSTRACT – Context - Alcoholism may interfere with nutritional status, but reports are often troubled by uncertainties about ingested diet and organ function, as well as by ongoing abuse and associated conditions. Objective - To identify nutritional and body compartment changes in stable alcoholics without confounding clinical and dietetic variables, a prospective observational pilot study was designed. Three well-matched populations were considered: subjects with chronic alcoholic pancreatitis, alcoholics without visceral disease, and healthy never-drinking adults (controls). Methods - Subjects (n = 60) were asymptomatic males with adequate diet, no superimposed disease or complication, and alcohol-free for at least 6 months. After exclusions, 48 patients were compared. Variables encompassed dietary recall, bioimpedance analysis, biochemical profile and inflammatory markers. Main outcome measures were body fat, lean body mass, serum lipids, C-reactive protein, and selected minerals and vitamins. Results - Both alcoholic populations suffered from reduced lean body mass (P = 0.001), with well-maintained body fat. Magnesium was depleted, and values of vitamin D and B12 correlated with alcohol abuse. LDL and total cholesterol was increased in alcoholics without pancreatitis (P = 0.04), but not in those with visceral damage. C-reactive protein and serum amyloid A correlated with duration of excessive drinking (P = 0.01). Conclusions - Undernutrition (diminished lean body mass, risk of magnesium and vitamin deficiencies) contrasted with dyslipidemia and increased cardiovascular risk. This second danger was masked during chronic pancreatitis but not in alcoholics without visceral disease. Further studies should focus special requirements of this population. HEADINGS - Alcoholism. Nutritional status. Sarcopenia. Dyslipidemias. Pancreatitis, alcoholic.

INTRODUCTION

Alcohol is the most common substance of abuse and it is responsible for 4.4% of the global burden of disease(24). In contrast to tobacco addiction, consumption is not decreasing and may even be on the rise in parts of the Western world(10). Alcoholism has been associated with a large number of nutritional and metabolic disorders, both acute and chronic(2, 4, 22), but it is not obvious how often these are a consequence of an irregular or unbalanced diet, and when they should be accounted on ethanol ingestion per se. Visceral derangements (liver, pancreas, heart, brain) as well as associated medical troubles (tuberculosis, hepatitis, HIV/AIDS, abuse of other chemicals) are not uncommon in immoderate consumers, and might analogously interfere with results of nutritional investigations(13). Bioimpedance analysis (BIA) and dual-energy absorptiometry have very rarely been employed in such patients, with incomplete consensus about actual impact by the disease(13, 19).

Given the interest of the subject and the scarcity of protocols in this area, a preliminary clinical study was designed. The aims were to conduct bioimpedance analysis and define biochemical as well as inflammatory status in alcoholics with and without chronic pancreatitis. The hypothesis was that even in asymptomatic subjects unencumbered by comorbidities, and with acceptable food pattern and nutritional status, alcoholism would still entail adverse repercussions for body composition and biochemical profile. METHODS

Ethical considerations All patients gave written informed consent, and this protocol was approved by the institutional Ethical Committee. Population Patients with chronic alcoholic pancreatitis confirmed by biochemical profile and imaging procedures (ultrasonography, computed tomography) were investigated. Only males were selected for greater

Hospital das Clínicas – HC, Faculdade de Medicina da Universidade de São Paulo – FMUSP, São Paulo, SP, Brasil. This research received no financial grant .No conflict of interest is declared. 1 Nutrology Residency Program, HC-FMUSP; 2 Pancreatic Diseases Service, HC-FMUSP; 3 Experimental Gastroenterology Laboratory, HC-FMUSP. 4 Department of Gastroenterology, FMUSP. Correspondence: Maria B. Sobral, RD – Hospital das Clinicas, ICHC – 9º andar – sala/9159 – 05403-900 – Sao Paulo, SP, Brasil. E-mail: biasobral@hotmail.com

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Sobral-Oliveira MB, Faintuch J, Guarita DR, Oliveira CP, Carrilho FJ. Nutritional profile of asymptomatic alcoholic patients

homogeneity, as they typically represent the majority of such cases. Alcoholic controls with a negative history for organ damage (pancreas, liver, heart or brain) composed Group II. Healthy controls free from ethanol or other substance abuse (Group III) were recruited as well. Inclusion criteria Requirements were age 18-65 years, clinically stable and asymptomatic, as well as ingesting regular meals or a dietitian-supervised diabetes diet. Exclusion criteria were any alcohol intake in the last 6 months, other chemical dependence, alcoholic cirrhosis, cardiomyopathy or dementia, surgically treated pancreatitis, infection, pseudocyst, fistula, jaundice, intestinal obstruction, consumptive diseases (cancer, tuberculosis, HIV/AIDS, hepatitis B or C, organ failures), previous nutritional diseases (protein-calorie malnutrition, obesity), use of dietary supplements (except for vitamins or minerals), hospitalization for any reason in the last 30 days, and refusal to participate in the protocol. Exclusions Initially 60 subjects (20 in each category) were enrolled, but due to matching requirements concerning Group I (age and BMI) as well as inclusion and exclusion criteria, final numbers in Group II and III were decreased to respectively 12 and 16 (total = 48). Experimental design Patients were submitted to an interview that included screening, informed consent, clinical history, nutritional assessment and dietary recall. Research team included a dietitian, a gastroenterologist and a gastroenterological surgeon, with access to other specialists if necessary. Bioimpedance analysis and biochemical tests were scheduled after an overnight fast. After completed documentation patients were contacted for additional information in case of doubts, inconsistencies or missing results. Definitions Diagnosis of diseases and comorbidities was based on clinical history and current treatment. Alcohol addiction was defined as intake of >100 g of ethanol/week (>two drinks four times a week for a population of moderate risk or concern), in accordance with the CARET protocol(6). Imaging studies along with additional diagnostic procedures were primarily collected from hospital files, however, specialized consultations were requested whenever appropriate. Dietary intake Dietary recall (7 days) was conducted by an experienced dietitian. Reason for this option was previous experience demonstrating differences in drinking pattern not only between weekdays and weekends, but also between ordinary days and those immediately before and after a weekend. Foods and drinks, including snacks and visits to bars and restaurants, were classified on the basis of ingredients, home and commercial

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portion sizes as well as cooking methods, and industrialized items according to composition. Special attention was given to binge drinking, as well as to miss meals because of lack of funds. Results concerning alcohol and macronutrients were processed by NutWin software (UNIFESP, Sao Paulo, Brazil 2007), encompassing both national and international food databanks TACO, IBGE, TBCA-USP, USDA, CENEXA, German, and General Table of Foods(5). Diet adequacy Daily alimentation was considered adequate if 80% or more of the recommendations of the American Diabetes Association or of the United States Department of Agriculture (USDA Food pyramid) were fulfilled(3, 25). Lifestyle and physical activities Patients at “Hospital das Clínicas” (São Paulo, SP, Brazil) are routinely instructed to lead an active life, employ a healthy diet matched to energy expenditure, and avoid sedentarism. However, no specific investigation was here conducted and no exercise protocol was in use during this study. Bioimpedance technique Body composition was measured by single-frequency (50 kHz) bioelectrical impedance analysis using a commercial device (BIA Quantum II, RJL Systems, Clinton Township, MI, USA). Four surface electrodes were placed onto clean degreased skin at limb ends in a standardized routine, measurements being performed on the right side of the body. Tests were conducted in the morning after voiding, by an experienced professional. Total body water (TBW), fat-free mass (FFM) and body fat were calculated using the equations of the apparatus. Normal-weight obesity was defined as BMI <25kg/m2 with body fat percentage over the gender-specific tertile(20). Laboratory assays Hemoglobin, serum albumin, liver and pancreatic enzymes, serum lipids, iron, zinc, phosphate, magnesium, calcium, vitamin D and vitamin B12 were measured by automated methods. Blood samples were collected in the morning subsequent to overnight fast. The intra- and inter-assay coefficients of variation did not exceed 3%-6% for all laboratory techniques. Inflammatory markers Systemic inflammation was monitored by white blood cell count, C-reactive protein, serum amyloid A and leptin. Statistical analysis Analysis of variance (ANOVA) and Kruskall-Wallis test were used according to normality assessment (KolmogorovSmirnov). Linear regression analysis (Pearson or Spearman as required) was employed regarding ethanol consumption and duration. For categorical variables (diabetes, pain) Chisquare analysis or Fischer Exact test were selected. SPSS for Windows, version 10.0, (Chicago, IL, USA) was employed. P-values of less than 0.05 were considered significant.

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RESULTS

Diabetic patients followed the hospital-adopted diet, in compliance with the recommendations of the American Diabetes Association(3). All others informed regularly taking nourishing meals at home, along with occasional vitamin supplements. Groups were well-matched regarding age and BMI, as pointed out in Table 1, and only males were recruited. Distilled spirits predominated, with long histories and expressive daily intakes, particularly in alcoholics without visceral lesions, which could drink more carelessly. The majority of those with chronic pancreatitis already suffered from diabetes, but pancreatic pain was less conspicuous in this series. General diet composition was acceptable, with about 1.01.2 g/kg/day of protein and less than 30% of the energy in the form of lipids. No patient received dietary supplements or vitamins in the last 3 months. No differences between the groups could be demonstrated (Table 2). Lean body mass and accompanying body water were diminished in both alcoholic populations (Groups I and II), when compared to controls. Body fat changes were not evident, but resistance, which tends to follow total adipose tissue, was higher in the same 2 groups (Table 3). Given the opposing tendencies of lean and fatty tissues, normal-weight TABLE 1. Preliminary findings Description Age (years) BMI (kg/m2) Drink type

Time (years)** Ethanol/day (g) Diabetes Abdominal pain

Pancreatitis 54.1 ± 11.4 23.7 ± 4.6 Distilled* 50% Beer 40% Others 10% 21.9 ± 9.2 252.5 ± 229.1 12/20 (60%) 7/20 (35%)

obesity might have resulted. Indeed it was detected in both alcoholic populations but the proportion was small. Inflammatory markers were numerically higher in pancreatitis cases but no significance occurred. A large scatter of the results somewhat interfered with analysis, even though ordinary confusion variables such as infection, inflammation and trauma were routinely ruled out (Table 4). Few derangements were detected among hepatic and pancreatic enzymes, which were mostly within the expected range, probably because eligibility criteria demanded patients free from exacerbations or ongoing alcoholism, and reporting stable health (Table 5). By the same token nutritional and metabolic measurements were rarely aberrant in this series, with excellent serum albumin, hemoglobin, calcium and other indices. Exceptions were represented by hyperglycemia and hypomagnesemia in subjects with chronic pancreatitis, along with somewhat elevated total and especially LDL-cholesterol in alcoholics of Group II, without visceral disease (Table 6). Amount of ethanol intake exhibited correlation with body fat as well as with vitamin B12 concentration, whereas systemic inflammation was a function of duration of dependence (Table 7).

Alcohol 55.1 ± 8.5 26.2 ± 6.8 Cognac 66.6% Distilled* 33.3%

Controls 54.1 ± 18.1 26.0 ± 3.7

Significance P = 0.977 P = 0.202

24.1 ± 6.8 408.4 ± 187.4 0/12 0/12

0/16 0/16

P = 0.491 P = 0.026 P = 0.000 P = 0.000

Alcohol 1645 ± 310 244 ± 50 62 ± 14 48 ± 14

Controls 1622 ± 542 225 ± 79 70 ± 21 49 ± 23

Significance P = 0.897 P = 0.759 P = 0.515 P = 0.856

* Distilled sugarcane beverage ** Consumption till discontinuation; currently all patients alcohol-free

TABLE 2. Dietary intake Component Total ingestion (kcal/day) Carbohydrate (g/day) Protein (g/day) Lipid (g/day)

Pancreatitis 1637 ± 546 224 ± 87 71 ± 24 51 ± 17

TABLE 3. Body composition Measurement Body fat (kg) Lean body mass (kg) Normal weight obesity Body water (L) Resistance (ohm) Reactance (ohm)

114

Pancreatitis

Alcohol

Controls

Significance

16.7 ± 6.3 51.1 ± 9.1 1/20 (5%) 38.4 ± 6.5 540 ± 80 71 ± 27

17.4 ± 4.3 53.9 ± 6.9 1/12 (8.3%) 40.1 ± 5.2 522 ± 56 86 ± 30

15.6 ± 6.2 61.9 ± 8.1 0% 46.3 ± 6.5 441 ± 51 62 ± 16

P = 0.713 P = 0.001 P = 0.688 P = 0.002 P = 0.000 P = 0.062

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Sobral-Oliveira MB, Faintuch J, Guarita DR, Oliveira CP, Carrilho FJ. Nutritional profile of asymptomatic alcoholic patients

TABLE 4. Inflammatory markers

Pancreatitis

Alcohol

Controls

Significance

C-reactive protein (mg/L)

4.8 ± 7.2

3.8 ± 4.4

2.7 ± 1.9

P = 0.529

Serum amyloid A (mg/L)

5.5 ± 5.9

5.1 ± 4.3

4.4 ± 3.1

P = 0.648

Variable

Leptin (ng/L)

4.7 ± 6.0

4.0 ± 1.7

6.8 ± 3.5

P = 0.267

WBC* (X103/mL)

7.7 ± 2.1

5.9 ± 2.1

6.0 ± 1.0

P = 0.070

* WBC – White blood cell count

TABLE 5. Hepatobiliary and pancreatic enzymes Enzyme

Pancreatitis

Alcohol

Controls

Significance

81 ± 63

72 ± 37

71 ± 24

P = 0.920

Lipase (U/L)

25.3 ± 24.4

30.3 ± 10.3

32.0 ± 8.2

P = 0.055

Aspartate aminotransferase (U/L)

24.4 ± 6.0

21.5 ± 4.6

24.3 ± 8.9

P = 0.406

Alanine aminotransferase (U/L)

27.5 ± 15.5

22.3 ± 9.2

25.1 ± 7.1

P = 0.671

Gamma-glutamyl transferase (U/L)

42.0± 26.2

56.1 ± 78.9

34.7 ± 24.1

P = 0.515

Amylase (U/L)

TABLE 6. General biochemical and nutritional indices Variable Albumin (g/dL) Hemoglobin (g/dL)

Pancreatitis

Alcohol

Controls

Significance

4.0 ± 0.5

4.1 ± 0.4

4.3 ± 0.3

P = 0.882

14.5 ± 1.2

14.9 ± 0.7

14.9 ± 1.1

P = 0.412

Total cholesterol (mg/dL)

163 ± 35

197 ± 22

175 ± 36

P = 0.026

VLDL (mg/dL)

25.2 ± 12.9

23.4 ± 10.7

24.5 ± 15.8

P = 0.795

LDL (mg/dL)

92 ± 34

125 ± 27

102 ± 37

P = 0.040

HDL (mg/dL)

45.5 ± 14.9

48.7 ± 19.4

48.1 ± 17.5

P = 0.841

Triglycerides (mg/dL)

117 ± 43

117 ± 53

123 ± 79

P = 0.952

Glucose (mg/dL)

138 ± 64

94 ± 14

94 ± 13

P = 0.020

Iron (µg/dL)

83 ± 22

94 ± 22

104 ± 28

P = 0.057

Zinc (µg/dL)

83 ± 18

91 ± 16

82 ± 12

P = 0.272

Phosphorus (mg/dL)

3.5 ± 0.5

3.3 ± 0.6

3.1 ± 0.4

P = 0.088

Calcium (mg/dL)

9.2 ± 1.3

9.5 ± 0.7

9.5 ± 0.5

P = 0.632

Magnesium (mg/dL)

1.9 ± 0.3

2.2 ± 0.2

2.3 ± 0.2

P = 0.042

Vitamin D (ng/mL)

31.4 ± 15.0

23.3 ± 7.9

27.8 ± 9.4

P = 0.279

Vitamin B12 (pg/mL)

612 ± 350

395 ± 119

607 ± 394

P = 0.149

VLDL: Very low density cholesterol; LDL: Low density cholesterol; HDL: High density cholesterol

DISCUSSION

TABLE 7. Correlations with alcohol addiction (Groups I + II) Duration of abuse

r

Significance

C-reactive protein

-0.455

P = 0.009

Serum amyloid A

-0.438

P = 0.011

Vitamin D

-0.347

P = 0.049

r

Significance

Body fat %

-0.352

P = 0.048

Vitamin B12

-0.465

P = 0.008

Volume of intake

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Consumption of ethanol in this series was immoderate, reaching around 400 g/day in Group II. In other words, more than 100% of the daily energy requirement (2800 kcal) was provided by this substrate, leaving comparatively little room for other foods. Sequelae of previous overindulgence in calories could be inferred from bioimpedance analysis, in the form of elevated resistance, which usually follows body fat, and in the case alcoholics without visceral damage also by higher total and LDL-cholesterol.

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Body fat was expected to be elevated not only in the relative sense, because of shrinkage of lean body mass. Given the substantial energy value of the addiction, patients should bear voluminous lipid deposits. Such speculations notwithstanding, they were in better physical and metabolic shape than anticipated. Indeed, obesity has never been frequent in the most abusive drinkers, namely those of low social class. Even better-off cases with access to good food only rarely gain huge amounts of weight. “Skid row” patients may even display severe protein-calorie malnutrition(4). Regression analysis confirmed that ethanol consumption was significantly but negatively linked to adipose tissue accumulation (Table 7). Counter intuitively, subjects who drank more exhibited less body fat. Recent investigations attempted to attribute the paradox to cortisol, which tends to be elevated during hazardous drinking and also negatively correlates with fat mass(19). It is unlikely that this hormone is responsible because corticosteroids are associated with fat anabolism, not catabolism, and obesity is a classic feature of Cushing’s syndrome (adrenal hypercortisolism). Actually, many more appetite-related and volume-regulating hormones seem do be deranged in alcoholics(1, 19). It is also worth mentioning that in some series, fat mass accumulation was not impaired(13). Normal or mildly increased body fat compartment contrasted with conspicuous reduction of lean body mass. Albeit an uncomfortable context for the patient because it tends to be associated with metabolic syndrome, there is insufficient information to predict how many cases of normal-weight obesity and its attending sequelae might actually result in such circumstances(5). Nevertheless, alcoholics without pancreatitis carried the burden of total and LDL-cholesterol elevation. It has been underscored that moderate alcohol consumption lowers the risk for diabetes in women, whereas the opposite occurs in cases of massive drinking(7). Also in comparatively young adults admitted to a drug treatment facility, a clustering of cardiovascular risk factors such as dyslipidemia, sedentarism and metabolic syndrome was highlighted(17). In parallel with normal or mildly elevated body fat depots, lean body mass erosion was a concern. Ethanol does not often impair muscle mass in experimental animals. However, if sedentarism and disuse atrophy is induced by casting of a limb, alcohol consumption will enhance muscle loss by 80%, in association with increased expression of atrogin-1 mRNA, reduction in 4E-BP1 and S6 phosphorylation, and increased AMP-activated kinase phosphorylation(26). Even in freely-moving rats, alcohol intoxication might blunt the anabolic effects of amino acids in muscle tissue, nominally in the form of leucine resistance, as evidenced by the impaired phosphorylation of 4E-BP1, eIF4G, S6K1, and mTOR(18). Persistent inflammation could also be a trigger of muscle wasting, as demonstrated not only in serious illnesses such as dialysis-requiring renal disease, heart insufficiency and chronic obstructive lung disease, but also in the standard

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aging process. TNF-alpha could be one of the underlying mechanisms, as this pro-inflammatory cytokine destabilizes MyoD, a muscle-specific transcription factor involved in satellite cell proliferation and differentiation, thus downregulating muscle regenerating capacity(9). Sarcopenia is well known in the classic Líber-De Carli model of murine alcoholism, however besides ethanol itself, other mechanisms could be involved such as oxidative stress, deficiency of magnesium or of vitamin D(14, 22, 24). Systemic inflammation was not overt in this series and did not directly match bioimpedance results, yet correlation with alcohol ingestion was robust (P = 0.009 for C-reactive protein, P = 0.011 for serum amyloid A). Magnesium deficiency as here registered is another wellknown abnormality in alcoholics, and replenishment has been suggested to attenuate withdrawal syndrome(16). Low concentrations of B-complex and D vitamin are not uncommon either(2, 4, 27). Vitamin B12, vitamin D, zinc and iron remained within the expected range, but the two vitamins significantly correlated with alcoholism. To the best of our knowledge, this is the first controlled investigation revealing that body composition and nutritional profile in asymptomatic individuals with access to a satisfactory diet, either without manifestations of organ damage or well compensated from this point of view, suffer an adverse impact of alcohol excess. Most clinical studies about malnutrition in alcoholics do not separate subjects with visceral disease from those without, or consequences of simply reduced energy intake from more specific alcohol effects(8). Few classic studies have been updated, references in modern surveys about protein-calorie and vitamin deficits often being 10-20 years old(15, 21). Only 2 series with disease-free addicted controls could be found(12, 23), addressing liver cirrhosis, not pancreatitis. In both of them alcoholics without visceral damage were classified as nutritionally normal, with just diminished skinfold fat in one of them(23). Studied patients were not active drinkers anymore, were not hospitalized and exhibited no acute disease, nevertheless they still carried a burden in the form of depressed lean body mass along with additional nutritional and metabolic aberrations. Diabetes and abdominal pain could not be incriminated for such an outcome because similar findings were proven in alcoholics without pancreatic disease. Our results emphasize a double jeopardy in the sense that diminished lean body mass or sarcopenia combined with potential vitamin deficiencies and hypomagnesemia was conspicuous, and consistent with undernutrition. At the same time, systemic inflammation and elevated cardiovascular risk in line with dyslipidemia and relatively increased body fat could not be ruled out. Additional studies should elucidate whether these hazards taper off or conversely persist as vulnerability in later periods even if total withdrawal is maintained, and optimal dietetic intake is assured. Available evidence regarding systemic inflammation and cardiovascular profile is not exceedingly optimistic, with signs of continued risk during several years despite complete abstinence(11).

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CONCLUSIONS

A two-tiered nutritional and metabolic danger was unveiled, in the form of undernutrition (diminished lean body mass, magnesium and vitamin deficiencies) combined with dyslipidemia and increased probability of cardiovascular complications. This second abnormality was masked during chronic pancreatitis but not in drinkers without visceral disease.

As expected chronic pancreatitis entailed specific derangements (diabetes, abdominal pain, potentially malabsorption) related to organ destruction, not specifically to ethanol. However, disease-free addicted persons with acceptable dietary ingestion displayed an abnormal phenotype as well. Further studies should focus nutritional and metabolic requirements of these populations, notably concerning long-term clinical course of sarcopenia and dyslipidemia.

Sobral-Oliveira MB, Faintuch J, Guarita DR, Oliveira CP, Carrilho FJ. Perfil nutricional de pacientes alcoólatras assintomáticos. Arq Gastroenterol. 2011;48(2);112-8. RESUMO – Contexto - O alcoolismo pode interferir no estado nutricional, todavia, os relatos frequentemente sofrem com o viés das incertezas sobre dieta consumida, danos orgânicos subjacentes e persistência do abuso. Objetivo – Para identificar alterações nutricionais e de compartimentos corpóreos em alcoólatras estáveis sem variáveis de confusão clínica e dietética, foi desenhado o presente estudo piloto observacional prospectivo. Três populações bem pareadas foram consideradas: casos de pancreatite crônica alcoólica, alcoólatras sem enfermidade visceral e adultos que nunca consumiram etanol (controles). Métodos - Os pacientes (n = 60) eram homens assintomáticos com dieta satisfatória, nenhuma evidência de enfermidade ou complicação exceto as do protocolo e afastados do etanol por no mínimo 6 meses. Após exclusões, 48 pacientes foram comparados. As variáveis abrangeram recordatório alimentar, análise de bioimpedância, perfil bioquímico e marcadores inflamatórios. Os principais resultados buscados foram gordura corporal, massa magra, lípides séricos, proteína C reativa e vitaminas e minerais selecionados. Resultados - Os dois grupos que ingeriam álcool exibiram redução da massa magra (P = 0,001) com gordura corporal bem conservada. O magnésio estava diminuído e as taxas de vitamina D e B12 se correlacionaram com o abuso de álcool. O colesterol total e LDL estavam aumentados nos alcoólatras sem pancreatite (P = 0,04), porém, não naqueles com dano pancreático. A proteína C reativa e o seroamilóide A correlacionaram-se com a duração do excesso etílico (P = 0,01). Conclusões - A desnutrição (menor massa magra, possibilidade de carência de magnésio e vitaminas) contrastou com a dislipidemia e o risco cardiovascular elevado. Este segundo perigo permaneceu mascarado na vigência de pancreatite crônica, porém, não nos alcoólatras sem lesão visceral. Estudos adicionais deverão focalizar as necessidades nutricionais específicas desta população. DESCRITORES - Alcoolismo. Estado nutricional. Sarcopenia. Dislipidemias. Pancreatite alcoólica.

REFERENCES 1.

Addolorato G, Leggio L, Hillemacher T, Kraus T, Jerlhag E, Bleich S. Hormones and drinking behaviour: new findings on ghrelin, insulin, leptin and volume-regulating hormones. An ESBRA symposium report. Drug Alcohol Rev. 2009;28:160-5. 2. Al-Sanouri I, Dikin M, Soubani AO. Critical care aspects of alcohol abuse. South Med J. 2005;98:372-81. 3. American Diabetes Association, Bantle JP, Wylie-Rosett J, Albright AL, Apovian CM, Clark NG, Franz MJ, Hoogwerf BJ, Lichtenstein AH, Mayer-Davis E, Mooradian AD, Wheeler ML. Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care. 2008;31 Suppl 1:S61-78. 4. Ashley MJ, Olin JS, Le Riche WH, Kornaczewski A, Schmidt W, Rankin JG. Social class and morbidity in clinically treated alcoholics. Drug Alcohol Depend. 1976;4:263-76. 5. Barnes AJ, Moore AA, Xu H, Ang A, Tallen L, Mirkin M, Ettner SL. Prevalence and correlates of at-risk drinking among older adults: the project SHARE study. J Gen Intern Med. 2010;25:840-6. 6. Bistriche Giuntini E, Lajolo FM, Wenzel de Menezes E. [Brazilian food composition table TBCA-USP (versions 3 and 4) in the international context]. Arch Latinoam Nutr. 2006;56:366-74. 7. Carlsson S, Hammar N, Grill V, Kaprio J. Alcohol consumption and the incidence of type 2 diabetes: a 20-year follow-up of the finnish twin cohort study. Diabetes Care. 2003;26:2785-90. 8. Carvalho L, Parise ER. Evaluation of nutritional status of nonhospitalized patients with liver cirrhosis. Arq Gastroenterol. 2006;43:269-74. 9. Degens H. The role of systemic inflammation in age-related muscle weakness and wasting. Scand J Med Sci Sports. 2010;20:28-38. 10. Department of Health. Safe, sensible social-consultation on further action. London, UK: Department of Health; 2008. 11. Di Gennaro C, Biggi A, Barilli AL, Fasoli E, Carra N, Novarini A, Delsignore R, Montanari A. Endothelial dysfunction and cardiovascular risk profile in long-term withdrawing alcoholics. J Hypertens. 2007;25:367-73.

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12. García-Valdecasas-Campelo E, González-Reimers E, Santolaria-Fernández F, De La Vega-Prieto MJ, Milena-Abril A, Sánchez-Pérez MJ, Martínez-Riera A, Rodríguez-Rodríguez E. Brain atrophy in alcoholics: relationship with alcohol intake; liver disease; nutritional status, and inflammation. Alcohol Alcohol. 2007;42:533-8. 13. González-Reimers E, García-Valdecasas-Campelo E, Santolaría-Fernandez F, Sánchez-Pérez MJ, Rodríguez-Rodríguez E, Gómez-Rodríguez MA, Viña-Rodríguez J. Prognostic value of nutritional status in alcoholics assessed by doube-energy X-ray absorptiometry. Alcohol Alcohol. 2008;43:314-9. 14. González-Reimers E, Durán-Castellón MC, López-Lirola A, Santolaria-Fernández F, Abreu-González P, Alvisa-Negrín J, Sánchez-Pérez MJ. Alcoholic myopathy: vitamina D deficiency is related to muscle fibre atrophy in a murine model. Alcohol Alcohol. 2010;45:223-30. 15. Halsted CH. Nutrition and alcoholic liver disease. Semin Liver Dis. 2004;24: 289-304. 16. Hornyak M, Haas P, Veit J, Gann H, Riemann D. Magnesium treatment of primary alcohol-dependent patients during subacute withdrawal: an open pilot study with polysomnography. Alcohol Clin Exp Res. 2004;28:1702-9. 17. Jarvis CM, Hayman LL, Braun LT, Schwertz DW, Ferrans CE, Piano MR. Cardiovascular risk factors and metabolic syndrome in alcohol- and nicotinedependent men and women. J Cardiovasc Nurs. 2007;22:429-35. 18. Lang CH, Frost RA, Deshpande N, Kumar V, Vary TC, Jefferson LS, Kimball SR. Alcohol impairs leucine-mediated phosphorylation of 4E-BP1, S6K1, eIF4G, and mTOR in skeletal muscle. Am J Physiol Endocrinol Metab. 2003;285: E1205-15. 19. Leggio L, Malandrino N, Ferrulli A, Cardone S, Miceli A, Gasbarrini G, Capristo E, Addolorato G. Is cortisol involved in the alcohol-related fat mass impairment? A longitudinal clinical study. Alcohol Alcohol. 2009;44:211-5. 20. Marques-Vidal P, Pécoud A, Hayoz D, Paccaud F, Mooser V, Waeber G, Vollenweider P. Normal weight obesity: relationship with lipids, glycaemic status, liver enzymes and inflammation. Nutr Metab Cardiovasc Dis. 2009;10:217-21. 21. Moreno Otero R, Cortés JR. [Nutrition and chronic alcohol abuse]. Nutr Hosp. 2008;23 (Suppl 2):3-7.

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22. Otis JS, Guidot DM. Procysteine stimulates expression of key anabolic factors and reduces plantaris atrophy in alcohol-fed rats. Alcohol Clin Exp Res. 2009;33:14509. 23. Panagaria N, Varma K, Nijhawan S, Mathur A, Rai RR. Quality of life and nutritional status in alcohol addicts and patients with chronic liver disease. Trop Gastroenterol. 2007;28:171-5. 24. Romani AM. Magnesium homeostasis and alcohol consumption. Magnes Res. 2008;21:197-204.

25. US Department of Agriculture, Center for Nutrition Policy and Promotion, Sample Menus for a 2000 Calorie Food Pattern; 2006. Available from: <www. MyPyramid.gov>. 26. Vargas R, Lang CH. Alcohol accelerates loss of muscle and impairs recovery of muscle mass resulting from disuse atrophy. Alcohol Clin Exp Res. 2008;32: 128-37. 27. Walker L, Brown P, Beeching NJ, Beadsworth MB. Managing alcohol withdrawal syndromes: the place of guidelines. Br J Hosp Med (Lond). 2009;70:444-9. Received 8/10/2010. Accepted 10/11/2010.

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ARTIGO ORIGINAL/ ORIGINAL ARTICLE

ARQGA/1547

PROSPECTIVE STUDY OF ULTRASOUND WITH PERFLUTRENE CONTRAST COMPARED TO MAGNETIC RESONANCE IMAGING IN THE DIAGNOSIS OF HEPATIC HEMANGIOMAS Joel SCHMILLEVITCH1, Luiz Arnaldo SZUTAN2, Fábio Gonçalves FERREIRA2, Maria de Fátima SANTOS2, Ricardo MINCIS3 and Ana GORSKI4

ABSTRACT – Context - The incidence of hepatic hemangiomas ranges from 0.4% to 20% in the general population. Conventional ultrasound is usually the first diagnostic method to identify these hemangiomas, typically as an incidental finding. Ultrasonography with second generation contrast materials is being used in various areas of hepatology, yielding similar results to those obtained with computerized tomography and magnetic resonance imaging in the diagnosis of hepatic hemangiomas. Objective - To evaluate the agreement between ultrasound with perflutrene contrast and magnetic resonance imaging in the diagnosis of hepatic hemangiomas. Methods - A total of 37 patients were prospectively examined between January 2006 and August 2008. A total of 57 hepatic nodules were documented in this group as incidental findings on routine ultrasound exams. The 37 patients were administered perflutrene contrast without adverse reactions, and were all submitted to magnetic resonance exams. Results - Conventional ultrasound identified 15 patients with nodules typical of hemangiomas and 22 patients with other nodules. In 35 patients, the contrast characteristics were consistent with hepatic hemangiomas. Conclusion - Agreement between the data obtained from ultrasound with contrast and magnetic resonance was 94.5%. In discordant cases, the magnetic resonance diagnosis prevailed. In the case which presented indeterminate findings on contrast ultrasonography, magnetic resonance was repeated after 3 months, confirming the diagnosis of a hepatic hemangioma. A biopsy was performed on the suspected malignant nodule which also confirmed the presence of a hepatic hemangioma. Ultrasonography with contrast has the advantages of being more accessible to the public at large and lower cost than magnetic resonance. The results of our study highlight the need for a new protocol in hepatic nodules incidentally identified on conventional ultrasonography. In the case of typical hemangiomas, conventional ultrasound is sufficient for diagnosis. However, for poorly defined nodules, ultrasonography with contrast is indicated. After confirming the presence of a hepatic hemangioma on contrast ultrasonography, no further exams are needed to finalize the diagnosis. HEADINGS - Hemangioma. Liver diseases. Ultrasonography. Contrast media. Magnetic resonance spectroscopy.

INTRODUCTION

Hemangiomas are the most common benign congenital tumor of the liver with an incidence ranging from 0.4% to 20% at autopsy(8, 9) and are more frequent in women. It is classified as a congenital vascular malformation or hamartoma. Conventional ultrasonography (US) is the imaging method routinely used for abdominal examinations given its lack of side effects, low cost and general availability (Figure 1). The identification of hepatic nodules as an incidental finding is common (incidentalomas)(5). This

method has low specificity in the differential diagnosis of hepatic nodules, while colored Doppler does not detect vascularization in the majority of hepatic hemangiomas(11). Computerized tomography (CT) and magnetic resonance (MR) are the imaging methods used to diagnose hepatic hemangiomas, both of which entail the use of contrast agents(2, 4, 7). Contrasts for use in ultrasonography have been undergoing development since 1968 and the latest contrasts, considered second generation, are used in more than 60 countries(15, 16).

Study conducted by the Surgery Department of the Faculty of Medical Sciences, Santa Casa of São Paulo and the Schmillevitch Diagnostics Centre, São Paulo, SP, Brasil. 1 Department of Surgery, Faculty of Medical Sciences, Santa Casa of São Paulo (FCM – SCSP); 2 Liver and Portal Hypertension Group of the Department of Surgery, FCM – SCSP; 3 Faculty of Medical Sciences of Santos, SP; 4 Director of the Schmillevitch Diagnostics Centre, São Paulo, SP, Brasil. Correspondence: Dr. Joel Schmillevitch – Rua Brasilio Machado, 444 – Santa Cecília – 01230 010 – São Paulo, SP, Brasil. E-mail: joel@schmillevitch.com.br

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FIGURE 1. Conventional ultrasonography revealing nodule with hepatic hemangioma features

The color Doppler ultrasound (US) first used in US exams with contrast yielded unsatisfactory results due to artifacts in the images and the fact that balls of dye disappeared rapidly. The pulse inverted harmonics and low mechanical index employed in today’s US technologies allow for real-time characterization of mediums in contrast without colored Doppler(15, 22). US exams using contrast produce mild side effects in a small number of patients(17, 19). The diagnostic concordance between contrast US and magnetic resonance MR is over 90% in the diagnosis of hepatic hemangiomas(4). In spite of numerous studies, the true value of contrast ultrasound has not yet been clearly defined in our milieu.The aim of this study was to evaluate the concordance between contrast ultrasound and magnetic resonance MR in the diagnosis of hepatic hemangiomas. METHODS

The diagnostic criteria for a typical hemangioma on conventional US were: solitary, circumscribed, hyperechoic nodule, with both dimensions less than 4 cm(14). The 37 patients first underwent US with contrast followed by MR in a double-blind study design. US with perflutrene contrast was performed using equipment from Medison (South Korea) model SA 9900 with inverse pulse harmonics and low mechanical index (0.04 to 0.1) and a 3.5 MHz transducer. Contrast was given by intravenous bolus injection of 0.5 mL of dye into a peripheral arm vein in all patients, followed by 10 mL of 0.9% saline solution. An additional dose of contrast was used in two patients with four and five nodules, respectively. No adverse contrast reactions were seen in any of the patients. The contrast US exam was split into three phases for analysis: a) arterial phase of approximately 10 to 30 seconds; b) portal phase of approximately 30 to 90 seconds; c) late phase of approximately 90 to 120 seconds. The exam was photographed and recorded on digital video discs, and lasted between 10 to 15 minutes. Of the 37 patients, 24 underwent ultrasound exam with contrast immediately after US, and 13 patients from 3 to 10 days after US. The author acquired the contrast and all exams were performed free of charge. MR imaging exams were done on 1.0 or 1.5 Tesla devices, within 2 to 32 days of the conventional US exam. The protocol for diagnosis of hepatic hemangioma included T1 and T2 weighted analysis, and administration of extracellular gadolinium with and without fat saturation(6). All patients signed an informed consent and the study was approved by the Research Ethics Committee of the Hospital Irmandade da Santa Casa de Misericórdia de São Paulo, SP, Brazil (protocol no. 500/07). RESULTS

A total of 37 patients were prospectively analyzed between January 2006 and August 2008. Twelve of these patients were seen at the Hospital Irmandade da Santa Casa de Misericórdia de São Paulo, SP, Brazil and the remainder (25) at the Schmillevitch Diagnostics Centre, São Paulo, SP. Of the 37 patients, 28 (75.67%) subjects were women and 9 (24.33%) men, with a mean age of 42.3 years. Patients were recruited by the Irmandade da Santa Casa de Misericórdia de São Paulo Hospital and the Schmillevitch Diagnostics Center and included cases with hepatic nodules as an incidental finding on conventional abdominal ultrasound exams. Fifty seven nodules were documented as incidental findings on routine ultrasound exam in patients without cancer or chronic hepatopathy. Nodules measured between 0.8 cm and 22 cm across.

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Conventional US identified 23 patients with solitary nodules and 14 patients with multiple nodules. Of these 57 nodules, 27 were hyperechoic and 30 were hypoechoic. Fifteen patients had nodules with typical characteristics of hepatic hemangiomas, while 22 had atypical nodules(10). All of the 30 hypoechoic nodules had correlation with varying degrees of diffuse hepatic steatosis (Figure 2). After the administration of perflutrene contrast, within a few seconds, peripheral enhancement of the hepatic nodules revealed progressive centripetal filling in the arterial phase. In nodules less than 2 cm in size, filling by contrast was diffuse (Figure 3). In the venous and late phases, filling by contrast of nodules greater than 2 cm, was partial or total whereas for nodules measuring less than 2 cm, the filling pattern remained diffuse or unaltered (Figure 4).

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Schmillevitch J, Szutan LA, Ferreira FG, Santos MF, Mincis R, Gorski A. Prospective study of ultrasound with perflutrene contrast compared to magnetic resonance imaging in the diagnosis of hepatic hemangiomas

FIGURE 2. Hypoechoic hepatic nodule detected on conventional ultrasonography exam

FIGURE 3. Ultrasonography with contrast showing diffuse filling of the nodule during arterial phase, characteristic of hepatic hemangioma

FIGURE 4. Ultrasonography with contrast showing partial filling during venous phase (hepatic hemangioma)

FIGURE 5. Magnetic resonance showing nodule with T2 hypersignal characteristic of hepatic hemangioma

Findings for US with contrast in 35 patients were consistent with hepatic hemangiomas (Table 1).

In one patient with a solitary nodule measuring 5.2 cm by 4.0 cm, leakage of contrast was observed in the venous and late phases (washout), characteristic of a malignant tumor. The exam was painless and there were no adverse reactions in any of the 37 patients. A total of 60 nodules were detected on MR, 3 of which measured less than 1 cm across and were not detected by US. The 60 nodules were all hypointense in T1 and hyperintense in T2 (Figure 5). After gadolinium administration, there was a centripetal enhancement with partial filling in 18 patients and impregnation centripetally with total filling in a further 9 patients (Figure 6). All of the 37 patients were diagnosed with hepatic hemangiomas by MR.

TABLE 1. US contrast Frequency

%

Hepatic hemangioma

35

94.59

Hepatic nodule with malignant characteristics

1

2.70

Indeterminate nodule

1

2.70

Total

37

100.00

One patient with a single nodule presented no contrast enhancement for all the three phases of the exam (indeterminate).

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Schmillevitch J, Szutan LA, Ferreira FG, Santos MF, Mincis R, Gorski A. Prospective study of ultrasound with perflutrene contrast compared to magnetic resonance imaging in the diagnosis of hepatic hemangiomas

FIGURE 6. Magnetic resonance showing late phase, partial filling of nodule (hepatic hemangioma) DISCUSSION

Incidentalomas or incidental findings on abdominal US of hepatic nodules are frequent. A significant proportion of these cases require other imaging methods to confirm the diagnosis. Medical conduct in the event of a typical hemangioma nodule on conventional US is diverse. Typically, the conventional exam is repeated after 3 to 6 months, and no other imaging exams are done. Some authors recommend a CT or MR in all cases of nodules greater than 1 mm(13, 14). Use of contrast in US has brought new perspectives to the method, and this approach is gradually becoming adopted in hepatology for the differential diagnosis of hepatic nodules, detection of primary carcinomas, transplant assessment, among others(12). Technical advances in US equipment such as pulse inverted harmonics and low mechanical index, allied with a second generation of contrast media, were fundamental in the development of the new method. Characteristics of enhancement by perflutrene contrast in this study demonstrated similar results to those reported by other authors. Diffuse staining in nodules less than 2 cm and peripheral staining in nodules greater than 2 cm with centripetal filling is partial or total. This pattern of contrast capture in hepatic hemangiomas is not seen in other benign or malignant liver nodules(3). The conduct of the referring doctor for a patient whose liver nodule had malignant characteristics on US exam,

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was to order a biopsy of the nodule, which resulted in a pathological diagnosis of hepatic hemangioma. There were no complications during the biopsy. In the case presenting an indeterminate nodule on contrast US, the requesting physician requested a repeat MR after 3 months, based on a presumptive diagnosis of hepatic hemangioma. The agreement between contrast US and MR in the diagnosis of hepatic hemangioma has been described as ranging from 88% to 96%(1). In our study, agreement was found in 35 of the 37 cases (94.5%) and the two discordant cases were given the MR diagnosis. Cases of error with contrast US most likely stem from histological changes in the nodules. False-positives and negatives occur on CT and MR for the same reasons(20, 21). Piscaglia et al.(17), in a 2006 study of 23.188 ultrasonography exams with contrast, found side effects in 27 cases (0.0086%), the most common being nausea, vomiting, and hypotension. In 2008, an analysis of 66.164 US exams using perflutrene contrast detected mild adverse reactions in 0.006%. These contrast agents are not nephrotoxic or cardiotoxic and may be used in patients with renal insufficiency. In our study sample, the exam was painless in all 37 patients and no adverse reactions were observed. Romanini et al.(18), in 2007, showed correlation between US with contrast and MR in the diagnosis of 575 hepatic tumors which were confirmed by biopsy. These authors found sensitivity of 98.1% and specificity of 95.7%, concluding that conventional US associated with contrast US reduced the cost of diagnosing hepatic nodules for hospitals and the public health service. An US with contrast has several disadvantages over MR, given the formerâ&#x20AC;&#x2122;s partial images of the liver and the fact that the exam is operator dependent. However, US with contrast has broader availability to the general public as the costs of the equipment of the exam itself are lower. It is also a painless exam, with rare side effects. A contrast US can be performed immediately after conventional US reducing time to reach diagnosis and stress and anxiety of the patient. The results of this study suggest the need for a new protocol for the diagnosis of hepatic nodules found incidentally on routine US exams. In patients with nodules detected on conventional US which are deemed typical of hepatic hemangiomas, follow-up using conventional US should suffice(13). However, in patients with undefined nodules on conventional US, an US with contrast should be the second imaging method indicated. If hepatic hemangioma is subsequently diagnosed, no further investigations are needed. .

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Schmillevitch J, Szutan LA, Ferreira FG, Santos MF, Mincis R, Gorski A. Prospective study of ultrasound with perflutrene contrast compared to magnetic resonance imaging in the diagnosis of hepatic hemangiomas

Schmillevitch J, Szutan LA, Ferreira FG, Santos MF, Mincis R, Gorski A. Estudo prospectivo comparando a ultrassonografia com o contraste perflutreno e a ressonância magnética no diagnóstico de hemangiomas hepáticos. Arq Gastroenterol. 2011;48(2):119-23. RESUMO – Contexto - O hemangioma hepático apresenta incidência entre 0,4% a 20% na população e a ultrassonografia convencional é geralmente o primeiro método diagnóstico a identificá-lo como achado incidental. A ultrassonografia com contrastes de segunda geração vem sendo utilizada em várias áreas da hepatologia, com resultados semelhantes à tomografia computadorizada e a ressonância magnética no diagnóstico dos hemangiomas hepáticos. Objetivo - Avaliar a concordância entre a ultrassonografia com o contraste perflutreno e a ressonância magnética no diagnóstico dos hemangiomas hepáticos. Métodos - Foram analisados prospectivamente 37 pacientes entre janeiro de 2006 e agosto de 2008 e identificados 57 nódulos como achados incidentais de exame de ultrassom de rotina. Nos 37 pacientes, foi administrado o contraste perflutreno, sem reações adversas. Os 37 pacientes realizaram exames de ressonância magnética. Resultados - A ultrassonografia convencional identificou em 15 pacientes nódulos com características típicas de hemangiomas e em 22 pacientes com nódulos com outras características Em 35 pacientes as características do contraste foram compatíveis com hemangiomas hepáticos. Conclusão - A concordância entre a ultrassonografia com contraste e a ressonância magnética foi de 94,5% e nos casos discordantes o diagnóstico foi realizado pela ressonância magnética. No caso indeterminado na ultrassonografia com contraste, a ressonância magnética foi repetida em 3 meses, confirmando o diagnostico de hemangioma hepático. No caso com nódulo sugestivo de malignidade na ultrassonografia com contraste, foi realizada biopsia do nódulo, com anatomopatológico de hemangioma hepático. A ultrassonografia com contraste apresenta vantagens de maior acesso a população e custos menores em relação à ressonância magnética. Os resultados deste trabalho sugerem novo protocolo para nódulos hepáticos identificados incidentalmente em exames de ultrassonografia convencional. Nos hemangiomas típicos, a ultrassonografia convencional seria suficiente. Nos casos com nódulos não definidos, a ultrassonografia com contraste a ser indicado, que ao confirmar o diagnóstico de hemangioma hepático, encerraria a instigação diagnóstica. HEADINGS – Hemangioma. Hepatopatias. Ultrassonografia. Meios de contraste. Espectroscopia de ressonância magnética.

REFERENCES 1.

Bauer A, Solbiati L. Ultrasound contrast agents. In: Solbiati L, Martegani A, Leen E, Correas JM, Burns PN, Becker D, editors. Contrast-enhanced ultrasound of liver diseases. Milan: Springer; 2003. p.21-6. 2. Charboneau JW. There is a hyperechoic mass in the liver: what does that mean? In: Cooperberg PL, editor. Categorical course in diagnostic radiology: findings at US - what do they mean? Chicago: RSNA; 2002. p.73–8. 3. Claudon M, Cosgrove D, Albrecht T, Bolondi L, Bosio M, Calliada F, Correas JM, Darge K, Dietrich C, D’Onofrio M, Evans DH, Filice C, Greiner L, Jäger K, Jong N, Leen E, Lencioni R, Lindsell D, Martegani A, Meairs S, Nolsøe C, Piscaglia F, Ricci P, Seidel G, Skjoldbye B, Solbiati L, Thorelius L, Tranquart F, Weskott HP, Whittingham T. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) – update 2008. Ultraschall Med. 2008;29:28-44. 4. Coumbaras M, Wedum D, Monnier-Cholley L, Dahan H, Tubiana JM, Arrivé L. CT and MR imaging features of pathologically proven atypical hemangiomas of the liver. AJR Am J Roentgenol. 2002;179:1457-63. 5. Gallix B, Aufort S. [Incidentalomas]. J Radiol. 2007;88:1048-60. 6. Goshima S, Kanematsu M, Kondo H, Yokoyama R, Kajita K, Tsuge Y, Watanabe H, Shiratori Y, Onozuka M, Moriyama N. Diffusion-weighted imaging of the liver: optimizing b value for the detection and characterization of benign and malignant hepatic lesions. J Magn Reson Imaging. 2008;28:691-7. 7. Herman P, Costa ML, Machado MA, Pugliese V, D’Albuquerque LA, Machado MC, Gama-Rodrigues JJ, Saad WA. Management of hepatic hemangiomas: a 14-year experience. J Gastrointest Surg. 2005;9:853-9. 8. Ishak KG. Benign tumors and pseudotumors of the liver. Appl Pathol. 1988;6:82-104. 9. Ishak KG, Goodman Z, Stocker JT. Atlas of tumor pathology: tumors of the liver and intrahepatic bile ducts. Washington: Armed Forces Institute of Pathology; 2001. 10. Jang HJ, Kim TK, Lim HK, Park SJ, Sim JS, Kim HY, Lee JH. Hepatic hemangioma: atypical appearances on CT, MR imaging, and sonography. AJR Am J Roentegerol. 2003;180:35-141. 11. Kudo M, Tochio H, Zhou P. Differentiation of hepatic tumors by color Doppler imaging: role of the maximum velocity and the pulsatility index of the intratumoral blood flow signal. Intervirology. 2004;47:154-61.

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12. Lanka B, Jang HJ, Kim TK, Burns PN, Wilson SR. Impact of contrast-enhanced ultrasonography in a tertiary clinical practice. J Ultrasound Med. 2007;26:1703-14. 13. Leifer DM, Middleton WD, Teefey SA, Menias CO, Leahy JR. Follow-up of patients at low risk for hepatic malignancy with a characteristic hemangioma at US. Radiology. 2000;214:167-72. 14. Machado MM, Rosa ACF, Lemes MS, Mota OM, da Silva OQ, Campoli PMO, Santana Filho JB, Barreto PA, Nunes RA, Barreto MC, Milhomem PM, Milhomem LM, Oliveira GB, Oliveira FB, Castro FCF, Brito AM, Barros N, Cerri GG. Hemangiomas hepáticos: aspectos ultra-sonográficos e clínicos. Radiol Bras. 2006;39:441-6. 15. Maruyama H, Matsutani S, Saisho H, Mine Y, Yuki H, Miyata K. Different behaviors of microbubbles in the liver: time-related quantitative analysis of two ultrasound contrast agents, Levovist and Definity. Ultrasound Med Biol. 2004;30:1035-40. 16. Maruyama H, Matsutani S, Saisho H, Mine Y, Kamiyama N, Hirata T, Sassamata M. Real time blood-pool images of contrast-enhanced ultrasound with definity in the detection of tumor nodules in the liver. Br J Radiol. 2005;78:512-8. 17. Piscaglia F, Bolondi L. The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol. 2006;32:1369-75. 18. Romanini L, Passamonti M, Aiani L, Cabassa P, Raieli G, Montermini I, Martegani A, Grazioli L, Calliada F. Economic assessment of contrast-enhanced ultrasonography for evaluation of focal liver lesions: a multicentre Italian experience. Eur Radiol. 2007;17:F99-106. 19. Schmillevitch J. Ultra-sonografia com contraste para o estudo de nódulos hepáticos. In: Mincis M, editor. Gastroenterologia e hepatologia. 4a ed. São Paulo: Leitura Médica; 2008. p.75-8. 20. Van den Bos IC, Hussain SM, de Man RA, Zondervan PE, Ijzermans JN, Preda A, Krestin GP. Magnetic resonance imaging of liver lesions: exceptions and atypical lesions. Curr Probl Radiol. 2008;37:95-103. 21. Vossen JA, Buijs M, Liapi E, Eng J, Bluemke DA, Kamel IR. Receiver operating characteristic analysis of diffusion-weighted magnetic resonance imaging in differentiating hepatic hemangioma from other hypervascular liver lesions. J Comput Assist Tomogr. 2008;32:750-6. 22. Wilson SR, Burns PN. Liver mass evaluation with ultrasound: the impact of microbubble contrast agents and pulse inversion imaging. Semin Liver Dis. 2001;21:147-59.

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Received 22/6/2010. Accepted 19/11/2010

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ARTIGO ORIGINAL/ ORIGINAL ARTICLE

ARQGA/1548

HBV AND HCV SEROLOGICAL MARKERS IN PATIENTS WITH THE HEPATOSPLENIC FORM OF MANSONIC SCHISTOSOMIASIS Jéfferson Luis de Almeida SILVA1, Veridiana Sales Barbosa de SOUZA1, Tatiana Aguiar Santos VILELLA1, Ana Lúcia C. DOMINGUES2 and Maria Rosângela Cunha Duarte COÊLHO1, 3

ABSTRACT – Context - Blood transfusion is one of the major risk factors for the transmission of the hepatitis B (HBV) and C (HCV) viruses. However, there are no reports describing the endoscopic transmission of these viruses in patients with the hepatosplenic form of schistosomiasis. Objective - To estimate the prevalence of serological markers of HBV and HCV in patients with the hepatosplenic form of schistosomiasis and evaluate the possible risk factors associated with these infections. Methods - A cross-sectional study was conducted on 230 patients with hepatosplenic form of schistosomiasis who attended a university hospital in Recife, Northeastern Brazil, from February to August 2008. The patients answered a standardized questionnaire about risk factors. Serum samples were analyzed for anti-HBc total, anti-HBs, HBsAg, and anti-HCV using enzyme-linked immunosorbent assays. Univariate analysis and multiple logistic regression were performed. Results - The prevalence was 30% for anti-HBc total and/or HBsAg and 7.4% for antiHCV. There was a higher frequency of the serological markers in females and in patients aged ≥50 years. A significant association was detected between the presence of anti-HCV and the receipt of six or more blood transfusions. There was no association of history and number of digestive endoscopies with the serological markers analyzed. Conclusions - We observed a higher prevalence of serological markers for HBV and a lower prevalence of anti-HCV. Our results indicate that females and patients of an advanced age are the most affected categories and that patients that received multiple transfusions are at a higher probability of HCV infection. HEADINGS – Biological markers. Hepatitis B. Hepatitis C. Schistosomiasis mansoni.

INTRODUCTION

Schistosomiasis remains one of the most prevalent parasitic infections in Brazil, which is considered one of the largest endemic foci of Schistosoma mansoni, and it is estimated that 6 to 8 million Brazilians are infected and 30 million are at risk of infection(24). In the Northeast of Brazil, especially in Pernambuco, Alagoas, and Bahia states, the highest prevalence of chronic mansonic schistosomiasis is observed, with more than 90% of patients presenting the mild form and 4%-10% presenting the severe form of the disease, denominated hepatosplenic(17). Studies point to the worsening of the clinical state of schistosomiasis due to infection with viral hepatitis because of the increased frequency of jaundice, ascites and liver failure. Additionally, there is an increase in viral persistence and the liver fibrosis develops more quickly(13, 31). All of these

factors contribute to the development of aggressive chronic liver disease. Egypt has the highest worldwide prevalence for the concomitant infection of schistosomiasis and viral hepatitis, where the rates vary from 19.6%-64% for the hepatitis B virus (HBV) and 10.3%-67% for the hepatitis C virus (HCV)(1, 10). In Brazil, concomitant infection has a lower prevalence; however, higher rates are observed in patients from hospitals, varying from 10.2%-15.8% for HBV and 0.5%-19.66% for HCV(2, 7, 23). In Pernambuco, a higher frequency of serological markers of these hepatitis was observed in patients with the hepatosplenic form of schistosomiasis (HSS), varying from 13.6%-40% for HBV and 11.9%-20% for HCV(18, 19, 30). Blood transfusions in patients with HSS, carried out due to episodes of upper gastrointestinal bleeding, represent a important risk factor for the transmission

Places of research achievement: Gastroenterology Outpatient Clinic at the Clinics Hospital and Division of Virology at Laboratory of Immunopathology Keizo Asami, both at Federal University of Pernambuco, Recife, PE, Brasil. Funding: FINEP/CT – SAÚDE (1455/03) Conflicts of interest: none declared 1 Laboratory of Immunopathology Keizo Asami (LIKA). Federal University of Pernambuco (UFPE);2 Departament of Clinical Medicine UFPE;3 Departament of Physiology and Pharmacology UFPE, Recife, PE, Brasil. Correspondence: Dr. Maria Rosângela Cunha Duarte Coêlho – Rua Manuel Lubambo, 118 – Afogados – 50850-040 – Recife, PE, Brasil. E-mail: rcoelholika@gmail.com

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Silva JLA, Souza VSB, Vilella TAS, Domingues ALC, Coêlho MRCD. HBV and HCV serological markers in patients with the hepatosplenic form of mansonic schistosomiasis

of HBV and HCV(28). Reports of probable interpersonal transmission of HBV and HCV through digestive endoscopy raised concerns regarding the endoscopic procedures(6, 8). Since patients with HSS often undergo periodic upper endoscopy for the evaluation and treatment of esophageal varices, this intervention may be a risk factor for the transmission of these viruses. Given the clinical relevance of schistosomiasis, especially in the Northeast of Brazil where its prevalence is high, the objective of this study was to estimate the frequency of HBV and HCV serological markers in patients with HSS and to evaluate the possible risk factors associated with these infections. METHODS

Study site and patient selection We enrolled patients who attended the Gastroenterology Outpatient Clinic at the Clinics Hospital, Federal University of Pernambuco, Recife, PE, Brazil, from February to August 2008. The study included patients of both genders who were diagnosed with HSS, confirmed by the clinical history of the patients (contact with water from a Schistosoma mansoni endemic area or with a history of treatment for schistosomiasis) and the presence of hepatosplenomegaly in a physical examination, combined with evidence of portal hypertension and periportal fibrosis (Symmers’ fibrosis) by ultrasound or a previous splenectomy. It was excluded patients presenting with symptoms of other liver diseases and those with other clinical forms of schistosomiasis. From the 238 invited patients, 8 refused to participate and the remaining 230 patients signed an informed consent statement. This cross-sectional study was approved by the Ethics Committee of Research from the Health Sciences Center, Federal University of Pernambuco, Brazil (research protocol number: 373/07). Data collection Through a standardized questionnaire, data were collected from each patient, including gender, age and the following potential risk factors for the transmission of HBV and HCV: history, period (before or after 1993) and number of blood transfusions, history and number of digestive endoscopies, history of sclerotherapy or elastic ligation of esophageal varices, history of surgery, history of splenectomy, history of dental treatment, presence of tattoos/piercing, history of intravenous drug use, frequency of male condom use and history of intercourse with other men. Collection of blood samples and serology for the hepatitis B and C viruses It was collected 10 mL of blood by venipuncture from each patient using tubes without anticoagulant. Sera were obtained by centrifugation of blood and stored at -20°C until the serologic tests were performed.

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Serological markers for HBV and HCV were investigated using commercially available enzyme-linked immunosorbent assays according to the manufacturer’s instructions. All samples were tested for anti-HBc total (Monolisa Anti-HBc Total Plus; Bio-Rad Laboratories, France) and anti-HBs (anti-HBs Monolisa Plus; Bio-Rad Laboratories, France). Only the samples reactive for anti-HBc total and non-reactive for anti-HBs were tested for HBsAg (HBsAg Hepatitis B; Wiener Lab, Argentina). The presence of antiHCV was investigated using the Hepatitis C anti-HCV (Wiener Lab, Argentina). Statistical analysis Data from each patient were analyzed using the Epi Info program version 6.04, where tests of association between the positivity of serological markers and each variable of the study were verified using the prevalence ratio (PR) and the 95% confidence interval (95% CI). The chi-square (χ2) and Fischer’s exact test were used, when appropriate, to determine whether the associations were statistically significant. Statistical significance was considered for P-values <0.05. In order to monitor the confusion effect, all of these associations were adjusted for age. The variables that showed a significance probability less than 20% (P<0.20) in univariate analysis were analyzed using the multiple logistic regression type forward in SPSS for Windows v. 11.0.1. RESULTS

Among the analysed patients, 58.7% (135/230) were females and the mean age was 55 ± 12.6 years. In respect to the age group distribution, 71.7% (165/230) were ≥50 years. The prevalence of serological markers of HBV was 30% (69/230), considering the positivity of anti-HBc total and/or HBsAg. We emphasize that 66.5% of patients showed no viral markers and were considered susceptible to HBV infection. The anti-HBs alone was found in 3.5% of patients (Table 1), whereas the prevalence of anti-HCV was 7.4% (17/230). TABLE1. Prevalence of serological markers for HBV in patients with the hepatosplenic form of schistosomiasis Positivity Serological markers Frequency % Anti-HBc total alone 26 11.3 Anti-HBc total + HBsAg 07 3.0 Anti-HBc total + Anti-HBs 36 15.7 Anti-HBs alone 08 3.5 No viral markers 153 66.5 Total 230 100.0

Tables 2 and 3 show the associations between the variables related to patients with HSS and the anti-HBc total and/or HBsAg and anti-HCV markers after adjustment for age of univariate analysis.

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TABLE 2. Association of variables related to patients with the hepatosplenic form of schistosomiasis, according to positivity for anti-HBc total and/ or HBsAg Anti-HBc total and/or HBsAg Variable Gender Female1 Male Blood transfusion Yes No1 Number of transfusions None1 1–5 6 or more Digestive Endoscopy Yes No1 Number of endoscopies None1 1–5 6 or more Sclerotherapy Yes No1 Elastic ligation of esophageal varices Yes No1 Surgery Yes No1 Splenectomy Yes No1 Dental treatment Yes No1 Use of male condoms Always1 Sometimes Never

Positive

Negative

PR

CI 95%

P

74.07 64.21

1 1.41

0.95–2.09

0.060

101 60

70.14 69.77

1.01 1

0.67–1.52

0.547

30.23 30.6 27.8

60 75 26

69.77 69.4 72.2

1 1.05 0.93

0.68–1.62 0.49–1.76

0.478 0.500

68 01

30.49 14.29

155 06

69.51 85.71

2.13 1

0.35–13.09

0.326

01 38 30

14.29 34.55 26.55

06 72 83

85.71 65.45 73.45

1 2.42 1.89

0.39–15.1 0.31–11.7

0.255 0.406

33 36

27 33.3

89 72

73 66.7

0.82 1

0.55–1.22

0.206

10 59

28.6 30.3

25 136

71.4 69.7

0.95 1

0.54–1.66

0.509

52 17

28.6 35.4

130 31

71.4 64.6

0.81 1

0.52–1.26

0.231

23 46

21.9 36.8

82 79

78.1 63.2

0.61 1

0.4–0.93

0.013

67 02

30.3 22.2

154 07

69.7 77.8

1.39 1

0.4–4.76

0.448

07 21 41

43.75 29.17 28.87

09 51 101

56.25 70.83 71.13

1 0.54 0.64

0.28–1.03 0.35–1.17

0.089 0.159

Freq.

%

Freq.

%

35 34

25.93 35.79

100 61

43 26

29.86 30.23

26 33 10

Reference group; Freq.: frequency; PR: prevalence ratio 95%; CI 95%: confidence interval

1

Serological markers were more frequently observed in females, representing 50.7% (35/69) and 58.8% (10/17) of the total positive cases for HBV and HCV, respectively. After adjusting for age, there was a greater probability for the presence of HBV markers in males, approaching statistical significance (Table 2). To variable age, which was grouped by age group, there was higher frequency of patients ≥50 years with positive

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serological markers of HBV (PR: 1.38; CI95%: 0.81–2.11; P = 0.337) and HCV (PR: 2.95; CI95%: 0.7–12.6; P = 0.162), however this difference was no statistically significant. A significant association was detected between the presence of anti-HCV and the receipt of six or more blood transfusions (Table 3). There was no evidence of association between history and number of digestive endoscopies, history of sclerotherapy

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Silva JLA, Souza VSB, Vilella TAS, Domingues ALC, Coêlho MRCD. HBV and HCV serological markers in patients with the hepatosplenic form of mansonic schistosomiasis

TABLE 3. Association of variables related to patients with the hepatosplenic form of schistosomiasis, according to positivity for anti-HCV

Gender Female1 Male Blood transfusion Yes No1 Number of transfusions None1 1–5 6 or more Period of transfusion None1 Before 1993 After 1993 Digestive endoscopy Yes No1 Number of endoscopies None1 1–5 6 or more Sclerotherapy Yes No1 Elastic ligation of esophageal varices Yes No1 Surgery Yes No1 Splenectomy Yes No1 Dental treatment Yes No1

Anti-HCV Negative

Positive

Variable

PR

95% CI

P

92.59 92.63

1 0.95

0.37–2.39

0.550

131 82

90.97 95.35

2.08 1

0.7–2.25

0.134

4.65 5.56 19.44

82 102 29

95.35 94.44 80.56

1 1.30 4.40

0.37–4.54 1.37–14.1

0.467 0.012

04 09 04

4.65 12.9 5.4

82 61 70

95.35 87.1 94.6

1 2.76 1.47

0.89– 8.7 0.69–5.56

0.061 0.417

17 00

7.62 00

206 07

92.38 100

–5 1

00 11 06

00 10 5.31

07 99 107

100 90 94.69

1 –5 –5

8 9

6.6 8.3

114 99

93.4 91.7

0.83 1

0.33–2.06

0.437

1 16

2.9 8.2

34 179

97.1 91.8

0.35 1

0.05–2.53

0.233

15 02

8.24 4.17

167 46

91.76 95.83

2.0 1

0.48–8.42

0.261

9 8

8.6 6.4

96 117

91.4 93.6

1.44 1

0.58–3.58

0.292

17 00

7.7 0

204 09

92.3 100

–5 1

Freq.

%

Freq.

%

10 07

7.41 7.37

125 88

13 04

9.03 4.65

04 06 07

Reference group. Freq.: frequency; PR: prevalence ratio 95%; CI 95%: confidence interval; PR undefined

1

or elastic ligation of esophageal varices. An association was identified between the history of splenectomy and the detection of anti-HBc total and/or HBsAg markers (Table 2). Among the seropositives for HBV or HCV, there was not found history of intravenous drug use or the presence of tattoos and/or piercing. Only two patients were identified with a history of intercourse with other men, one was positive for anti-HBc total alone and the other one was positive for anti-HBc total and anti-HBs markers.

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The variables gender, age and history of splenectomy demonstrated a significance probability below 20% (P<0.20) in univariate analysis for HBV, were included in a multiple logistic regression type forward. After multivariate analysis, only a history of splenectomy remained as a protective factor for the presence of anti-HBc total and/or HBsAg (Odds Ratio = 0.49, 95% CI: 0.27-0.89, P = 0.020). Additionally, serological markers for both viruses were simultaneously identified in eight patients, revealing a prevalence of 3.5% for HBV/HCV coinfection.

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DISCUSSION

Compared to other Brazilians studies of patients with HSS, the 30% prevalence of anti-HBc total and/or HBsAg was higher in this study, whereas the 7.4% prevalence of anti-HCV was lower(2, 7, 23, 30). The prevalence of HBV and HCV serological markers in schistosomiasis patients ranging over according to origin of the patients involved and the endemic nature of parasitosis in the region evaluated. Fieldwork studies detected a lower prevalence of these markers than identified in this report(29, 32) because the frequency of HSS is reduced, even in endemic areas, and ranges from 2%–7%(3). Furthermore, these individuals are less exposed to the risk of HBV and HCV transmission since they are less likely to undergo diagnostic (digestive endoscopy) or therapeutic (blood transfusions) procedures than outpatients or hospitalized patients. The high prevalence of these markers in Egyptian studies is due the parenteral treatment of schistosomiasis with reuse of inadequately sterilized syringes during the decades from 1920 to 1980, which is considered the main risk factor in this country(12). The presence of anti-HBc total alone in 11.3% of patients can be explained by false-positive reactions, the immunological window, late immunity expression (when the levels of antiHBs decay below the limit of detection of the serological tests and anti-HBc remains positive) or the persistence of chronic infection(11). Anti-HBc positivity can occur concomitantly with low HBV viral load during a chronic infection when HBsAg is not detected by serological methods. These cases could suggest an occult HBV infection(25). In this situation, only the polymerase chain reaction (PCR), which that detects viral genetic material, would elucidate the clinical condition of these individuals. Regarding the low frequency of anti-HBs alone, the characteristic marker of vaccine response, we observed that part of the analyzed population came from country cities and belonged to a low social class that do not receive an HBV vaccination as routine practice. It is noteworthy that in the Reference Centers for Immunobiology Specials, the Brazilian Ministry of Health provides the HBV vaccine for patients with anatomical or functional asplenia and related diseases, among other indications, through the National Immunization Program. Therefore, it would be recommend the serological screening and vaccination to the susceptible patients. Additionally, the high prevalence of HBV serologic markers observed in this study may be influenced by the lack of condom use in males that were positive for these markers. The high prevalence of the serological markers in females and in patients aged ≥50 years reflects the profile of the patients attending at study site. However, other studies have identified a higher prevalence in men(22) also above 50 years(2). Males are more likely to be exposed to schistosomiasis due to increased contact with potentially contaminated water,

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especially in occupational activities, such as agriculture(26). The large number of cases in patients of an advanced age reflects the cumulative exposure to risk factors, such as blood transfusions and surgeries, possibly made in the period before the inclusion of serological screening for HBV and HCV as obligatory hospital examinations. The high frequency of blood transfusions among patients positive for the serological markers is in agreement with other studies(13, 15), which showed that blood transfusion is one of the most important risk factors for the transmission of HBV and HCV. Moreover, the number of transfusions received also represents an important risk factor for HCV infection, demonstrated by the significant association to the receipt of multiple transfusions. Likewise, the period in which the transfusions were received is important because before 1993 there was no serological screening for HCV in Brazil’s blood banks. However, we did not observe an association with this variable because of the low frequency of anti-HCV in the study population. The protective effect of splenectomy related to the presence of anti-HBc total and/or HBsAg was an unexpected finding. This procedure is considered of high complexity and requires a blood transfusion during surgery. In the majority of cases, it was probably executed in a period before the inclusion of serological screening for HBV; thus we can admit the hypothesis of HBV transmission by blood transfusion in these patients. Therefore, this association may be under the influence of a survival bias. Since hepatitis B is one of the major factors for the more severe clinic evolution of schistosomiasis, the infected patients may have died, causing a reduction in the number of splenectomized patients positive for HBV markers and affecting the association between the variables. It is also possible to consider that, once having undergone splenectomy, these patients have been protected against future upper gastrointestinal bleeding, which minimized the chance of exposure to infection through blood transfusions. There is controversy in the scientific literature with respect to the association between the history of digestive endoscopy and presence of serological and molecular markers for HBV and HCV in patients without schistosomiasis. Some case-control studies indicated a high risk of HCV transmission through endoscopy(9, 16), whereas prospective studies did not identify patients with seroconversion for HBV infection(20), as observed for HCV(21), after having undergone the procedure. Due to the lack of patients without a history of digestive endoscopy and positive serology for HCV in this study, we were unable to establish a significant association with this variable. However, we identified an increased probability of the presence of anti-HBc total and/or HBsAg in patients who underwent endoscopy, although it was not statistically significant. Viral transmission during endoscopy can be attributed to mistakes made during the cleaning and disinfection of the device. Studies have demonstrated the contamination of endoscopes after procedures in HBV(5) and HCV positives(27) patients.

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However, the viral genomes are eradicated when an effective device reprocessing is applied, as determined by PCR(4, 14). We conclude that this study revealed the higher prevalence of serological markers of HBV and the lower prevalence of anti-HCV in patients with HSS. Our results indicate that females and patients of an advanced age are the most affected categories and patients that received multiple transfusions are at a higher probability of HCV infection.

ACKNOWLEDGEMENTS

The authors thank Research and Projects Financing (FINEP), the Outpatient Clinic of Gastroenterology at the Clinics Hospital, the Division of Virology at Laboratory of Immunopathology Keizo Asami and Ulysses Montarroyos for their help with the statistical analyses.

Silva JLA, Souza VSB, Vilella TAS, Domingues ALC, Coêlho MRCD. Marcadores sorológicos do VHB e VHC em pacientes com esquistossomose mansônica na forma hepatoesplênica. Arq Gastroenterol. 2011;48(2):124-30. RESUMO – Contexto - A transfusão sanguínea destaca-se entre os fatores de risco implicados na transmissão dos vírus das hepatites B (VHB) e C (VHC); entretanto não há relatos da transmissão endoscópica destes vírus em pacientes com esquistossomose na forma hepatoesplênica. Objetivo Estimar a prevalência dos marcadores sorológicos do VHB e VHC em pacientes com esquistossomose hepatoesplênica e avaliar os possíveis fatores de risco associados a essas infecções. Métodos - Estudo do tipo transversal, com 230 pacientes com esquistossomose hepatoesplênica atendidos em um Hospital Universitário de Recife, PE, Brasil, no período de fevereiro a agosto de 2008. Os pacientes responderam a um questionário padronizado sobre os fatores de risco. Nas amostras de soro foram pesquisados o anti-HBc total, o anti-HBs, o HBsAg e o anti-VHC por ensaio imunoenzimático. As análises estatísticas utilizadas foram a univariada e a regressão logística múltipla. Resultados - Encontrou-se prevalência de 30% para anti-HBc total e/ou HBsAg e 7,4% para o anti-VHC. Houve maior frequência de pacientes positivos do sexo feminino e idade ≥50 anos para os marcadores analisados. Verificou-se associação significativa entre a presença do anti-HCV e a categoria de seis ou mais transfusões. Não foi constatada associação do antecedente e número de endoscopias digestivas com os marcadores sorológicos analisados. Conclusões - Constatou-se maior prevalência de marcadores sorológicos do VHB e menor prevalência para o anti-VHC. Evidenciou-se o sexo feminino e paciente de idade avançada como as categorias mais atingidas e maior probabilidade da infecção pelo VHC em pacientes politransfundidos. DESCRITORES – Marcadores biológicos. Hepatite B. Hepatite C. Esquistossomose mansônica.

REFERENCES 1.

Angelico M, Renganathan E, Gandin C, Fathy M, Profili MC, Refai W, De Santis A, Nagi A, Amin G, Capocaccia L, Callea F, Rapicetta M, Badr G, Rocchi G. Chronic liver disease in the Alexandria governorate, Egypt: contribution of schistosomiasis and hepatitis infections. J Hepatol. 1997;26:236-43. 2. Aquino RT, Chieffi PP, Catunda SM, Araújo MF, Ribeiro MC, Taddeo EF, Rolim EG. Hepatitis B and C virus markers among patients with hepatosplenic mansonic schistosomiasis. Rev Inst Med Trop São Paulo. 2000;42:313-20. 3. Barreto VST, Domingues ALC. Doença hepática na esquistossomose. In: Coelho J, editor.: Aparelho digestivo. Clínica e cirurgia. 2a ed. Rio de Janeiro: Medsi; 1996. p.1071-4. 4. Bécheur H, Harzic M, Colardelle P, Deny P, Coste T, Dubeaux B, Chochon M, Roussin-Bretagne S, Doll J, Andrieu J. [Hepatitis C virus contamination of endoscopes and biopsy forceps]. Gastroenterol Clin Biol. 2000;24:906-10. 5. Bisset L, Cossart YE, Selby W, West R, Catterson D, O’Hara K, Vickery K. A prospective study of the efficacy of routine decontamination for gastrointestinal endoscopes and the risk factors for failure. Am J Infect Control. 2006;34:274-8. 6. Bronowicki JP, Venard V, Botté C, Monhoven N, Gastin I, Choné L, Hudziak H, Rhin B, Delanoë C, Lefaou A, Bigard MA, Gaucher P. Patient-to-patient transmission of hepatitis C virus during colonoscopy. N Engl J Med. 1997;337:237-40. 7. Conceição MJ, Argento CA, Chagas VL, Takiya CM, Moura DC, Silva SC. Prognosis of schistosomiasis mansoni patients infected with hepatitis B virus. Mem Inst Oswaldo Cruz. 1998;93:255-8. 8. Davis AR, Pink JM, Kowalik AM, Wylie BR, McCaughan GW. Multiple endoscopies in a Sydney blood donor found positive for hepatitis B and C antibodies. Med J Aust. 1996;164:571. 9. Delarocque-Astagneau E, Pillonel J, Valk H, Perra A, Laperche S, Desenclos JC. An incident case–control study of modes of hepatitis C virus transmission in France. Ann Epidemiol. 2007;17:755-62. 10. el-Sayed HF, Abaza SM, Mehanna S, Winch PJ. The prevalence of hepatitis B and C infections among immigrants to a newly reclaimed area endemic for

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Schistosoma mansoni in Sinai, Egypt. Acta Trop. 1997;68:229-37. 11. Figueiredo JFC, Angerami RN. Aconselhamento a doadores e infecção oculta pelo VHB. Braz J Infect Dis. 2006;10:29-31. 12. Frank C, Mohamed MK, Strickland GT, Lavanchy D, Arthur RR, Magder LS, El Khoby T, Abdel-Wahab Y, Aly Ohn ES, Anwar W, Sallam I. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet. 2000;355:887-91. 13. Gad A, Tanaka E, Orii K, Rokuhara A, Nooman Z, Serwah AH, Shoair M, Yoshizawa K, Kiyosawa K. Relationship between hepatitis C virus infection and schistosomal liver disease: not simply an additive effect. J Gastroenterol. 2001;36:753-8. 14. Ishino Y, Ido K, Sugano K. Contamination with hepatitis B virus DNA in gastrointestinal endoscope channels: risk of infection on reuse after on-site cleaning. Endoscopy. 2005;37:548-51. 15. Kamal S, Madwar M, Bianchi L, Tawil AE, Fawzy R, Peters T, Rasenack JW. Clinical, virological and histopathological features: long-term follow-up in patients with hepatitis C co-infected with S. mansoni. Liver. 2000;20:281-9. 16. Karmochkine M, Carrat F, Dos Santos O, Cacoub P, Raguin G. A case–control study of risk factors for hepatitis C infection in patients with unexplained routes of infection. J Viral Hepat. 2006;13:775-82. 17. Katz N, Peixoto SV. [Critical analysis of the estimated number of schistosomiasis mansoni carriers in Brazil]. Rev Soc Bras Med Trop. 2000;33:303-8. 18. Lacerda CM, Ramos H, Melo IS, Machado IS. Prevalência do anti-HCV e de marcadores do vírus B na esquistossomose hepatoesplênica. An Fac Med Univ Fed Pernamb. 1993;38:30-2. 19. Meira MRL, Figuerêdo-Silva J, Silveira MJC, Kelner S, Montenegro LT. Surgical hepatoesplênic schistosomiasis and hepatite B: a serological, histological and immunohistochemical study of 30 cases. An Fac Med Univ Fed Pernamb. 1999;44:77-81. 20. Mele A, Spada E, Saglioca L, Ragni P, Tosti ME, Gallo G, Moiraghi A, Balocchini E, Sangalli M, Lopalco PL, Stroffoli T. Risk of parenterally transmitted hepatitis following exposure to surgery or other invasive procedures: results from the hepatitis surveillance system in Italy. J Hepatol. 2001;35:284-9.

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21. Mikhail NN, Lewis DL, Omar N, Taha H, El-Badawy A, Abdel-Mawgoud N, Abdel-Hamid M, Strickland GT. Prospective study of cross-infection from upper-GI endoscopy in a hepatitis C–prevalent population. Gastrointest Endosc. 2007;65:584-8. 22. Mudawi HM, Simth HM, Fletcher IA, Fedail SS. Prevalence and common genotypes of HCV infection in Sudanese patients with hepatosplenic schistosomiasis. J Med Virol. 2007;79(9):1322-4. 23. Pereira LMMB, Spinelli V, Lacerda C, Mies S, Massarollo PCB, McFarlane LG. Hepatites B e C na Esquistossomose mansoni. GED Gastroenterol Endosc Dig. 2001;20:71-7. 24. Pordeus LC, Aguiar LR, Quinino LRM, Barbosa CS. A ocorrência das formas aguda e crônica da esquistossomose mansônica no Brasil no período de 1997 a 2006: uma revisão de literatura. Epidemiol Serv Saúde. 2008;17:163-75. 25. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M, Craxì A, Donato F, Ferrari C, Gaeta GB, Gerlich WH, Levrero M, Locarnini S, Michalak T, Mondelli MU, Pawlotsky JM, Pollicino T, Prati D, Puoti M, Samuel D, Shouval D, Smedile A, Squadrito G, Trépo C, Villa E, Will H, Zanetti AR, Zoulim F. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J Hepatol. 2008;49:652–7. 26. Resendes APC, Souza-Santos R, Barbosa CS. Internação hospitalar e mortalidade por esquistossomose mansônica no Estado de Pernambuco, Brasil, 1992/2000. Cad Saúde Pública. 2005;21:1392-401.

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27. Sakai N, Tatsuta M, Iishi H, Yano H, Osaka S, Aoki A. Effectiveness of manual cleaning and disinfection of gastroendoscopes with 3% glutaraldehyde for decreasing the risk of transmission of hepatitis C virus. Am J Gastroenterol. 2001;96:1803-6. 28. Serufo JC, Lambertucci JR. Esquistossomose e hepatites virais: uma revisão. Rev Soc Bras Med Trop. 1997;30:313-22. 29. Serufo JC, Antunes CMF, Pinto-Silva RA, Gerspacher-Lara R, Rayes AAM, Drummond SC, Reis CMF, Martins MJ, Mingoti SA, Lambertucci JR. Chronic carriers of hepatitis B surface antigen in an endemic area for Schistossomiasis mansoni in Brazil. Mem Inst Oswaldo Cruz. 1998;93(suppl. 1):249-53. 30. Silva JLA, Coêlho MRCD, Souza VSB, Domingues ALC. Soroprevalência de hepatite C em pacientes com esquistossomose. Rev Para Med. 2008;22:27-32. 31. Strickland GT, Elhefni H, Salman T, Waked I, Abdel-Hamid M, Mikhail NN, Esmat G, Fix A. Role of hepatitis C infection in chronic liver disease in Egypt. Am J Trop Med Hyg. 2002;67:436-42. 32. Tavares-Neto J, Prata A, Paraná R, Valente VB, Vitvitski L, Figueiredo JFC. Very low prevalence of hepatitis C virus infection in rural communities of Northeastern Brazil with a high prevalence of Schistosoma mansoni. Rev Soc Bras Med Trop. 2005;38:290-3. Received 13/9/2010. Accepted 12/1/2011.

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ARTIGO ORIGINAL / ORIGINAL ARTICLE

ARQGA/1549

PREVALENCE OF CELIAC DISEASE IN SIBLINGS OF IRANIAN PATIENTS WITH CELIAC DISEASE Bashir CHOMEILI1, Majid AMINZADEH2, Amir Kamal HARDANI1, Payam FATHIZADEH3, Pooya CHOMEILI1 and Azarakhsh AZARAN3 ABSTRACT – Context - Celiac disease, one of the best-known autoimmune human leukocyte antigen-dependent disorders, has a relatively increased prevalence in first-degree relatives. Objective - To determine the prevalence of celiac disease in siblings of patients with confirmed celiac disease. Methods - Siblings of confirmed celiac disease patients in our center were identified and enrolled in this study. Their serum immunoglobulin A and tissue transglutaminase antibody-enzyme-linked immunosorbent assay (anti-tissue transglutaminase, immunoglobulin A, and immunoglobulin G) were measured and multiple endoscopic duodenal biopsy specimens were obtained with parental consensus. Celiac disease was confirmed by observation of characteristic histological changes. Results A total of 49 children (male, 29; female, 20; age, 2–16 years) with confirmed celiac disease in a pediatric gastroenterology ward were studied from 1999 to 2006. We found 30 siblings (female, 16) all shared in both parents. The only measurement available was for immunoglobulin A tissue transglutaminase antibody. A duodenal biopsy was performed in all 30 siblings. Clinical findings such as abdominal pain, fatigue, growth retardation and diarrhea were found in 53.3% of the completely studied siblings, and positive serology without histological changes was identified in four cases. Both serology and biopsy (confirmed new cases) were positive in 2 of the 30 siblings. Conclusion - High prevalence of celiac disease among siblings of patients with confirmed celiac disease necessitates serologic screening (and confirmatory biopsy if indicated) in families having celiac disease. It is advantageous to diagnose the disease as soon as possible because early diagnosis and diet intervention may prevent serious complications such as growth retardation, short stature, chronic diarrhea, and malignancy. HEADINGS - Celiac disease, epidemiology. Siblings. Iran.

INTRODUCTION

Celiac disease (CD), a permanent sensitivity to gliadin, is a common chronic and autoimmune disorder with different frequencies in different geographical areas(7, 10, 14, 16, 20) . The prevalence of CD exhibits an iceberg effect; the number of asymptomatic cases with positive serology and biopsy is 5- to 7-fold higher than typical symptomatic individuals exhibiting signs and symptoms including abdominal pain, growth retardation, short stature, chronic diarrhea, iron deficiency anemia that is refractive to treatment and intestinal lymphoma(6, 12, 21, 29) . Serologic tests such as the anti-endomysium IgA antibody test (EMA), the anti-tissue transglutaminase immunoglobulin (Ig) A antibody test (anti-tTG Ab) and HLA DQ2 or DQ8 genotype testing are useful for evaluation of asymptomatic subjects as well as patients with diabetes mellitus, thyroiditis, Down syndrome, Turner syndrome, William syndrome, IgA deficiency and first-degree relatives of patients with CD(1, 4, 5, 17).

It is therefore logical to screen these populations for other autoimmune diseases. Anti-gliadin antibody, antiendomysium antibody and anti-tissue transglutaminase antibody (anti-tTG Ab) are the most popular serologic tests used for this screening(15, 19). However, some researchers believe that positive anti-tTG Ab is sufficient to diagnose CD in up to 80% of cases. Since these antibodies may also be found in normal risk-free children, the consensus is still in favor of performing a duodenal biopsy and identifying typical histological changes. This analysis has been considered the gold standard for diagnosis of CD(30). All available data are from Western populations, but Eastern areas have higher rates of consanguineous marriage, which is an additional risk factor for disorders like CD. This study aimed to identify a prevalence of typical CD among siblings of children confirmed previously to have CD and to compare the predictive value of a serologic test with intestinal histopathological evidence for diagnosing a new case in the same family.

Institution: Diabetes Research Center, Department of Pediatrics, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. All the authors declare that there is no conflict of interest concerning this research. Source of Funding: Research deputy, Ahvaz Jundishapur University of Medical Sciences. 1 Pediatric Gastroenterology Unit; 2 Pediatric Endocrinology Unit, Diabetes Research Center; 3 Pathology Lab, Apadana private Hospital – Ahvaz, Iran. Correspondence: Dr. Majid Aminzadeh – Diabetes Research Center – Ahvaz Jundishapur University of Medical Sciences, Golestan, Ahvaz, I. R. Iran. E-mail: aminzadeh_m@ajums.ac.ir

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METHODS

Siblings of confirmed CD patients living in Khuzestan province in southwestern Iran, who were diagnosed by or referred to the authors between 1999 and 2006, were enrolled in this study. Criteria for diagnosis of CD were as follows: clinical findings including growth retardation, short stature, abdominal pain and/or distension, proximal muscle atrophy, chronic diarrhea and fatigue, along with serologic tests and

confirmation by duodenal biopsy results. A comprehensive discussion was conducted with the parents on the subject of the disease and the importance and necessity of screening in high risk but apparently healthy first-degree relatives with a particular emphasis on siblings. Signed written consent was obtained from the parents. The study was approved (Approval No. p/8/20/437) by the ethical committee of Ahvaz Jundishapur University of Medical Sciences (AJUMS), Iran. In addition to a physical

TABLE 1. Details of the studied siblings of known cases of celiac disease Anti- tTG Case No. Sex Age/Y Sign & symptom Ab level* 1 M 6 None 8.2* 2 F 5 None 2.9 3 F 8 CAP, SS 1222 4 F 4 D 508 5 M 14 P, A 18.9 6 M 13 None 6.8 7 M 3 None 6.2 8 F 5 PD 3.5 9 M 2 None 2.4 10 M 3 None 3 11 M 3 None 5.7 12 F 6 F 2.4 13 M 12 F,CAP, A 113 14 F 3 None 2.4 15 M 7 None 5.3 16 M 5 PD, D, P 26.1 17 M 3 None 5 18 F 6 PD 18.9 19 M 5 SS,P 6.6 20 F 12 None 2.1 21 M 7 None 3.7 22 F 2 None 2.6 23 F 13 C 2.6 24 F 4 None 3.6 25 M 5 I,F,SS 1.6 26 M 6 None 8.7 27 M 10 I, D, CAP,PD 82.6 28 M 7 None 2.3 29 M 3 None 5.8 30 M 5 None 15.2 31 F 2 CAP 2.5 32 M 16 None 1.1 33 F 14 A 7.8 34 M 14 CAP, A, F >600 35 M 7 None 4.4 36 F 10 CAP 24.9 37 M 3 None 2 38 F 5 None 8.2 39 M 5 None 1.8

1st DUO.Biopsy

2nd DUO.Biopsy

Neg Neg CD CD Neg Neg Neg Neg Neg Neg NA Neg S Neg Neg Neg NA S Neg Neg NA NA Neg Neg Neg Neg Neg NA Neg Neg Neg NA Neg S NA Neg NA S NA

ND ND CD CD ND ND ND ND ND ND ND ND refused ND ND ND ND refused ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND Neg ND ND ND Neg ND

Final diagnosis and action AFU AFU CD, Tx CD, Tx AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU AFU

Abbreviations: DUO: duodenal; CAP: chronic abdominal pain; A: anorexia; F: fatigability; PD: pallor & dizziness; D: diarrhea; P: poor weight gain; SS: short stature; I: impatience; C: constipation; CD: celiac disease; Tx: treatment; S: suspicious; NA: did not attend; AFU: advised follow up; N: normal; Neg: negative; ND: not done * U/mL

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Chomeili B, Aminzadeh M, Hardani AK, Fathizadeh P, Chomeili P, Azaran A. Prevalence of celiac disease in siblings of Iranian patients with celiac disease

examination, a history of possible signs of CD was obtained and auxiliary data were collected from all individuals. A full laboratory assessment (cell blood count, erythrocyte sedimentation rate, blood urea nitrogen (BUN), creatinine, urinalysis, and stool examination for parasites, leukocytes, occult blood, etc.) was performed in all patients to rule out other possible systemic or gastrointestinal diseases. Serologic screening was performed by assessment of serum IgA (to identify possible selective IgA-deficient subjects) and anti-tTG (IgA and IgG). We used the Celi-check kit (Germany), ELISA method, and ELISA reader (ELx800, BIO-TEK Instruments, Inc., USA). Blood samples were obtained following overnight fasting and kept at -20ºC until the laboratory procedures were performed. As recommended by the manufacturer, we established our own normal range based upon our technique, control, equipment, and patient population according to our own established procedure. Our laboratory setting processed a cutoff point of 20 U/mL. Additional results (≥20 U/mL) were considered as positive for anti-tTG. HLA typing facilities were not available for selecting siblings for duodenal biopsy, so endoscopy and duodenal biopsy were performed using an Olympus endoscope on the same day that the serology test was performed to avoid observer bias for all of the 30 siblings in the study. A duodenal biopsy specimen with a villus/crypt (v/c) ratio higher than 3 (without infiltration of chronic inflammatory cells) was considered as normal, whereas a decrease of v/c along with infiltration of the lamina propria with several degrees of chronic inflammatory cells indicated a diagnosis of varying degrees of atrophy as follows: 2.5 to 1.5, mild villus atrophy; 1 to 0.5, moderate (partial) villus atrophy; and less than 0.5, severe (subtotal/ total) villus atrophy. The sample was reported as suspicious if, in addition to intraepithelial infiltration, assessment of the v/c was not possible because of inappropriate orientation or absence of muscularis mucosa.

TABLE 2. Frequency and sex distribution of clinical signs or symptoms in 16 of 30 siblings of the studied patients with celiac disease Signs & symptoms % Female Male Abdominal pain 37.5 3 3 Anorexia 25 1 3 Fatigability 25 1 3 Pallor and dizziness 25 2 2 Diarrhea 18.75 1 2 Poor weight gain 18.75 3 Short stature 18.75 1 2 Impatience 12.5 2 Constipation 6.25 1 Note: There was more than one sign or symptom in some patients

TABLE 3. Results of serology and biopsy in 9 (of 16 clinically involved) siblings Sex Age Anti-tTG Biopsy Comment F 8 + definite treatment F 4 + definite treatment M 14 suspicious 2nd biopsy, did not attend F 10 + suspicious 2nd biopsy, did not attend M 12 + suspicious 2nd biopsy, negative F 5 suspicious 2nd biopsy, negative M 5 + negative follow-up M 10 + negative follow-up M 5 + negative follow-up M = Male; F = Female; anti-tTG antibody ≥20 IU considered +

and after recommendation for a second biopsy, two individuals refused whereas the other two were found to have normal histology in a second biopsy.

RESULTS

DISCUSSION

The study originally included 49 confirmed CD patients since 1999 to 2006 (29 males, 20 females; mean age, 7.5 ± 2.5 years). We were not able to locate 7 families as a result of a change in address or loss of follow-up documentation. Two families chose to not participate and in 7 other families the index case was an only child. As a result, 39 children from 33 remaining families were enrolled in this study. Nine children did not permit an endoscopic biopsy and were excluded. This left 30 children (16 males, 14 females) participate in the study. Details of the siblings who participated are provided in Table 1. One or multiple clinical signs or symptoms were found in 53.3% (7 males, 9 females) of the 30 siblings (Table 2). Abnormal tTG was identified in 44% (4 males, 3 females) of the 16 siblings with clinical signs and symptoms (Table 3) and in 33% of the 30 studied siblings. Two girls (6.6%) had characteristic intestinal changes compatible with diagnosis of CD (presence of both intraepithelial infiltration and villus atrophy). Serology also was positive in both. Four biopsy samples (from two males and two females) were suspicious,

Several studies have performed screening of CD in high-risk populations. People at higher risk than normal individuals tend to have Down syndrome, Turner syndrome, selective IgA deficiency or other autoimmune diseases such as diabetes mellitus and dermatitis herpetiformis. First-degree relatives of subjects with CD are also at a higher risk for CD(2, 13). The frequency of CD in the general population depends upon the geographical area (environmental factors) and ethnicity (genetic factors)(4, 27). For instance, incidence of CD has been reported as high as 0.01%–0.5% and 1.2% of the total population in Sweden and England, respectively. Rates are higher in Arabian countries, with 0.5%–1.0% of the total population having CD(11). There have been on reports on the frequency of CD in Iran. This difference in prevalence suggests the presence of different risks in high-risk groups as well. Some other factors such as the higher incidence of consanguineous marriage in Middle Eastern countries may increase these frequencies significantly. HLA typing is mainly used for diagnosing CD in cases with doubtful clinical,

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serologic, and histological findings. This can be performed by several methods, but it is costly and time consuming(31). Recently, a new method involving HLA typing of six single nucleotide polymorphism (SNPs) has been found to be efficient and cost-effective. The increased sensitivity and specificity of this method increases the chances of identifying CD in high-risk populations(18). Because all serologic tests are based upon assessments of serum IgA (using mucosal antibody against gliadin) and one of the high-risk groups has IgA deficiency, each serology test should be accompanied with a measurement of native IgA at the same time. Sensitivity and specificity of IgA-Ab to tTG has been reported to be sufficiently high to be considered as a diagnostic test in about 80% of situations where obtaining a biopsy is not possible(8, 28). The specificity of the anti-tTG Ab is not significantly different from that of the anti-endomysium antibody, but we prefer it because it requires fewer operators. The gold standard for diagnosis is histopathology of biopsy specimens, accompanied by clinical and histological response to a gliadin-free diet and then recurrence of histological findings after the gliadin rechallenge test, which is particularly important for children below 2 years of age(9, 23, 24). This method of confirmation is difficult for everyone. Therefore, in this study, as in many others, only one typical histological finding has been considered for confirmation of the presence of the disease. Therefore, in two newly diagnosed cases of CD, we considered the clinical response (observed following administration of a gluten-free diet) as the final confirmation of the diagnosis. Biopsy is recommended even when negative results are obtained in serologic screening when suspicious clinical signs or symptoms are evident(3, 25). A similar study was performed using HLA typing and small bowel histology in Asian first-degree relatives of children with CD by Srivastava et al.(26). This study identified a 4.4% prevalence of histologically confirmed CD. Our confirmed prevalence was 6.6%. Unfortunately, the genetic test and HLA typing were not available at the time our study was performed. On the basis of the rules and limitations described above, with respect to the routine screening methods for CD, it was necessary to screen all siblings with anti-tTG Ab and perform endoscopy with duodenal biopsy at the same time. These analyses were performed in a double-blinded fashion. We do not recommend intestinal biopsy to screen CD in all cases when HLA typing and serologic testing are available. A better option would be to use the flow chart prepared by Srivastava et al.(26). This study performs both serology and biopsy screening. These data can be used also for assessing the value of serologic screening in high-risk individuals. Seven patients (23.3%) were found to have positive tTG, but only 2 of 7 (6.6% of all enrolled 30 cases) were confirmed by biopsy. However, 2 of the patients with suspicious biopsies refused follow-up when a second biopsy was recommended. Suspicious biopsies were repeated immediately to rule out the possibility of inappropriate sampling (method or place) or preparation.

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Our results are comparable with those of other Western studies that show a 2%–6% prevalence of clinical CD and up to 10% intestinal involvement without clinical signs in first-degree relatives of individuals with CD(5, 7, 21). On the other hand, compatibility of anti-tTG antibody and biopsy has been reported to be 80%–95% in some studies(5, 22, 29), but was found to be 58.8% in our study (this includes the refusal of follow-up in two patients with suspicious first biopsies). Some studies have reported that a subject with a negative biopsy but a positive anti tTG Ab (similar to case numbers 27 and 34 in our study— (Table 1)) could be classified as a CD patient in the future. Follow-up of such patients and duodenal biopsy is recommended. We advised the members of our study group to schedule follow-up visits in the future. We were unable to find any other study performed in Iran that was similar to the present study. The low positive predictive value of anti-tTG Ab for true histologic CD (discrepancy between serologic and histological disease) in the present study (two of seven) in comparison with other studies may be rationalized as follows: (i) as the frequency of disease in a high-risk population increases, it may lead to a higher frequency of autoimmunity alone (positive serology without intestinal disease), which would be indicated by an increased prevalence of islet cell auto antibodies in first-degree relatives of diabetic patients relative to the normal population. (ii) Because CD can develop in elderly individuals, there is a possibility that some of the serologically positive cases progress to true disease in the future. Long-term follow-up and biopsy over subsequent years will identify additional histologically positive cases in these families. This could be considered also for siblings with negative anti tTG antibody. (iii) We might have lost two cases of true CD because two individuals with suspicious biopsies refused a second biopsy. (iv) Autoimmunity alone is a very mild form of disease on one side of the wide spectrum of this pathology. (v) Except for two of the Ab-positive subjects (cases no. 16 and 36), all others had very high levels of serum Ab, so inappropriate techniques or cutoffs could not be the cause of this discrepancy. Finally, the unavailability of genetic testing and HLA typing, the loss of follow-up because of relocation of families, unavailability of other families, and refusal to participate in re-testing or to provide biopsies must be considered as limitations of this study. CONCLUSION

The high prevalence (6.6%) of CD in siblings of patients with CD identified in this study and other studies confirm the necessity and importance of instituting a screening program for first-degree relatives of children with CD to identify the disease and administer a strict gluten-free diet to prevent serious complications. ACKNOWLEDGEMENTS

The authors wish to thank the Vice Chancellor of research of Ahvaz Jundishapur University of Medical Sciences for financial support.

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Chomeili B, Aminzadeh M, Hardani AK, Fathzadeh P, Chomeili P, Azaran A. Prevalência de doença celíaca em filhos de pais iranianos com doença celíaca. Arq Gastroenterol. 2011;48(2):131-5. RESUMO – Contexto - A doença celíaca, uma das mais conhecidas enfermidades autoimunes humanas, leucocitária antígeno-dependente, tem prevalência relativamente maior em parentes de primeiro grau. Objetivo - Determinar a prevalência de doença celíaca em irmãos de pacientes confirmadamente celíacos, filhos dos mesmos pais. Métodos - Os irmãos de pacientes com doença celíaca confirmada no Department of Pediatrics, Ahvaz Jundishapur University of Medical Sciences, em Ahvaz, Iran, foram identificados e incluídos no estudo. A imunoglobulina A sérica e o anticorpo transglutaminase tecidual por ensaio imunoenzimático (anti-transglutaminase tecidual, imunoglobulina A e imunoglobulina G) foram medidos e múltiplas biopsias endoscópicas duodenais foram obtidas com o consenso dos pais. A doença celíaca foi confirmada pela observação das características histológicas. Resultados - Um total de 49 crianças (29 do sexo masculino; 20 do sexo feminino; de 2 a 16 anos) com diagnóstico confirmado de doença celíaca em uma enfermaria de gastroenterologia pediátrica foi estudado de 1999 a 2006. Encontraram-se 30 irmãos (16 do sexo feminino) e todos compartilhavam os mesmos pais dos pacientes. A única medida disponível foi do anticorpo tecidual imunoglobulina A transglutaminase. A biopsia duodenal foi realizada em todos os 30 irmãos. As manifestações clínicas como dor abdominal, fadiga, retardo do crescimento e diarréia foram encontradas em 53,3% dos irmãos estudados completamente, e a sorologia positiva sem alterações histológicas foi identificada em quatro casos. Ambas, sorologia e biopsia (novos casos confirmados) foram positivas em 2 dos 30 irmãos. Conclusão - A prevalência de doença celíaca entre irmãos de pais confirmadamente celíacos exige triagem sorológica e biopsia de confirmação, se indicada, em familiares com doença celíaca. Diagnosticar a doença o mais rápido possível traz vantagens, pois o diagnóstico precoce e a intervenção dietética podem prevenir complicações graves, como retardo do crescimento, baixa estatura, diarreia crônica e malignidade. DESCRITORES – Doença celíaca, epidemiologia. Irmãos. Irã.

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Blackwell PJ, Hill PG, Holmes GK. Autoantibodies to human tissue transglutaminase: superior predictors of coeliac disease. Scand J Gastroenterol. 2002;37:1282-5. Book L, Zone JJ, Neuhausen SL. Prevalence of celiac disease among relatives of sib pairs with celiac disease in U. S. families. Am J Gastroenterol. 2003;98:377-81. Branski D, Fasano A, Troncone R. Latest developments in the pathogenesis and treatment of celiac disease. J Pediatr. 2006;149:295-300. Carnicer J, Farré C, Varea V, Vilar P, Moreno J, Artigas J. Prevalence of coelic disease in Down’s syndrome. Eur J Gastroenterol Hepatol. 2001;13:263-7. Cataldo F, Marino V. Increased prevalence of autoimmune disease in firstdegree relatives of patients with celiac disease. J Pediatr Gastroenterol Nutr. 2003;36:470-3. Catassi C, Bearzi I, Holmes GK. Association of celiac disease and intestinal lymphomas and other cancers. Gastroenterology. 2005;128:S79-86. Ertekin V, Selimoğlu MA, Kardaş F, Aktaş E. Prevalence of celiac disease in Turkish children. J Clin Gastroenterol. 2005;39:689-91. Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med. 2002;346:180-8. Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology. 2001;120:636-51. Fasano A, Berti I, Gerarduzzi T, Not T, Colletti RB, Drago S, Elitsur Y, Green PH, Guandalini S, Hill ID, Pietzak M, Ventura A, Thorpe M, Kryszak D, Fornaroli F, Wasserman SS, Murray JA, Horvath K. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003;163:286-92. Fasano A, Catassi C. Coeliac disease in children. Best Pract Res Clin Gastroenterol. 2005;19:467-78. Green PH, Fleischauer AT, Bhagat G, Goyal R, Jabri B, Neugut AI. Risk of malignancy in patients with celiac disease. Am J Med. 2003;115:191-5. Gudjonsdottir AH, Nilsson S, EK J, Kristiansson B, Ascher H. The risk of celiac disease in 107 families with at least two affected siblings. J Pediatr Gastroenterol Nutr. 2004;38:338-42. Hill I, Fasano A, Schwartz R, Counts D, Glock M, Horvath K. The prevalence of celiac disease in at-risk groups of children in the United States. J Pediatr. 2000;136:86-90. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, Hoffenberg EJ, Horvath K, Murray JA, Pivor M, Seidman EG; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guideline for the diagnosis and treatment of celiac disease in children: recommendation of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40:1-19. Hoffenberg EJ, MacKenzie T, Barriga KJ, Eisenbarth GS, Bao F, Haas JE, Erlich H, Bugawan Tl T, Sokol RJ, Taki I, Norris JM, Rewers M. A prospective

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study of the incidence of childhood celiac disease. J Pediatr. 2003;143:308-14. Kagnoff MF. Celiac disease: pathogenesis of a model immunogenetic disease. J Clin Invest. 2007;117:41-9. Koskinen L, Romanos J, Kaukinen K, Mustalahti K, Korponay-Szabo I, Barisani D, Bardella MT, Ziberna F, Vatta S, Széles G, Pocsai Z, Karell K, Haimila K, Adány R, Not T, Ventura A, Mäki M, Partanen J, Wijmenga C, Saavalainen P. Cost-effective HLA typing with tagging SNPs predicts celiac disease risk haplotypes in the Finnish, Hungarian, and Italian populations. Immunogenetics. 2009;61:247-56. Liu E, Li M, Bao F, Miao D, Rewers MJ, Eisenbarth GS, Hoffenberg EJ. Need for quantitative assessment of transglutaminase autoantibodies for celiac disease in screening-identified children. J Pediatr. 2005;146:494-9. Mäki M, Mustalahti K, Kokkonen J, Kulmala P, Haapalahti M, Karttunen T, Ilonen J, Laurila K, Dahlbom I, Hansson T, Höpfl P, Knip M. Prevalence of celiac disease among children in Finland. N Engl J Med. 2003;348:2517-24. McOmber ME, Shulman RJ. Recurrent abdominal pain and irritable bowel syndrome in children. Curr Opin Pediatr. 2007;19:581-5. Mearin ML. Celiac disease among children and adolescents. Curr Probl Pediatr Adolesc Health Care. 2007;37:86-105. Norris JM, Barriga K, Hoffenberg EJ, Taki I, Miao D, Haas JE, Emery LM, Sokol RJ, Erlich HA, Eisenbarth GS, Rewers M. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA. 2005;293:2343-51. Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child. 1990;65:909-11. Shamir R. Advances in celiac disease. Gastroenterol Clin North Am. 2003;32:931-47. Srivastava A, Yachha SK, Mathias A, Parveen F, Poddar U, Agrawal S. Prevalence, human leukocyte antigen typing and strategy for screening among Asian first-degree relatives of children with celiac disease. J Gastroenterol Hepatol. 2010;25:319-24. Sulkanen S, Halttunen T, Laurila K, Kolho KL, Korponay-Szabó IR, Sarnesto A, Savilahti E, Collin P, Mäki M. Tissue transglutaminase enzyme-linked immunosorbent assay in detecting celiac disease. Gastroenterology. 1998;115:1322-28. Troncone R, Maurano F, Rossi M, Micillo M, Greco L, Auricchio R, Salerno G, Salvatore F, Sacchetti L. IgA antibodies to tissue transglutaminase: an effective diagnostic test for celiac disease. J Pediatr. 1999;134:166-71. van Rijn JC, Grote FK, Oostdijk W, Wit JM. Short stature and the probability of coeliac disease, in the absence of gastrointestinal symptoms. Arch Dis Child. 2004;89:882-3.

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Received 30/8/2010. Accepted 28/12/2010.

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ARTIGO ORIGINAL/ ORIGINAL ARTICLE

ARQGA/1550

THE VALUE OF HIGH-RESOLUTION ANOSCOPY IN THE DIAGNOSIS OF ANAL CANCER PRECURSOR LESIONS IN HIV-POSITIVE PATIENTS Felicidad GIMENEZ1, Ivan Tramujas da COSTA-e-SILVA2, Adriana DAUMAS2, José de ARAÚJO3, Sara Grigna MEDEIROS4 and Luiz FERREIRA5

ABSTRACT – Context – Anal cancer, although a still rare disease, is being observed in ascending rates among some population segments known to be at risk for the development of the disease. Human papillomavirus (HPV) infection, immunodepression and anal intercourse are some factors associated with the development of the malignancy. Its similarities to cervical cancer have led to many studies aiming to establish guidelines for detecting and treating precursor lesions of anal cancer, with the goal of prevention. Highresolution anoscopy is routinely used for the diagnosis of anal cancer precursor lesions in many centers but the medical literature is still deficient concerning the role of this diagnostic modality. Objectives - To evaluate diagnostic validation and precision measures of high-resolution anoscopy in comparison to histopathological results of anal biopsies performed in HIV-positive patients treated at the Tropical Medicine Foundation of Amazonas, AM, Brazil. To observe any possible association between some risk factors for the development of anal cancer and the presence of anal squamous intraepithelial lesions. Methods – A hundred and twenty-eight HIV-positive patients were submitted to anal canal cytological sampling for the detection of HPV infection by a PCR based method. High-resolution anoscopy was then performed after topical application of acetic acid 3% in the anal canal for 2 minutes. Eventual acetowhite lesions that were detected were recorded in respect to location, and classified by their tinctorial pattern, distribution aspect, relief, surface and vascular pattern. Biopsies of acetowhite lesions were performed under local anesthesia and the specimens sent to histopathological analysis. The patients were interviewed for the presence of anal cancer risk factors. Results - The prevalences of anal HPV infection and of anal squamous intraepithelial lesions in the studied population were, respectively, 79% and 39.1%. High-resolution anoscopy showed sensibility of 90%, specificity of 19.23%, positive predictive value of 41.67%, negative predictive value of 75%, and a kappa coefficient of 0.076. From the analyzed lesions, high-grade squamous intraepithelial lesions was more frequently observed in association to dense (68%), flat (61%), smooth (61%), non-papillary (83%) and normal vascular pattern (70%) acetowhite lesions, while low-grade squamous intraepithelial lesions tended to be associated to dense (66%), flat-raised or raised (68%), granular (59%), non-papillary (62%) and normal vascular pattern (53%) acetowhite lesions. No statistical significance was observed as to the association of epidemiological characteristics and of most of the investigated anal cancer risk factors and presence of acetowhite lesions or anal squamous intraepithelial lesions. However, anal receptive sex and anal HPV infection were significantly associated to anal squamous intraepithelial lesions (P = 0.0493 and P = 0.006, respectively). Conclusion - High-resolution anoscopy demonstrated to be a sensitive, but not specific test for the detection of anal squamous intraepithelial lesions. Risk factors anal receptive sex and anal HPV infection were significantly associated to the presence of anal squamous intraepithelial lesions. Based on high-resolution anoscopy image data, acetowhite lesions relief and surface pattern were prone to distinguish between low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions. HEADINGS – Anus neoplasms. HIV. Papillomavirus infection. Proctoscopy.

This research was developed at the Tropical Medicine Foundation of Amazonas, Manaus, AM, Brazil This research was supported by the National Program of DST-AIDS, Ministry of Health of Brazil – UNESCO (grant 914BRA1101). Conflict of Interest: none 1 Getulio Vargas University Hospital, Federal University of Amazonas; 2 Division of Clinical Surgery, Federal University of the Amazonas; 3 Pathological Anatomy Department Tropical Medicine Foundation of Amazonas; 5 Federal University of Amazonas; 6 Department of Pathology and Forensic Sciencies, Federal University of Amazonas, Manaus, AM, Brasil Correspondence: Dr. Felicidad Santos Gimenez – Rua Afonso Pena, 589 – Praça 14 – 69033-720 – Manaus, AM, Brasil. E-mail: felicidadgimenez@yahoo.com.br

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Gimenez F, Costa-e-Silva IT, Daumas A, Araújo J, Medeiros SG, Ferreira L. The value of high-resolution anoscopy in the diagnosis of anal cancer precursor lesions in HIV-positive patients

INTRODUCTION

Anal cancer has a low incidence corresponding to 1.5% of all tumors detected in the digestive tract in the United States(42). In Brazil, according to the National Institute of Cancer (INCA), the incidence of anal cancer is reported in association to the incidence of colorectal cancer. In 2009, 4.24 men/100,000 and 4.44 women/100,000 were reported to have colorectal cancer in the state of Amazonas. This type of cancer is ranked as the 4th most detected type in Brazil, and 6th in the north of Brazil(4). The number of new cases of cancer has significantly increased in distinct groups of population, defined as groups at risk to develop the malignancy(28). They are composed of either immune compromised individuals or individuals engaged in recognized risky activities, namely participation in anal receptive intercourse (especially males)(9, 10, 33, 40), immunosuppressed transplanted patients(36), individuals with a history of sexually transmitted diseases (STD)(5, 24, 25,30), women presenting a history of cervical cancer or of cervical, vulvar or vaginal squamous intraepithelial lesions(10), individuals with chronic anal inflammation due to fistulas, fissures and hemorrhoids(40), tobacco smokers(16), and individuals with anal cancer due to genetic factors(14). Among STD, the human papillomavirus (HPV) is well known for causing epithelial proliferative lesions and, based on its oncogenic potential, to evolve into benign warts or highgrade lesions that can turn to skin and mucous malignant tumors(31, 50). HPV infection and development of precursor lesions of cervical cancer generally occur in the transformation zone (squamocolumnar junction) of the uterine cervix. Similarly, the anal transitional zone corresponds to the junction of the anal stratified squamous epithelium to the glandular epithelium of the rectum(27), an area where HPV infects cells of the basal layer of the epithelium through micro lesions(12). Cell and tissue atypical changes in the anogenital area are called anal squamous intraepithelial lesions (ASIL), which, according to the oncogenic potential of the resident HPV type, may or may not evolve into anal cancer(45). The incidence in the number of cases of cervical cancer has been reduced from 40/100,000 to 8/100,000 in countries where cervical cancer precursor lesions are routinely monitored(41). Based on similarity between ASIL and cervical precursor lesions, a similar routine has been proposed for diagnosing pre-cancerous anal lesions(29). Consequently, a cytology test equivalent to the Pap smear to diagnose cervical cancer is also used to diagnose anal lesions. However, even though this test is efficient, inexpensive(44) and highly sensitive (98%) to detect cellular alterations, it has low specificity (50%)(37). So in cases of anal cell changes with signs of dysplasia of any magnitude, tend to indicate the use of anuscopy with magnified a procedure similar to cervical(8, 23). In this example, it is observed, with special attention, the squamocolumnar transition zone after topical application of acetic acid 3%, lesions suspected to be produced by the cytopathic effect of HPV will become whitish and underwent

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biopsy(26). The histopathological result of a high resolution anoscopy (HRA) monitored biopsy is considered the goldstandard test for confirming the presence of an anal squamous intraepithelial lesion(35, 43). However, even though HRA is a tool routinely used in the diagnosis of anal lesions, there is little information in the medical literature regarding the success of this medical diagnostic technique regarding the detection of anal cancer precursor lesions. This study was designed to investigate the importance of high-resolution anoscopy as a diagnostic tool to recognize anal lesions associated to ASIL, in order to validate its utilization in the continuous monitoring program of HIV-positive patients treated at Tropical Medicine Foundation of Amazonas (FMTAM), Manaus, AM, Brazil, a population sub-group that has a well-known high potential to develop anal cancer precursor lesions. The research will also evaluate in the population sample treated at the institution: 1) the association among the presence of risk factors for the development of anal cancer and the findings of acetowhite lesions (AWL) at HRA and of ASIL at histopathological analyses; 2) the association between the histopathological results that followed HRA monitored biopsies and the presence of HPV anal infection, according to PCR analysis; and 3) the prevalence of ASIL and HPV infection in the studied population. METHODS

After approval at the Ethics in Research Committee of FMT-AM, a primary transversal descriptive diagnostic study was performed in 128 HIV-positive patients of both genders seen in the coloproctology outpatient clinic of the institution. All the patients signed an informed consent agreement. After anal canal cytological sampling for the performance of a PCR based HPV detection test according to the method described by Bauer and Manos(2), patients were submitted to HRA, by three colorectal surgeons (FSG, ITCS, AGDPG), after topical application of 3% acetic acid, in the anal canal, for 2 minutes. Observed AWL had their location, tinctorial characteristics (acetowhite negative, tenuous or dense), aspect (focal or coalescent), relief (flat, slightly elevated, or elevated lesions), surface (smooth or granular; papillary or nonpapillary), as well as vascular profile (normal or atypical; warty vessels or no warty vessels, punctation or no punctation, mosaicism or no mosaicism) documented according to a modified version of the Barcelona classification (2002)(49). Biopsies of AWL were performed for histopathological analysis under local anesthesia. When no AWL was observed, biopsies were performed in a standardized location (just above the pectinate line at the 7 o’clock position, considering 12 o’clock the anterior commissure). The histopathological results of the anal biopsies were classified as: negative (including benign inflammatory alterations), low-grade squamous intraepithelial lesions (LSIL, including anal condyloma) or high-grade squamous intraepithelial lesions (HSIL)(3).

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The criteria investigated to define groups at risk to develop anal cancer were as follows: report of anal receptive intercourse, number of sexual partners in the last 5 years, age at which individuals became sexually active, actual and past patient information for STD, HPV infection status, T CD4+ lymphocyte levels below 200 cell/μL, use of antiretroviral therapy (HAART), presence of benign concomitant diseases, history of smoking and of drug addiction. Data were evaluated in contingency tables in which values were statistically analyzed by Pearson’s chi-square test or Fisher’s exact test. Independent variables such as age were analyzed by the Mann-Whitney U test. Agreement between the presence of AWL at HRA and the histopathological diagnosis of ASIL was evaluated by kappa statistics interpreted according to Landis and Koch criteria (<0.00 = poor; 0.00 – 0.20 = weak; 0.21 – 0.40 = regular; 0.41 – 0.60 = moderate; 0.61 – 0.80 = strong; 0.81 – 1.00 = almost perfect). Significance level values of 0.05 and confidence intervals of 95% were established for all analysis. RESULTS

Table 1 shows the distribution of HIV-positive patients as to receptive anal sex, number of sexual partners in the last 5 years, onset of sexual activity, presence or history of STD and HPV infection in relation to the presence of ACW lesions and ASIL. Table 2 correlates CD4 cells counts, use of highly-active antiretroviral therapy, presence of concomitant benign diseases,

smoking and illicit drug addiction with the presence of ACW lesions and ASIL in HIV-positive patients. Table 3 depicts the diagnostic validation and precision measures of high-resolution anoscopy obtained in this study in comparison to the gold-standard histopathology. Table 4 denotes the phenotypic characteristics of HRA of HIV-positive patients, relative to the results of the histopathological analyses of the anal biopsies performed after topical application of 3% acetic acid. Table 5 correlates the results of PCR for HPV and histopathological results of anal biopsies performed in HIVpositive patients. Figures 1 to 6 depict phenotypic HRA characteristics of AWL and indicate their correlation with corresponding PCR for HPV and histopathological findings. DISCUSSION

Data analysis of factors involved in anal carcinogenesis Acetowhite lesion No statistical significance was observed in the correlation between risk factors for anal cancer and the occurrence of AWL (P>0.05) (Tables 1 and 2). Intraepithelial lesions Nevertheless, of 89 patients participating in anal intercourse, 40 presented ASIL (44.94%) at anal biopsies, while only 10

TABLE 1. Distribution of HIV-positive patients, individuals participating in anal receptive intercourse, number of partners in the last 5 years, age at which individuals became sexually active, actual and past patient information for STD, HPV infection information regarding presence of squamous intraepithelial lesions Variable Anal intercourse Yes No Nr sexual partners last 5 years ≤ 10 > 10 Sexual activity initiation ≤ 14 years-old > 14 years-old History of STD Yes No History of HPV Yes No

Acetowhite lesions Positive Negative n % n %

Total

P-value*

Anal intraepithelial lesion Positive Negative n % n %

Total

0.6083* 76 32

85.39 82.05

13 7

14.61 17.95

89 39

0.0493* 40 10

44.94 25.64

49 29

55.06 74.36

89 39

0.7632* 80 24

83.33 88.89

16 3

16.67 11.11

96 27

0.3806* 35 13

36.46 48.15

61 14

63.54 51.85

96 27

0.128* 35 67

76.09 88.16

11 9

23.91 11.84

46 76

60 48

85.71 82.76

10 10

14.29 17.24

70 58

88 20

86.27 76.92

14 6

13.73 23.08

102 26

P-value*

0.1688* 14 34

30.43 44.74

32 42

69.57 55.26

46 76

27 23

38.57 30.66

43 35

61.43 60.34

70 58

46 4

45.10 15.38

56 22

54.90 84.62

102 26

0.647*

0.9547*

0.241*

0.006*

Value in bold indicates P-value with statistical difference at the 5% level * Pearson’s chi-square test or Fisher’s exact test

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Gimenez F, Costa-e-Silva IT, Daumas A, Araújo J, Medeiros SG, Ferreira L. The value of high-resolution anoscopy in the diagnosis of anal cancer precursor lesions in HIV-positive patients

TABLE 2. Distribution of HIV-positive patients according to T-CD4 cell counts, use of highly active anti-retroviral therapy (HAART), presence of concomitant benign anal diseases, smoking, drug addiction in correlation to high-resolution anoscopy and histopathological findings. Acetowhite lesions Total P-value* Anal intraepithelial lesion Total P-value* Variable Positive Negative Positive Negative n % n % n % n % T-CD4 count 0.26* 0.06* 26 78.78 7 21.21 33 8 24.24 25 75.76 33 < 200/μl 76 87.35 11 12.64 87 38 43.68 49 56.32 87 ≥ 200/μl HAART 0.8423* 0.3134* Yes 49 85.96 8 14.04 57 19 33.33 38 66.67 57 No 59 83.10 12 16.90 71 31 43.66 40 56.34 71 Benign anal diseases 0.3215* 0.8845* Yes 92 85.98 15 14.02 107 42 39.25 65 60.75 107 No 16 76.19 5 23.81 21 8 38.10 13 61.90 21 Smoking 0.3146* 0.513* Yes 38 79.17 10 20.83 48 17 35.42 31 64.58 48 No 70 87.50 10 12.50 80 33 41.25 47 58.75 80 Drug addiction 0.5077* 0.8053* 28 12 42.86 16 57.15 28 Yes 22 78.57 6 21.43 No 86 86 14 14 100 38 38 62 62 100 Value in bold indicates P-value with statistical difference at the 5% level * Pearson’s chi-square test or Fisher’s exact test

TABLE 3. Diagnostic efficiency of high resolution anoscopy HRA/Pathology ASIL+* AWL+* 45 AWL-* 5 Total 50

ASIL-* 63 15 78

*AWL+ = positive acetowhite lesions; AWL- = negative acetowhite lesions. ASIL+ = positive histopathology; ASIL- = negative histopathology. Accuracy = 46.87% Sensitivity = 90% Specificity = 19.23%

Positive predictive value = 41.67% Negative predictive value = 75% False positive = 89.76% False negative = 10% ASIL prevalence = 39.1% Chi-square test P = 0.2142 Kappa test = 0.076

(25.64%) of those who did not mention anal intercourse activity had the same diagnosis (P = 0.04930) (Table 1). Palefsky et al.(29) observed a relationship between ASIL and anal receptive sex in HIV-positive patients. They reported that 50% of HIV-positive men-who-have-sex-with-men (MSM) in their study presented ASIL. Fox et al.(13) reported ASIL was found in HIV-positive MSM in a prevalence of 26% and 36% in two cohort studies undertaken at the USA mainly before the advent of HAART. Gimenez et al.(18) have previously reported a prevalence of ASIL in HIV-positive MSM of 42% (P = 0.03). Regarding the number of sexual partners in the last 5 years, there was no statistical significance in the correlation with histopathological diagnoses of ASIL of any grade. Thirty-five (36.46%) individuals who reported having less than 10 partners presented ASIL, while 13 (48.15%) of those that had more than 10 partners also presented the same histopathological finding (Table 1). These results are inconsistent with a study by Frisch et al.(15) in which it was observed that more than 10 sexual partners increased the risk of cancer by 5 times in

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Total 108 20 128

women and 2.8 times in men. Klencke and Palefsky(22) observed that, in this case, the exposure to various HPV types is the real risk factor to the increasing incidence of ASIL and of anal and cervical cancer observed in these patients. The average age for first engaging in sexual activity was 14.65 years in the patients studied herein. There was no statistical significance in the correlation between age at which individuals began sexual activity and ASIL. Of 46 patients who began having sex as early as 14 years old, 14 (30.43%) were ASIL positive. Seventy-six individuals started having sex after the age of 14; among those, 34 (44.74%) were ASIL positive (Table 1). In comparison, Frisch et al.(15) observed moderately elevated risk for anal cancer in females who started having sex earlier than 16 years old in comparison to women who first had sexual intercourse after the age of 20 years. Seventy patients reported an actual or past history of STD; among these, 27 (38.57%) presented ASIL. Twenty-three (30.66%) patients with no STD history presented lesions. Therefore, there was no statistical significance between the

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TABLE 4. Correlation between image characteristics of high-resolution anoscopy and histopathological results Histopathology Anoscopy Neg % LSIL % HSIL % Tinctorial characteristics

Total

Negative AWL

15

75.00

4

20%

1

5%

20

Dense AWL

28

44.44

22

34.92

13

20.63

63

Tenuous AWL

35

77.78

6

13.33

4

8.89

45

Lesion distribution aspect Focal

30

56.60

14

26.42

9

16.98

53

Coalescent

33

60.00

14

25.45

8

14.55

55

Relief Flat

49

74.24

6

9.09

11

16.67

6 66

Slightly elevated

9

37.50

10

41.67

5

20.83

24

Elevated

5

27.78

12

66.67

1

5.56

18

P* 0.005

0.921

<0.001

0.002

Surface Smooth Granular Papillary Nonpapillary Vascular Profile

44 18 4 74

68.75 41.86 21.05 67.89

9 19 12 20

14.06 44.19 63.16 18.35

11 6 3 15

17.19 13.95 15.79 13.76

64 43 19 109

Normal atypical warty vessels no warty vessels punctation no punctation mosaicism no mosaicism

52 6 3 59 1 62 1 61

63.41 46.15 42.86 59.00 33.33 59.61 50.00 58.09

17 5 3 25 2 26 1 27

20.73 38.46 42.86 25 66.67 25 50 25.71

13 2 1 16 0 16 0 17

15.85 15.38 14.29 16 0 15.38 0 16.19

82 13 7 100 3 104 2 105

<0.001

0.3631 0.5691 0.2248 0.666

Neg: ASIL negative, including inflammatory alterations, LSIL: low-grade squamous intraepithelial lesion, HSIL: high-grade squamous intraepithelial lesion, AWL: acetowhite lesion

TABLE 5. Correlation between presence of HPV anal infection and anal cancer precursor lesions PCR/ histopathology HPV+ HPVTotal

ASIL+

%

ASIL-

%

Total

P-value

46 4 50

45.10 15.38

56 22 78

54.90 84.62

102 26 128

0.006

HPV+: presence of HPV, HPV-: absence of HPV. ASIL+: presence of anal cancer precursor lesion; ASIL-: absence of anal cancer precursor lesion

two groups (Table 1). Regarding anal cancer, Frisch et al.(15) observed a relationship between STD and anal neoplastic development. In 2002, Frisch(17) reported that most STD related to anal cancer were also associated with HPV infection. Statistical significance was observed between the presence of anal papillomavirus infection, according to PCR results, and ASIL (P = 0.006). Forty-six HPV positive patients (45.10%) presented ASIL, while only four (15.38%) noninfected patients presented lesions (Table 1). Palefsky et al.(32) observed, back in 1998, that nearly all HIV-positive male

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patients with lymphocytes T-CD4 counts less than 500/mm³ they were following in the city of San Francisco presented PCR detected anal HPV infection. They also reported that 72% of HIV-positive males with CD4 counts less than 200/mm³ had abnormal anal cytology, so that, taken together, both findings pointed to a probable high prevalence of ASIL in these patients. Indeed, commenting about a work performed by his group in the San Francisco bay to investigate his earlier assumptions and published in 2008, Palefsky states that the prevalence of ASIL of any grade in HIV-positive MSM was

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57% (43% HSIL) and that HPV infection was detected in 88% of these patients, 72% of whom were oncogenic HPV(34). Thirty-three of the patients studied herein presented T-CD4 levels below 200 cells/µL, eight (24.24%) of those were ASIL positive. Among those patients presenting T-CD4 cells counts above 200/µL, 38 (43.68%) were ASIL positive, demonstrating no correlation between T-CD4 levels and ASIL (Table 2). The same was observed in patients who were under HAART. Nineteen patients (33.33%) that received the medication were ASIL positive, while 31 (43.66%) patients who did not use the medication were also positive for ASIL (Table 2). Abramowitz et al.(1) also observed no correlation in the association of levels of T-CD4 lymphocytes, use of HAART and ASIL. On the other hand, Piketty et al.(38) reported a high prevalence of ASIL (64%) in patients using HAART when their immunity was restored and Palefsky(34) described an increase in number of cases of anal and cervical cancer despite the use of HAART. There was also no statistical significance in the association between ASIL and the presence of anal benign diseases (hemorrhoids, hypertrophied papilla, anal fistula, anal fissure, mucosal prolapse, anal pruritus, and proctitis) in the 107 individuals in whom these characteristics were studied. Among these patients, 42 (39.25%) were positive for ASIL, while 8 of 27 patients (38.10%) who did not present any listed disease were also positive (Table 2). These results are not consistent with the findings of Frisch et al.(14) and Tseng et al.(47) who noticed a significant relation between benign anal lesions and anal cancer, although no case of anal cancer was observed among our patients. Our data did not find any association of smoking with the presence of ASIL. We observed that among 48 smokers, 17 (35.42%) were positive for ASIL, while 70 (87.50%) nonsmokers also presented ASIL (Table 2). Contrarily (considering ASIL a stage of anal cancer development), Tseng at al.(47) reported an association between smoking and anal cancer and Daling et al.(11) showed that smoking was associated with an odds ratio of 3.9 to develop anal cancer. There was no statistical significance between the presence of ASIL and addiction to hallucinogen drugs. Among drug users, 42.86% presented intraephitelial lesions, while 38% of non-drug users also presented ASIL (Table 2). In contrast, Ching-hong et al.(6) reported statistical significance for this factor (P = 0.03), while Piketty et al.(37) reported 34% of cases of ASIL in HPV positive heterosexual individuals using drugs. Diagnostic accuracy of HRA HRA was associated with high sensitivity (90%) but low specificity (19.23%) for the diagnosis of ASIL, with a negative predictive value of 75% and a low positive predictive value of 41.67% (Table 3). False positive and false negative rates were, respectively, 89.76% and 10%. Sensitivity and specificity rates of HRA vary greatly in the literature, since this is still a very subjective, as well as user, equipment and other-comorbidity-dependent test(7, 19, 26, 46). Values vary from 59%(26) to 100%(46) for sensitivity and from 66%(46) to 74%(24) for specificity. However, more concordantly with our results,

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Tuon et al.(48) reported for cervical colposcopy, a much more widely employed and studied method, a specificity rate as low as 19%. Correlating the presence of AWL with the histopathological diagnosis of ASIL, there was no statistical significance between the variables according to the chi-square test (0.2142), whereas the kappa test (0.076) showed low evidence of agreement between the variables. This is possibly a consequence of the fact that lesions such as hypertrophied papillae, hemorrhoids and inflammation in anal canal used to stain positively by acetic acid, a reflection of the 63 acetowhite-positive lesions that were negative for ASIL, as well as due to HRA interpretative differences among three individual observers. Diagnostic agreement between HRA images and histopathology Regarding tinctorial quality of HRA a significant relationship was observed relative to the presence of histopathologically confirmed ASIL (P = 0.005), for of 20 patients with HRA negative for AWL, 15 (75%) had negative histopathological results, 4 (20%) presented LSIL and 1 (5%) HSIL. Likewise, regarding dense AWL, 28 (44.44%) of 63 patients had negative histopathological results, 22 (34.92%) presented LSIL and 13 (20.63%) HSIL. On the other hand, of 45 individuals with tenuous AWL, 35 (77.78%) had negative histopathological results, 6 (13.33%) presented LSIL and 4 (8.89%) HSIL. A proportion of HSIL (72%) and LSIL (69%) lesions were described as dense AWL. Based on the odds ratio, dense AWL were 2.3 times more likely to be an HSIL than a tenuous lesion (21% of dense AWL lesions were HSIL compared to 9% of tenuous AWL lesions). But, accordingly, a dense AWL was 2.7 times more likely to be an LSIL than a tenuous lesion. Regarding the relief of lesions observed at HRA, flat lesions tended to be mainly negative for ASIL, but HSIL lesions were more frequently flat at HRA than LSIL. While slightly elevated lesions were more often either negative for ASIL or LSIL, elevated lesions tended to be LSIL. These results showed statistical significance (P<0.001). HSIL lesions tended to be significantly more associated to flat AWL than LSIL (P<0.001). A high-grade lesion was 3 times more prone to be flat than to be elevated (16% of flat lesions were HSIL compared to 5% of elevated lesions). Comparatively, Jay et al.(21) observed that flat lesions were 4 times more frequently associated to HSIL than elevated lesions (39% of flat lesions were HSIL compared to 9% of elevated lesions). When surface aspect was analyzed, smooth lesions were more frequently observed in relation to negative histopathological results, whereas a granular aspect was not prone to be HSIL and a papillary aspect was more frequently associated to low-grade lesions (P = 0.002). Among lesions described as smooth, the probability of them being HSIL were 1.2 times higher than being LSIL (17% of HSIL lesions were smoothv compared to 14% of granular lesions). Jay et al.(21) found that smooth lesions were 2 times more likely to be HSIL than granular lesions

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FIGURE 1. Positive acetowhile lesion, dense, focal, flat, smooth, nonpapillary, HPV positive. Histopathology: HSIL

FIGURE 4. Mosaicism, HPV positive. Histopathology: LSIL

FIGURE 2. Acetowhite lesion dense, coalescent, slightly elevated, papillary, HPV positive. Histopathology: HSIL

FIGURE 5. Acetowhite lesion dense, coalescent, elevated, granular, punctation, HPV positive. Histopathology: condiloma

FIGURE 3. Acetowhite lesion, dense, coalescent, slightly elevated, papillary, HPV positive. Histopathology: LSIL

FIGURE 6. Acetowhite lesion dense, slightly elevated, granular, HPV positive. Histopathology: LSIL

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(31% of smooth lesions were HSIL compared to 13% of granular lesions). Regarding the description of lesions being either papillary or non-papillary, a higher proportion of HSIL (83%) than LSIL (62%) was described as non-papillary (P = 0.001). Non-papillary lesions had a 0.87 times greater chance to be associated to HSIL than LSIL. Jay et al.(21) reported that non-papillary lesions were twice as likely to be HSIL than papillary lesions (34% of non-papillary lesions were HSIL compared to 14% of papillary lesions). There was no statistical significance for the remaining studied aspects of the lesions and their vascular pattern (Table 4), which is not consistent with the findings of Jay et al.(21), in which warty vessels, punctation and mosaicism all presented a statistical significance at the level of 0.001. Our data indicate that of the HSIL lesions analyzed 68% were dense AWL, 61% were flat, 61% were smooth, 83% were non-papillary and 70% presented a normal vascular pattern. Regarding LSIL lesions, 66% of them were dense AWL, 68% were slightly elevated or elevated, 59% were granular, 62% were non-papillary and 53% presented normal vascular pattern. ASIL prevalence Fifty patients were diagnosed as having ASIL (39.1%) at histopathology: 32 (25%) presented low grade lesions and 18 (14.1%) presented high-grade lesions. These results are similar to other findings in the literature for the prevalence of ASIL, where LSIL ranges from 35.7%(20) to 42%(38), while HSIL from 7.1%(18) to 26%(21). HPV prevalence The observed HPV prevalence in the HIV-positive patients studied was of 79%. Other similar findings in the literature present prevalence from 80%(38) to 98%(39).

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Correlation between anal cancer precursor lesions and HPV infection Among 50 patients presenting ASIL, 46 were HPV positive, consistent with a 92% prevalence. Among 32 patients who had LSIL, 30 (93.75%) were HPV positive, while of 18 patients with HSIL, 16 (88.88%) had HPV infection. In a systematic review, 1,824 patients were studied, including 472 and 360 presenting HSIL and LSIL, respectively. The prevalence of HPV in patients presenting HSIL and LSIL was 71.91% and 88%, respectively(20). Based on the data presented in Table 5, a prevalence of 45% of ASIL was observed HIV-positive patients co-infected with HPV. CONCLUSIONS

HRA was a highly sensitive method for the detection of ASIL considering the tinctorial quality, relief and surface aspect of AWL which enhanced the capability of distinction between high- and low-grade anal squamous lesions. Nevertheless, due to its poor observed specificity a complementary histopathological study is mandatory in order not to miss unsuspected atypical lesions. The prevalence of anal HPV infection and of ASIL in the studied HIV-positive patients was of, respectively, 79% and 39.1% (25% LSIL and 14.1% HSIL). Anal intercourse and anal HPV infection were highly correlated with the presence of ASIL. ACKNOWLEDGMENTS

We are grateful to Rosilene Andrade, Pathologist at the Tropical Medicine Foundation of Amazonas; Junia Raquel Ferreira Dutra, Assistant Professor of the Pharmaceutical Sciences College at the Federal University of Amazonas; and Enrique José Ortellado Rosty, Physician of the Federal University of Amazonas.

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Gimenez F, Costa-e-Silva IT, Daumas A, Araújo J, Medeiros SG, Ferreira L. Anuscopia de alta resolução: valor diagnóstico em lesões precursoras de câncer anal em pacientes soropositivos.. Arq Gastroenterol. 2011;48(2):136-45. RESUMO – Contexto – O câncer anal, muito embora ainda seja uma doença rara, vem sendo observado com frequência ascendente em alguns grupos populacionais considerados sob risco para o desenvolvimento da doença. Infecção pelo vírus do papiloma humano (HPV), imunossupressão e o sexo anoreceptivo são alguns dos fatores associados ao desenvolvimento da neoplasia. Suas semelhanças com o câncer do colo do útero levaram muitos estudos voltados para o estabelecimento de regras para a detecção e tratamento de lesões precursoras do câncer anal, tudo com o objetivo de prevenir a doença. A anuscopia com magnificação de imagem é rotineiramente utilizada para o diagnóstico de lesões precursoras do câncer anal em muitos centros, mas a literatura médica ainda é escassa a respeito do papel a ser desempenhado por essa modalidade diagnóstica. Objetivos – Avaliar as medidas de validação e precisão diagnósticas da anuscopia com magnificação de imagem em comparação com resultados histopatológicos de biopsias anais realizadas em pacientes HIV-positivos tratados na Fundação de Medicina Tropical do Amazonas, Manaus, AM, Brasil. Observar qualquer possível associação entre alguns fatores de risco para o desenvolvimento do câncer anal e a presença de lesões intraepiteliais escamosas anais. Métodos – Cento e vinte e oito pacientes HIV-positivos foram submetidos a coleta de material celular anal para a realização da detecção da presença de HPV pela reação em cadeia da polimerase. Anuscopias com magnificação de imagem foram realizadas após a aplicação tópica de ácido acético a 3% no canal anal por 2 minutos. As lesões acetobrancas eventualmente observadas foram registradas com respeito a sua localização e classificadas quanto ao seu padrão tintorial, aspecto de distribuição, relevo, características de sua superfície e vascularidade. Foram realizadas biopsias das lesões acetobrancas sob anestesia local e os espécimes foram remetidos para estudo histopatológico. Os pacientes foram entrevistados em relação à presença de fatores de risco para o câncer anal. Resultados – As prevalências de infecção anal pelo HPV e de lesões intraepiteliais escamosas anais na amostra populacional estudada foram de 79% e 39,1%, respectivamente. A sensibilidade e a especificidade da anuscopia com magnificação de imagem foram, respectivamente, de 90% e 19,23%, enquanto que o valor preditivo positivo foi de 41,67%, o valor preditivo negativo foi de 75% e o coeficiente kappa de 0,076. Com respeito às lesões analisadas de alto grau foram mais frequentemente observadas em associação com lesões acetobrancas densas (68%), planas (61%), lisas (61%), não-papilíferas (83%) e com padrão vascular normal (70%), enquanto que lesões de baixo-grau tenderam a se associar a lesões aetobrancas densas (66%), plano-elevadas ou elevadas (68%), granulares (59%), não-papilíferas (62%) e de padrão vascular normal (53%). Não se observou significância estatística na associação entre características epidemiológicas e a maioria dos fatores de risco para o câncer anal e a presença de lesão acetobrancas ou de lesões intraepiteliais escamosas anais. Entretanto, o sexo anorreceptivo e a detecção de infecção anal por HPV, segundo a técnica da reação da cadeia de polimerase, associaram-se significantemente com lesões intraepiteliais escamosas anais (P = 0,0493 e P =0,006, respectivamente). Conclusões – A anuscopia com magnificação de imagem demonstrou ser um método diagnostico sensível, mas inespecífico para a detecção de lesões intraepiteliais escamosas anais. Os fatores de risco sexo anorreceptivo e infecção anal pelo HPV associaram-se significantemente à presença de lesões intraepiteliais escamosas anais. Com base nos achados da anuscopia com magnificação de imagem, o relevo e o aspecto morfológico da distribuição das lesões acetobrancas na superfície do canal anal tenderam a permitir a distinção entre lesões de baixo e alto grau. DESCRITORES – Neoplasias do ânus. HIV. Infecções por papilomavírus. Proctoscopia.

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18. Gimenez FS, Costa e Silva IT, Guimarães ADP, Ferreira LCL, Araújo JR, Rocha RP, Atala LS, Avi SV, Talhari S. Prevalência de lesões precursoras do câncer anal em indivíduos HIV positivos atendidos na Fundação de Medicina Tropical do Amazonas, experiência inicial em Manaus. Rev Bras Coloproctol. 2008;28:72-6. 19. Hammes LS. Correlação entre achados colposcópicos e diagnóstico histológico segundo a classificação colposcópica da federação internacional de patologia cervical e colposcopia de 2002 [dissertação]. Porto Alegre: Universidade Federal do Rio Grande do Sul; 2004. 20. Hoots BE, Palefsky JM, Pimenta JM, Smith JS. Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. Int J Cancer. 2009;124:2375-83. 21. Jay N, Berry JM, Hogeboom CJ, Holly EA, Darragh TM, Palefsky JM. Colposcopic appearance of anal squamous intraepithelial lesions: relationship to histopathology. Dis Colon Rectum. 1997;40:919-28. 22. Klencke BJ, Palefsky JM. Anal cancer: an HIV-associated cancer. Hematol Oncol Clin North Am. 2003;17:859-72. 23. Kuppers V. Significance of colposcopy in cancer prevention. Gynakol Prax. 2005;29:69-86. 24. Martin F, Bower M. Anal intraepithelial neoplasia in HIV positive people. Sex Transm Infect. 2001;77:327-31. 25. Martins CR. HPV-induced anal dysplasia: what do we know and what can we do about it? Hopkins HIV Rep. 2001;133-5. 26. Mathews WC, Sitapati A, Caperna JC, Barber RE, Tugent A, Go U. Measurement characteristics of anal citology, histopathology and high-resolution anoscopic visual impression in an anal dysplasia screening program. J Acquir Immune Defic Syndr. 2004;37:1610-5. 27. Melbye M, Sprogel P. Aetiological parallel between anal cancer and cervical cancer. Lancet. 1991;338:657-9. 28. Nadal RS, Manzione CR. Citologia como método para detecção de lesões precursoras do carcinoma anal. Rev Bras Coloproctol. 2005;25:72-4. 29. Palefsky JM, Holly EA, Hogeboom CJ, Berry JM, Jay N, Darragh TM. Anal cytology as a screening tool for anal squamous intraepithelial lesions. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;14:415-22. 30. Palefsky JM. Human papillomavirus infection and anogenital neoplasia in human immunodeficiency virus-positive men and women. J Natl Cancer Inst Monogr. 1998;(23):15-20. 31. Palefsky JM, Holly EA, Hogeboom CJ, Ralston ML, DaCosta MM, Botts R, Berry JM, Jay N, Darragh TM. Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraephitelial lesions in HIVpositive and HIV-negative homosexual men. J Acquir Immune Defic-Syndr Hum Retrovirol. 1998;17:314-9. 32. Palesky JM, Holly EA, Ralstson ML, Jay N. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)positive and high-risk HIV-negative homosexual men. J Infect Dis. 1998;177:361-7. 33. Palefsky JM, Holly EA, Ralston ML, Jay N, Berry JM, Darragh TM. High incidence of anal high-grade squamous intraepithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS. 1998;12:495-503. 34. Palefsky J. Human papillomavirus–related disease in people with HIV. Curr Opin HIV AIDS. 2009;4:52-6. 35. Panther LA, Wagner K, Proper J, Fugelso DK, Chatis PA, Weeden W, Nasser IA, Doweiko JP, Dezube BJ. High resolution anoscopy findings for men who have sex with men: inaccuracy of anal cytology as a predictor of histologic high-grade anal intraepithelial neoplasia and the impact of HIV serostatus. Clin Infect Dis.

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2004;38:1490-2. 36. Penn I. Occurrence of cancers in immunosuppressed organ transplant recipients. Clin Transpl. 1998;147-58. 37. Piketty C, Darragh TM, Da Costa M, Bruneval P, Heard I, Kazatchkine MD, Palefsky JM. High prevalence of anal human papillomavirus infection and anal cancer precursors among HIV-infected persons in the absence of anal intercourse. Ann Intern Med. 2003;138:453-9. 38. Piketty C, Darragh TM, Heard I, Da Costa M, Bruneval P, Kazatchkine MD, Palefsky JM. High prevalence of anal squamous intaepithelial lesions in HIV– positive men despite the use of highly active antiretroviral therapy. Sex Transm Dis. 2004;31:96-9. 39. Pokomandy A, Rouleau D, Ghattas, G, Vézina S, Coté P, Macleod J, Allaire G, Franco EL, Coutlée F. Prevalence, clearance and incidence of anal human papillomavirus infection in HIV-infected men: the HIPVIRG cohort study. J Infect Dis. 2009;199:965-973. 40. Prieto Reyes M, Vázquez Márquez L. [Anal epidermoid carcinoma: a rare incidence or a rare diagnosis?] Rev Esp Enferm Dig. 1997;2:128-32. 41. Qualters JR, Lee LNC, Smith RA, Aubert RE. Breast and cervical cancer surveillance, United State, 1973–1987. MMWR CDC Surveill Summ. 1992;41(2):17. 42. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med. 2000;342:792-800. 43. Scholefield JH, Johnson J, Hitchcock A, Kocjan G, Smith JH, Smith PA, Ferryman S, Byass P. Guidelines for anal cytology-to-make cytological diagnosis and follow up much more reliable. Cytopathology. 1998;9:15-22. 44. Silva ITC, Gimenez FS, Guimarães RAS, Camelo RT, Melo MND, Barros FS, Guimarães ADP, Cabral CRB, Guimarães EL. Citologia anal como método de rastreamento para detecção precoce do câncer anal: esfregaços com algodão hidrófilo são mesmos insatisfatórios? Acta Cir Bras. 2005;20:109-114. 45. Spence AR, Franco EL, Ferenczy A. The role of human papillomavirus in cancer: evidence to date. Am J Cancer. 2005;4:49-64. 46. Tramujas da Costa e Silva I, de Lima Ferreira LC, Santos Gimenez F, Gonçalves Guimarães RA, Botinelly Fujimoto L, Barbosa Cabral CR, Venturim Mozzer R, de Souza Atala L. High-resolution anoscopy in the diagnosis of anal cancer precursor lesions in renal graft recipients. Ann Surg Oncol. 2008;15:1470-5. 47. Tseng HF, Morgenstern H, Mack TM, Peters RK. Risk factors for anal cancer: results of a population-based case-control study. Cancer Causes Control. 2003;14:837-46. 48. Tuon FFB, Bittencourt MS, Panichi MA, Pinto AP. Avaliação da sensibilidade e especificidade dos exames citopatológicos e colposcópico em relação ao exame histológico na identificação de lesões intra-epiteliais cervicais. Rev Assoc Med Bras. 2002;48:140-4. 49. Walker P, Dexeus S, De Palo G, Barrasso R, Campion M, Girardi F, Jakob C, Roy M. International terminology of colposcopy: an update report from the International Federation for Cervical Pathology and Colposcopy. Obstet Gynecol. 2003;101:175-77. 50. Zaki SR, Judd R, Coffield LM, Greer P, Rolston F, Evatt BL. Human papillomavirus infeccion and anal carcinoma. Retrospective analysis by in situ hybridization and the polymerase chain reaction. Am J Pathol. 1992;140:1345-55.

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Received 20/10/2010. Accepted 12/1/2011.

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ISLET TRANSPLANTATION IN RODENTS. Do encapsulated islets really work? Yngrid Ellyn Dias Maciel de SOUZA1, Eleazar CHAIB2, Patricia Graça de LACERDA1, Alessandra CRESCENZI3, Arnaldo BERNAL-FILHO3 and Luiz Augusto Carneiro D’ALBUQUERQUE2 ABSTRACT – Context - Diabetes mellitus type I affects around 240 million people in the world and only in the USA 7.8% of the population. It has been estimated that the costs of its complications account for 5% to 10% of the total healthcare spending around the world. According to World Health Organization, 300 million people are expected to develop diabetes mellitus by the year 2025. The pancreatic islet transplantation is expected to be less invasive than a pancreas transplant, which is currently the most commonly used approach. Objectives - To compare the encapsulated and free islet transplantation in rodents looking at sites of islet implantation, number of injected islets, viability and immunosuppression. Methods - A literature search was conducted using MEDLINE/PUBMED and SCIELO with terms about islet transplantation in the rodent from 2000 to 2010. We found 2,636 articles but only 56 articles from 2000 to 2010 were selected. Results - In these 56 articles used, 34% were encapsulated and 66% were nonencapsulated islets. Analyzing both types of islets transplantation, the majority of the encapsulated islets were implanted into the peritoneal cavity and the nonencapsulated islets into the liver, through the portal vein. In addition, the great advantage of the peritoneal cavity as the site of islet transplantation is its blood supply. Both vascular endothelial cells and vascular endothelial growth factor were used to stimulate angiogenesis of the islet grafts, increasing the vascularization rapidly after implantation. It also has been proven that there is influence of the capsules, since the larger the capsule more chances there are of central necrosis. In some articles, the use of immunosuppression demonstrated to increase the life expectancy of the graft. Conclusion - While significant progress has been made in the islets transplantation field, many obstacles remain to be overcome. Microencapsulation provides a means to transplant islets without immunosuppressive agents and may enable the performance of xenotransplantation. The use of alternative donor sources, fewer islets per capsule and the appropriate deployment location, such as the peritoneal cavity, may give a future perspective to the application of immunoprotective capsules and viability in clinical practice. A variety of strategies, such as genetic engineering, co-encapsulation, improvement in oxygen supply or the establishment of hypoxia resistance will also improve the islet transplantation performance. It remains to be determined which combination of strategies with encapsulation can fulfill the promise of establishing a simple and safe transplantation as a cure for diabetes. HEADINGS - Diabetes mellitus, type I. Islets of Langerhans transplantation. Rodentia.

INTRODUCTION

Diabetes mellitus (DM) type I affects around 240 million people in the world(1) and only in the USA 7.8% of the population(55). It has been estimated that the costs of its complications account for 5% to 10%(20) of the total healthcare spending around the world. According to World Health Organization, 300 million people are expected to develop DM by the year 2025. Islet transplantation has been considered a safer alternative than whole-organ transplantation and a potentially alternative treatment to conventional exogenous-insulin therapy(16). The main benefit of islet transplantation is the ability to inject it in vascularized organs and it can be considered less invasive. The acute rejection still is a major problem. New alternatives to avoid the rejection have been developed such as, thymic manipulation, co-transplant with other cell types (bone

marrow cells, Sertoli cells etc.), liver transplantation(27, 37, 41, 42) and encapsulated islets. With immunoprotection by encapsulation, islets are enclosed in a matrix surrounded by semipermeable membrane, which allows for the passage of small molecules like insulin and glucose, but not for the entry of the much larger cells and antibodies of the immune system. Such a physical barrier can thus prevent allograft rejection, which depends on recognition of the Major Histocompatibility Complex (MHC) by host lymphocytes. Furthermore it can prevent antibody-mediated cytotoxicity, which plays a role in the autoimmune destruction of beta cells, as well as in allograft and xenograft rejection(31, 59). Immunoprotection by encapsulation can thus enable transplantation of islet tissue in the absence of immunossupression. Our aim is to compare the encapsulated and free islet transplantation in rodents looking at site of

1 Universidade Nove de Julho, São Paulo, SP; 2 Faculdade de Medicina da Universidade de São Paulo, USP, 3 Curso de Pós-graduação, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil. Correspondence: Prof. Eleazar Chaib – Department of Gastroenterology – University of Sao Paulo School of Medicine – Av. Dr Arnaldo, 455 – 3º andar – 01246-903, São Paulo, SP, Brazil. E-mail: eleazarchaib@yahoo.co.uk

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Souza YEDM, Chaib E, Lacerda PG, Crescenzi A, Bernal-Filho A, D’Albuquerque LAC. Islet transplantation in rodents. Do encapsulated islets really work?

implantation, number of islets, viability and type of immunosuppression. METHODS

This research was made through MEDLINE/PUBMED and SCIELO web sites looking for papers on the content “islet transplantation in the rodent”. We found 2,636 articles but only 56 articles from 2000 to 2010 were selected based on the relevance. Thirty-five (35%) were about encapsulated islet and sixty-five (65%) nonencapsulated islet. There were articles about xenografts, isografts and allografts. RESULTS

The best islet survival rate in encapsulated islet transplantation was achieved in the peritoneal cavity with an average of 4216 islets implanted per capsule, lasting an average of 100 days functionally (Table 1). TABLE 1. Sites of implantation of encapsulated islets and islets survival rate (days) Encapsulated No. of islets per Author Results days capsule Peritoneal cavity 2000 70 Tatarkiewicz et al.(53) 3000 21-70 Omer et al.(35) IS+: 18 ± 8 16000 Figliuzzi et al.(11) IS-: 7.5 ± 0.2 1200 >365 Yun Lee et al.(63) 3000 80 Remuzzi A et al.(39) 100 14 O’Sullivan et al.(36) Subcutaneous tissue 200 to 1000 ±6 Sorenby et al.(48) 125 to 375 28 Sorenby et al.(49) Liver 1500 95 ± 3 Schneider S. et al.(44) IS+: with immunosuppression; IS - : without immunosuppression

Encapsulated islet

The most widely used implantation sites of encapsulated islets (Figure 1). In contrast, the best islet survival rate in the nonencapsulated islets was achieved by injecting islets into the liver, with an average of 1475 islets implanted per capsule, lasting an average of 164 days with the use of immunosuppression (Table 2). TABLE 2. Sites of implantation of nonencapsulated islets and islets survival rate (days) Nonencapsulated Author No. of islets Results days Liver 600 > 365 Ikebukuro et al.(19) 1500 365 Spadella et al.(50) 1500 97 ± 2 Schneider et al.(44) 4000 70 Omer et al.(35) 600 30 Taira M. et al.(52) 600 250 Ikebukuro et al.(18) IS+: 10.5 ± 8.44 500 to 1500 Hara et al.(16) IS-: 12.0 ± 2.65 1500 126 Lee. et al.(29) Kidney 250 28 Olsson et al.(34) 2000 > 100 Sawada et al.(42) > 60 Lan et al.(27) 2500 41 Hamamoto et al.(14) 1500 80 –120 Kover et al.(24) 200 or 20 56 Hiramatsu et al.(17) 1500 ± 200 150 Socha-Urbanek et al.(47) 3000 to 3200 19.5 ± 5.8 Laumonier et al.(28) 4000 70 Omer et al.(35) 30 30 – 40 Sharma et al.(46) 500 to 1500 11.0 ± 2.63 Hara et al.(16) 60 Han et al.(15) IS+: with immunosuppression; IS-: without immunosuppression

Other sites of implantation were: subcutaneous tissue (n = 2500 islets; 58 days of viability), peritoneal cavity (n = 10000 islets; 37 days of viability) and bone marrow (n = 1250 islets; 21 days of viability). DISCUSSION

Peritoneal cavity Subcutaneous tissue Liver

FIGURE 1. Most common sites of implantation of encapsulated islets

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The concept of islet transplantation is not new. Investigators as early as the English surgeon Charles Pybus (1882–1975) attempted to transplant pancreatic tissue to cure diabetes. Most, however, credit the recent era of islet transplantation research to Paul Lacy’s studies dating back to more than 3 decades. Lacy’s group(25) described a novel method to isolate islets using collagenase, paving the way for future of in vitro and in vivo islet experiments. According to Hara et al.(16), Ballinger and Lacy demonstrated that intraportal islet transplantation corrected experimental

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diabetes in rodents; since then, many transplantation sites have been tested. Subsequent studies showed that transplanted islets could reverse diabetes in both rodents and non-human primates(23, 43) . Lacy(26) observed the feasibility of islet cell transplantation as a therapeutic approach in the probable prevention of the diabetes complications in individuals. Improvements in isolation techniques and immunosuppressive regimens conducted in the first human clinical trials of islet transplantation in the mid of 1980. Tzakiset et al.(57) described the first successful trial of human islet allotransplantation resulting in longterm reversal of diabetes. Despite continued procedural improvements, only about 10% of islet recipients in the late of 1990 achieved euglycemia. Shapiro et al.(45) described seven consecutive patients who achieved euglycemia after islet transplantation using a steroid-free protocol and large numbers of donor islets. In the last 10 years numerous studies were made on islet transplantation in the rodent. We reviewed 56 of these studies; 19 articles (34%) concerned encapsulated islet and 37 (66%) non-encapsulated islet. Nonencapsulated islets may be injected into the liver (4, 16, 18, 19, 35, 44, 50, 52) , kidney(5, 14, 15, 16, 17, 24, 27, 28, 32, 34, 35, 42, 46, 47), peritoneal cavity(11, 35), bone marrow(41) and subcutaneous tissue(22, 48). Ikebukuro et al.(19) showed that islets and bone marrow cells, when injected into the liver using irradiation as immunosuppression, can increase the functionality of the cells for more than 365 days. In addition, Kawakami et al.(22) discovered that basic fibroblast growth factor could increase vascularization and thus achieve islets viability for 112 days, when islets were injected in the subcutaneous tissue. Many factors can influence the islet viability and it is important to review them. While significant progress has been made in the islet transplantation field, many obstacles remain that currently preclude its widespread application. Three of the most important limitations are low tension of O2 where the islets are implanted, the limited supply of islets for transplantation and also the currently inadequate means for preventing islet rejection. Encapsulated islets have been used in two ways: microencapsulated islets and macro-encapsulated islets. Macroencapsulated islets have the advantage of being retrievable so that the functions of islets inside can be evaluated at anytime. In contrast, micro-encapsulated islets are one or a few islets enclosed in semi-permeable membranes, which can provide a surface for diffusion, therefore maintaining the functions of islets inside. However, they are irretrievable after transplantation(38). When islets are transplanted, 50% of the tissue may be lost in the first few days; this is thought to be due to hypoxic death before vascularization develops(36). Revascularization begins in 7-10 days after transplant, when there’s already ischemic damage(21, 33). This delayed and insufficient revascularization deprives these islets of oxygen, resulting in cell death and graft failure(12). The great advantage of the liver as the site of islet transplantation is dual blood supply, which allows the total occlusion of the

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portal venules, caused by embolization and the non-infarted site of transplantation, which is nourished by blood(4). In the renal subcapsular space, islets are easily retrieved for histological study. However, vascularization is poor and leads to a low tension of oxygen. When the islets are implanted into the rodent’s peritoneal cavity there is plenty of blood supply to use of, which facilitates the wait for a new revascularization, but it is randomly chosen. Trying to increase the blood supply of the graft soon after implantation, Cheng et al.(5) have injected vascular endothelial cells L and vascular endothelial growth factor (VEGF) to stimulate angiogenesis. The use of growth factors was made of in other works too(5, 33, 62). They saw that in chronically isquemic tissues these factors where decreased and that premature islet revascularization could improve the outcome of islet transplantation and enhance the graft survival. Yu et al.(62) combined SDF-1alfa and VEGF achieving not only new vessels but mature and stable ones. In a different way, joining bone marrow - derived mesenchymal stem cells function as VEGF secretor to pancreatic islets, Figliuzzi et al.(12) also promoted vascularization. Johansson et al.(21) questioned the early capability of forming new blood vessels, lost days later. They saw that the islets attract blood vessels but fail to grow and connect to recipient blood vessels. He then inhibited the angiostatic factors and restored that capability without any growth factors. All of these different approaches towards a better vascularization are new and of these, need yet to be sorted the best one. The difficulty in isolating an adequate number of islets lies on the fact that multiple donors are needed to get patients off exogenous insulin after islet transplantation. Therefore, it is crucial to prepare large numbers of viable and functional islets from a single donor pancreas for clinical transplantation. It has been proven that the volume of the capsules influences, since the larger the capsule more chances are there of central necrosis(36). Besides necrosis, a major concern is that the low tension of O2 can lead the release of proinflammatory factors. These pro-inflammatory factors elicit a host immune response even in the encapsulated islets. An alternative to prevent these factors is the use of capsules. These can reduce immunogenicity by preventing cellular immune reactions while simultaneously transfers nutrients, oxygen and therapeutic factors. This permits the imitation of moment-to-moment fine regulation of the missing therapeutic factors, avoids a lifetime of immunosuppressive therapy and allows the use of non-human cells, thus overcoming the limited supply of human donor cells(65). Zhao et al.(64) have demonstrated that encapsulated islets cultured in 3D peptide nanofiber provides a superior simulated microenvironment for improving the viability and the secretion function of the islets. Graft failure of encapsulated islets is usually interpreted as a consequence of a nonspecific body reaction against the capsules that results in fibrotic overgrowth of the capsules,

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with ischemia and subsequent necrosis of the islets (9). Pericapsular overgrowth should not impose a problem as long as the majority of the islet-containing microcapsules is not affected by overgrowth, and remains efficient(6). However, macrophage-derived factors from the overgrown part of the graft may affect the non-overgrown part. An alternative to these are capsules with new components. Zimmermann et al.(65) have demonstrated that alginate based matrix with BaCl2 crystals enhances the immunoprotecting encapsulation and therefore stabilizes the membrane when in contact with the external Ba2+. Yun et al.(63) have reported that PEG-based chemical immunomodulation can provide a semi-permanent effective therapy that protects transplanted islets at least for 1 year when accompanied by cyclosporine. Furthermore, Vériter et al.(58) have tested originals alginates with respect to sterile lyophilized high mannuronated and they have had an optimum result with high mannuronated with high viscosity alginate. Another option is the use of TheraCyteTM which is suited for the maintenance of islets in vivo by allowing cells to be loaded into the chamber at controlled densities and spatial configurations and the promotion of vascularization by the outer membrane of the device(51). In addition, Teramura et al.(54) have proposed as up-to-the-minute method for islet microencapsulation with amphiphilic poly (ethylene glyocol)conjugated phospholipid derivative (PEG-lipid) and DNA hybridization. This enables an individually islet encapsulation and no central necrosis have been observed. Qi et al.(38) have suggested the use of polyvinyl alcohol macro-encapsulated islets for long-term preservation (7 days) is better, because they allow overcoming the obstacles of insufficient donors and the side effects of immunosuppressive drugs. In the past decades, allograft survival improved because the development of new and more specific immunosuppressive agents. Recently it was stated that porcine islet xenotransplantation is possible using cyclosporine A (CsA) as an immunosuppressive agent. They isolated islets from adult pigs, cultured for 1.5-3 weeks and transplanted in rodents using CsA. The treatment with CsA achieved graft survival to over 134 days(40). A further immunosuppressive agent used is AEB-071 (AEB). AEB-071 is a specific inhibitor of protein kinase C, which prevents T-lymphocyte activation. Merani et al.(32) investigated the effect of AEB on rat islet allotransplantation alone or in combination with CTLA4-Ig, mycophenolate mofetil or CsA in rodent allogeneic islets transplant model. They demonstrated that AEB is an appropriate immunosuppressive agent for islet transplantation, because it can prolong islet graft survival alone or with CsA, without toxicity on glucose metabolism. In another study, researchers combined CsA with FTY720 in islet xenotransplantation. They found that this combination inhibited almost all morphological signs of pig-to-rat islet xenograft rejection for up to 24 days after transplantation(30). Fotiadis et al.(13) used mycophenolatemofetil (MMF) and CsA to check the positive or adverse effects of MMF as a

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single agent. They proved that the administration of MMF as immunosuppression agent was safe in an experimental model of islet allotransplantation and was equally effective with cyclosporine, with less toxicity. Balamurugan et al.(2) described the effect of CsA, FK506 or prednisolone monotherapy on preventing monkey islet graft rejection after xenotransplantation in a rodent model. Histological examination indicated that monkey islets survived in the presence of continuous high-dose of immunosuppressive monotherapy in rodents. Most immunosuppressive drugs, that support successful allograft survival act by inhibiting or depleting T lymphocytes. Tautomycetin (TMC) is a specific inhibitor of protein phosphatase 1, which has a role in cell-cycle control and T-cell activation and promotes T-cell-specific apoptosis. Wee et al.(60) investigated the effect of TMC alone and in combination with CsA on rodent islet transplantation. They suggested that CsA and TMC act synergistically to reduce the function of T-effector cells and enhance regulatory cell function in a rodent islet allotransplantation model. Tacrolimus (FK506) is a different immunosuppressive agent used in the islet transplantation. Balibreadel et al.(3) evaluated in vitro islet low-dose tacrolimus response after pro-inflammatory stimulation. They found that in vitro cytoprotective effect of low-dose tacrolimus on isolated rodent islets decreases both oxidative stress and apoptosis markers after stimulation of pro-inflammatory mediators. Activation of both the coagulation and the complement cascades is one of the serious obstacles to successful island engraftment. Tokodai et al.(56) suggested that C5a- inhibitory peptide combined with gabexatemesilate may be a useful approach to control the instant blood-mediated inflammatory reaction induced in clinical islet transplantation and one that is free of side effects. It was demonstrated that graft survival of allograft islets transfected with indoleamine 2, 3-dioxygenase (IDO) transplanted without any immunosuppression was superior to the control group. It is known that IDO exerts immunoregulatory functions suppressing T-cell responses. These data demonstrated that IDO expression induced in islets by lipofection improved metabolic control of streptozotocindiabetic rodents and prolonged allograft survival(10). The cytoprotection of chitosan hydrogels in xenogeneic islet transplantation was demonstrated by Yang et al.(61). It has showed that islets encapsulated in chitosan hydrogels secreted insulin in response to the glucose stimulation as naked islets with higher cell survival. This study indicates that the chitosan hydrogels deliver and protect encapsulated islets successfully in xenotransplantation. Finally, a better insight into the causes of microencapsulated islet graft failure may help in finding a way to improve graft survival. One important observation is that microencapsulated autograft and allograft survival rates are similar, which implies that graft failure is not caused by rejection due to allograft recognition(7). If graft failure cannot be explained by allogratrejection, others factors must be involved. De Vos et al.(8) have showed that there

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is a gradual decrease in islet function, a gradual increase in central necrosis, a continuous increased replication of islet cells, and a nonprogressive overgrowth of a portion of microencapsulated islet graft. Three important aspects of the microencapsulated islet graft technique may be associated with these phenomena. The first is related to the biocompatibility, which explains the occurrence of overgrowth. The second is related to the immunoprotective properties of the microcapsules. Immunoprotection is incomplete because capsules may allow the passage of small pro-inflammatory factors, which lead to cell death and dysfunction. The third factor is related to the great distance between the encapsulated islets and the blood supply. An important consequence of the great diffusion distance is the limited supply of oxygen, which leads to hypoxia, causes islet dysfunction and necrosis, and may be responsible for the increase in islet replication.

CONCLUSION

While significant progress has been made in the islets transplantation field, many obstacles remain to be overcome. Microencapsulation provides a means to transplant islets without immunosuppressive agents and may enable the performance of xenotransplantation. The use of alternative donor sources, fewer islets per capsule and the appropriate deployment location, such as the peritoneal cavity, may give a future perspective to the application of immunoprotective capsules and viability in clinical practice. A variety of strategies, such as genetic engineering, co-encapsulation, improvement in oxygen supply or the establishment of hypoxia resistance will also improve the islet transplantation performance. It remains to be determined which combination of strategies with encapsulation can fulfill the promise of establishing a simple and safe transplantation as a cure for diabetes.

Souza YEDM, Chaib E, Lacerda PG, Crescenzi A, Bernal-Filho A, D’Albuquerque LAC. Transplante de ilhotas de Langerhans em modelos experimentais em roedores. Ilhotas encapsuladas realmente funcionam? Arq Gastroenterol. 2011;48(2):146-52. RESUMO – Contexto - Diabetes mellitus tipo I afeta cerca de 240 milhões de pessoas no mundo e 7,8% só nos EUA. Foi estimado que o custo de suas complicações fosse de 5%-10% dos custos mundiais em saúde. De acordo com a OMS (Organização Mundial de Saúde), espera-se que cerca de 300 milhões de pessoas desenvolvam o diabetes mellitus até o ano de 2025. É esperado que o transplante de ilhotas pancreáticas seja menos invasivo que o transplante pancreático, opção atual de maior uso. Objetivos - Comparar as ilhotas encapsuladas e as ilhotas livres em roedores nos seguintes aspectos: local de implantação das ilhotas, número de ilhotas, viabilidade e imunossupressão. Métodos - A pesquisa bibliográfica foi conduzida com o uso de citações do MEDLINE/PUBMED e SCIELO que apresentassem termos sobre transplante de ilhotas em roedores no período de 2000 a 2010. Foram achados 2.636 artigos, mas somente 56 desse período foram selecionados. Resultados - Nos 56 artigos utilizados, 34% eram encapsulados e 66% eram não-encapsulados. Analisando ambos os tipos de transplante de ilhotas, a maioria delas encapsuladas, foi implantada na cavidade peritonial e as não-encapsuladas, através da veia porta, no fígado. A grande vantagem da cavidade peritonial como local de transplante era a oferta sanguínea. As células endoteliais e o fator de crescimento endotelial foram usados para estimular a angiogênese nas ilhotas, aumentando a vascularização rapidamente após a implantação. Foi também provada a influência das cápsulas, dado que quanto maior a cápsula maior era a chance de necrose central. Em alguns artigos, o uso de imunossupressão demonstrou aumento da expectativa de vida do enxerto. Conclusão - Enquanto algum progresso significativo não tenha sido obtido no campo de transplante de ilhotas, restam ainda muitos obstáculos a serem vencidos. A microencapsulação viabiliza o transplante de ilhotas sem o uso de imunossupressores, o que pode permitir o xenotransplante. O uso de fontes doadoras alternativas, menor quantidade de ilhotas por cápsula e local de implantação adequado, como a cavidade peritonial, podem dar melhor perspectiva na aplicação de cápsulas imunoprotegidas, aumentando viabilidade na prática clínica. Uma série de estratégias, como engenharia genética, coencapsulamento, melhora da oferta de oxigênio ou o estabelecimento de resistência à hipóxia também podem aprimorar os resultados do transplante de ilhotas. Devese determinar ainda qual a combinação de estratégias com relação ao uso de ilhotas encapsuladas que possam cumprir com as promessas de um transplante simples e seguro para a cura do diabetes. DESCRITORES - Diabetes mellitus tipo I. Transplante das ilhotas pancreáticas. Roedores.

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GASTROENTEROLOGIA EXPERIMENTAL/EXPERIMENTAL GASTROENTEROLOGY

ARQGA/1552

HEPATIC AND BIOCHEMICAL REPERCUSSIONS OF A POLYUNSATURATED FAT-RICH HYPERCALORIC AND HYPERLIPIDIC DIET IN WISTAR RATS Idália M. B. BURLAMAQUI1, Conceição A. DORNELAS2, José Telmo VALENÇA Jr2, Francisco J. C. MESQUITA3, Lara B. VERAS4 and Lusmar Veras RODRIGUES2 ABSTRACT - Context - Non-alcoholic fatty liver disease is characterized by lipid deposits in the hepatocytes and has been associated with obesity, dyslipidemia and type-2 diabetes. It is considered a hepatic manifestation of the metabolic syndrome, of which the main component is insulin resistance leading to hyperinsulinemia and increased production of inflammatory cytokines. Saturated fat promotes hypertriglyceridemia and hyperinsulinemia, reduces levels of high-density cholesterol and increases levels of low-density cholesterol, while polyunsaturated fat is associated with hypolipidemic, antiinflammatory and imunoregulating action. Objective – To evaluate the hepatic and biochemical repercussions of a polyunsaturated fat-rich diet in Wistar rats. Methods - Twenty-two rats were distributed equally in two groups: GI – standard diet (Biobase Bio-tec Ratos e Camundongos®) providing 3.000 kcal/kg and GII – hypercaloric and hyperlipidic diet providing 4.250 kcal/kg (ω-6:ω-3 = 3:1). The animals were euthanized after 23 weeks of experiment. The weight, biochemical parameters and hepatohistological changes were registered. Results - Findings were submitted to variance analysis with the level of statistical significance at 5%. The average weight did not differ significantly between the groups at baseline (P = 0.711), but was greater in Group II by the end of the experiment (P = 0.000). The levels of triglycerides (P = 0.039), total cholesterol (P = 0.015) and HDL (P = 0.005) were higher in Group I than in Group II. Macrovesicular steatosis was significantly more common in Group II than in Group I (P = 0.03). Conclusion - Hypercaloric and hyperlipidic diet rich in polyunsaturated fat promotes weight gain and favors the development of hepatic steatosis while reducing serum levels of triglycerides, total cholesterol and HDL. HEADINGS – Fatty liver. Obesity. Dyslipidemias. Diabetes mellitus, type 2. Rats.

INTRODUCTION

A fat-rich diet is a risk factor for obesity(16). Extensive research has shown that dietary fat affects a range of metabolic functions, depending on the quantity and composition of fatty acids(9). Diets rich in polyunsaturated fat (PUFA), especially ω-3 and ω-9, are associated with hypolipidemic, antiinflammatory and imunoregulating action. On the other hand, saturated fats and trans fats are known to promote hypertriglyceridemia and hyperinsulinemia, reduce levels of high-density cholesterol (HDL) and increase levels of low-density cholesterol (LDL)(18). Non-alcoholic fatty liver disease (NAFLD) is the most common type of chronic liver injury in many countries(3, 13). Manifestations range from simple steatosis to non-alcoholic steatohepatitis (NASH) to fibrosis, cirrhosis and hepatocellular carcinoma(27). The

prevalence of NAFLD, which is currently 15%−40% among Western populations and 9%−40% among Asian populations(14), has increased dramatically over the past 15 years, mostly due to its association with the world’s two largest current epidemics: obesity and type-2 diabetes mellitus (DM2)(1). Current research on nutritional change is revealing the important role played by NAFLD in metabolic and cardiovascular complications. NAFLD is considered a hepatic manifestation of the metabolic syndrome, of which the main component is insulin resistance followed by hiperinsulinemia(4, 19, 25, 32) and is characterized by increased uptake, synthesis and accumulation of fatty acids in the hepatocytes, leading to lipogenesis and fatty liver(3). In addition, mitochondrial oxidation defects can cause the fatty acid synthesis to increase to the detriment of triacylglycerol secretion, thereby contributing to hepatic steatosis(30). Hyperinsulinemia

This work was performed in the Surgical Department, Federal University of Ceará Medical School, Fortaleza, CE, Brazil. 1 Department of Surgery, Federal University of Ceará; 2 Department of Pathology and Forensic Medicine, Federal University of Ceará; 3 School of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; 4 School of Medicine, Medical School, Juazeiro do Norte, CE, Brazil. Correspondence: Dr. Idália Maria Brasil Burlamaqui – Avenida Beira Mar, 3680 – apt. 2001 – Meireles – 60465-121 – Foratleza, CE, Brasil. E-mail: idaliaburlamaqui87@ hotmail.com

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also induces oxidative stress with the consequent peroxidation of lipids in the hepatocyte membrane and production of cytokines, especially tumor necrosis factor-alpha (TNF-α)(3, 36). Recent studies have shown that the adipose tissue secretes not only inflammatory cytokines such as interleukin–6 (IL-6) and TNF-α, but also adiponectin-an, insulin-sensitizing and antiinflammatory adipocytokine with multiple beneficial effects on the clinical complications of obesity(24). The hepatoprotective action of adiponectin has been described in several clinical and experimental studies. Low serum levels of adiponectin in obese humans constitute an independent risk factor for NAFLD, including hepatic dysfunction of variable severity(39). Thus, in one study, patients with NASH experienced a reduction of over 50% in adiponectin levels compared to normals(22). Adiponectin levels are reported to decline by 20%−40% during the transition from simple steatosis to steatohepatitis(22, 37). In patients with NASH, very low levels of adiponectin have been associated with severe inflammation, suggesting that adiponectin deficiency is an important risk factor for the development of steatosis, steatohepatitis and other forms of liver damage(5). Since hypercaloric and hyperlipidic diets can induce liver damage, dyslipidemia and DM2, it may be hypothesized that PUFA-rich diets (containing ω-3 and ω-9) offer cardiovascular, hepatic and metabolic protection. Thus, the present study was designed to evaluate the hepatic and biochemical repercussions of a polyunsaturated fat-rich, hypercaloric and hyperlipidic diet in Wistar rats. METHODS

Animals and diets The study was previously approved by the Federal University of Ceará (UFC), Fortaleza, CE, Brazil, Ethics Committee for Animal Research (CEPA/UFC) under protocol #11/06 and was conducted according to the International Guiding Principles for Biomedical Research Involving Animals (CIOMS, 1985). Twenty-two, 180-250 g, 8-week-old male Wistar rats (Rattus norvegicus albinus, Mammalia, Rodentia, Muridae) supplied by the UFC laboratory animal facility were used in the experiments. During the adaptation period, the rats were dewormed with pyrantel pamoate and oxantel pamoate (Basken®) at 1 mL/kg. The animals were randomly assigned to two groups at 8 weeks of life, accommodated in individual cages and euthanized in the 23rd week of the experiment. All animals had access to food and water ad libitum. Group I (GI): Control group of 11 animals receiving standard diet. The diet (Biobase Bio-tec Ratos e Camundongos®) provided a total of 3.000 kcal/kg (Tables 1 and 2).

TABLE 2. Lipid profile and ratios between ω-3, ω-6 and ω-9 fatty acids in standard diet and hypercaloric and hyperlipidic diet Type of fat Standard diet Hyperlipidic diet Polyunsaturated 54% 19% Monounsaturated 24% 29% Saturated 15% 6% 0.4 : 1 1.5 :1 ω9/ω6 8 : 1 3 : 1 ω6/ω3 Polyunsaturated/saturated 5.2 : 1 >60% ω-6 7.6 : 1 >50% ω-9 % ω-6 and 9

Group II (GII): Treatment group of 11 animals receiving a hypercaloric and hyperlipidic diet. The diet consisted of 15 g standard diet + 20 g Nutri Diabetic® + 5 mL canola oil and was rich in polyunsaturated fat and omega fatty acids, providing a total of 4.250 kcal/kg (Tables 2 and 3). Euthanasia and collection of blood and liver samples Following anesthesia by intraperitoneal injection of 80 mg/kg ketamine and 8 mg/kg xylazine, the animals were placed in dorsal decubitus on a wooden board with all four limbs immobilized and submitted to laparotomy by xyphopubic median incision and exposure of the abdominal cavity. Blood was collected from the abdominal aorta and tested biochemically for glycemia, uric acid, aspartate transaminase (AST), alanine transaminase (ALT), gammaglutamyl transpeptidase (GGT), triglycerides, HDL and total cholesterol. Subsequently, a 1-cm3 liver fragment retrieved by left hepatectomy was submitted to anatomopathological analysis at the Department of Pathology and Legal Medicine (School of Medicine, UFC). Finally, euthanasia was induced by aortic bleeding. Histological study of liver samples Following fixation in 10% formaldehyde, the liver samples were embedded in paraffin and stained with hematoxylineosin (H-E). Hepatic steatosis was classified in four grades based on the histological findings (Table 4)(8). Statistical analysis The statistical analysis was performed with the software SPSS v.16.0 for Windows®. All laboratory variables were normal with regard to the distribution of variance homogeneity. Average values were analyzed with Student’s t test. Fisher’s exact test was used to verify the association between diet type and the presence of hepatic steatosis. The level of statistical significance was set at 5% (P<0.05).

TABLE 1. Composition of standard (normoglycidic, hypolipidic and high-protein) diet (Biobase Biotec® Ratos e Camundongos) Food Amount (g) Kcal Carbohydrate (g) Protein (g) 40 120 17.6 8.8 Biobase Bio-tec® TOTAL 40 120 17.6 8.8 Total distribution of calories 70.4 35.2 Calories (%) 58.66% 29.34%

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Lipid (g) 1.6 1.6 14.4 12.00%

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TABLE 3. Composition of hypercaloric and hyperlipidic diet Food

Amount (g)

Kcal

Carbohydrate (g)

Protein (g)

Lipid (g)

15

45

6.6

3.3

0.6

Nutri Diabetic®

20

80

11

3.2

2.6

Canola oil

5

45

0

0

5

TOTAL

40

170

16.6

6.5

8.2

70.4

26

73.8

41.36%

15.28%

43.36%

Biobase Bio-tec

®

Total distribution of calories Calories (%) TABLE 4. Classification of steatosis Grade 0 1 2 3

triglycerides (P = 0.039), total cholesterol (P = 0.015) and HDL (P = 0.005) (Table 5).

Macrovesicular steatosis Absent Mild (>0% to 33%) Moderate (>33% to 66%) Severe (>66%)

Weight distribution The average weight did not differ significantly between the groups at baseline (P = 0.711), but was greater in Group II by the end of the experiment (P = 0.000) (Table 6).

RESULTS

Biochemical analysis The tests revealed statistically significant differences between Group I and Group II with regard to the levels of

Anatomopathological findings The number of animals with macrovesicular steatosis was significantly greater in Group II (HD) than in Group I (P = 0.03) (Table 7; Figures 1 and 2).

TABLE 5. Biochemical findings for Groups I and II Laboratory Test

Group I Average ± standard diet

Group II Average ± standard diet

P-value

Glycemia (mg/dL)

136.09 ± 28.01

150.00 ± 24.91

0.261

Uric Acid (mg/dL)

1.39 ± 0.36

1.15 ± 0.36

0.165

AST (U/L)

87.54 ± 35.27

66.64 ± 19.10

0.129

ALT (U/L)

42.31 ± 12.39

33.36 ± 11.71

0.117

GGT (U/L)

0.40 ± 0.33

0.50 ± 0.68

0.700

CRP

0.5 ± 0.00

0.5 ± 0.00

1.000

Triglycerides (mg/dL)

80.09 ± 22.36

59.44 ± 18.10

0.039*

Total cholesterol (mg/dL)

70.91 ± 18.08

53.44 ± 8.12

0.015*

HDL (mg/dL)

62.55 ± 11.75

48.22 ± 7.25

0.005*

* Statistically significant difference (P<0.05)

TABLE 6. Weight distribution (g) of Group I and Group II at baseline and by the end of the experiment Group

n

I II

11 11

Group

Average (g) ± Standard deviation Baseline Final 200.8 ± 11.1 385.0 ± 16.4 203.4 ± 17.0 431.6 ± 20.1

* By the end of the experiment the average weight was greater in Group II than in Group I (P = 0.000)

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TABLE 7. Fisher’s exact test Absence of steatosis

Presence of steatosis

I

9 (81.8%)

2 (18.2%)

II

3 (27.3%)

8 (72.7%)*

P = 0.03

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FIGURE 2. Histopathological section of liver tissue from rat 9, Group II, showing macrovesicular steatosis grade 1 (H-E; 400X) FIGURE 1. Histopathological section of liver tissue from rat 2, Group I, showing macrovesicular steatosis grade 0 (H-E; 400X)

DISCUSSION

Recent research has drawn attention to the association between NAFLD and a number of health problems, including obesity, dyslipidemia, type-2 diabetes and cancer. The pathogenesis of NAFLD is not completely understood, but insulin resistance, oxidative stress and inflammation all play an important role in the development and progression of the disorder(23, 26, 29). In addition, unusually high levels of circulating free fatty acids have been correlated with NAFLD severity(15). Changes in dietary fat composition can affect metabolic functions and lead to changes in body weight and composition(28). In the present study, animals fed with a PUFA-rich diet displayed significant weight gain, as observed in other studies(18). PUFA-rich diets have been associated with reduced food intake(17), probably, because animals receiving high-fat diets, as opposed to high-calorie diets, require less energy for lipid deposition(34). In addition, epidemiological studies have found an inverse relation between the incidence of cardiovascular disease and the intake of ω-3 PUFA(21, 31). The effect of different types of PUFA on body adiposity has been the object of much controversy. PUFA-rich diets with large amounts of ω-3 and ω-6 were recently reported, respectively, to reduce lipolysis and increase dietary lipid uptake in the adipose tissue. Both fatty acids caused changes in liver metabolism and favored lipid deposition(17). The levels of triglycerides, total cholesterol and HDL were lower in animals receiving the enhanced diet (Table 5). Positive effects of ω-3 fatty acids on the reduction of triglycerides and total cholesterol serum levels have been reported in several other studies using animal or human models(2, 33). Omega-3 fatty acids can inhibit the activity of diacylglycerol

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acyltransferase-a catalyst of triglyceride synthesis(35). Rats fed with ω-3 fatty acid have been shown to have reduced total cholesterol serum levels due to increased biliary cholesterol excretion(6). C-reactive protein (CRP) is produced in the liver. However, high CRP serum levels are considered a non-specific indicator of inflammation. Contrary to expectations, all the animals in our study had CRP levels below 0.5 mg/dL. Higher levels were expected, especially in Group II, due to the increased intake of calories and fat, greater weight and consequently greater probability of inflammation. The low CRP levels observed may be attributed to the antiinflammatory action of ω-3 fatty acids(38). The study diet was expected to produce a protective effect on the liver, but the histological analysis showed steatosis to be statistically more predominant in Group II than in Group I (Table 7). Possibly, the lower adiponectin levels in the significantly heavier animals of Group II may not have been sufficiently insulin-sensitizing and antiinflammatory to prevent the development of NAFLD. Studies using rats have shown that lipid deposition in the liver is related to oxidative stress and that lipid peroxidation increases in proportion to the severity of hepatic steatosis(12). This may explain why hepatic steatosis was observed in a much greater proportion of the animals receiving hypercaloric and hyperlipidic food (72.7%) than in animals receiving the standard diet (18.2%). In other words, the risk of steatosis was greater in the treatment group because lipid peroxidation favors the development of NASH(11, 23). Interestingly, though hepatic steatosis is often associated with slightly or moderately increased levels of ALT and AST(10), both parameters remained normal in Group II. Confirming the findings of other researchers(7, 20), our study shows that although diets rich in polyunsaturated fatty acids improve the serum lipid profile, they can also cause undesirable changes in hepatic metabolism and lipid deposition.

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CONCLUSIONS

ACKNOWLEDGEMENTS

These results show that a hypercaloric and hyperlipidic diet rich in polyunsaturated fat promotes weight gain and favors the development of hepatic steatosis while reducing serum levels of triglycerides, total cholesterol and HDL.

This study was supported by the following Brazilian agencies: the National Council for Scientific and Technological Development (CNPq); Surgical Department, Federal University of Ceará Medical School; and the Experimental Surgery Laboratory (LABCEX), Federal University of Ceará, Medical School.

Burlamaqui IMB, Dornelas CA, Valença Jr JT, Mesquita FJC, Veras LB, Rodrigues LV. Repercussões hepáticas e bioquímicas da dieta hipercalórica e hiperlipídica rica em gordura poliinsaturada em ratos Wistar. Arq Gastroenterol. 2011;48(2):153-8. RESUMO - Contexto - A doença hepática gordurosa não-alcoólica caracteriza-se por depósito de lipídios nos hepatócitos. Desperta grande interesse por sua associação com obesidade, dislipidemias e diabetes mellitus tipo 2. É considerada a manifestação hepática da síndrome metabólica, cujo principal componente é a resistência à insulina, com consequente hiperinsulinemia e produção aumentada de citocinas inflamatórias. Dietas ricas em gorduras saturadas promovem hipertrigliceridemia, diminuição do colesterol de alta densidade, aumento do colesterol de baixa densidade e hiperinsulinemia, enquanto dietas ricas em gordura poliinsaturada podem apresentar efeitos hipolipidêmicos, antiinflamatórios e imunorreguladores. Objetivo - Investigar as repercussões hepáticas e bioquímicas da dieta rica em gordura poliinsaturada em ratos Wistar. Métodos - Os animais (22) foram distribuídos nos grupos GI-dieta padrão (Biobase Bio-tec Ratos e Camundongos®) com 3000 kcal/kg e GII-dieta hipercalórica e hiperlipídica, com 4250 kcal/kg, relação ω-6: ω-3 = 3:1. Foram mortos após 23 semanas de administração das dietas. Avaliaram-se peso, exames bioquímicos e alterações histológicas do fígado. Resultados – Foram utilizados testes de análise de variância com nível de significância de 5% (P<0,05). Não houve diferença significante na média de peso entre os grupos (P = 0,711) no início, entretanto GII apresentou maior média que GI ao final do experimento (P = 0,000). GI mostrou níveis significantemente mais elevados de triglicerídeos (P = 0,03), colesterol total (P = 0,039) e HDL (P = 0,015) do que GII. O GII apresentou maior média de esteatose macrovesicular do que GI (P = 0,005). Conclusão - A dieta hipercalórica e hiperlipídica, rica em gordura poliinsaturada, promove esteatose hepática e incremento de peso, contudo reduz os níveis séricos de triglicerídeos, colesterol total e HDL. DESCRITORES - Fígado gorduroso. Obesidade. Dislipidemias. Diabetes mellitus tipo 2. Ratos.

REFERENCES 1.

Adams LA, Angulo P. Recent concepts in non-alcoholic fatty liver disease. Diabet Med. 2005;22:1129-33. 2. Aguilera AA, Díaz GH, Barcelata ML, Guerrero OA, Ros RM. Effects of fish oil on hypertension, plasma lipids and tumor necrosis factor-α in rats with sucroseinduced metabolic syndrome. J Nutr Biochem. 2004;15:350-7. 3. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221-31. 4. Arrospide MT. Hígado graso no alcohólico. Rev Gastroenterol Peru. 2003; 23:49-57. 5. Aygun C, Senturk O, Hulagu S, Uraz S, Celebi A, Konduk, T, Mutlu B, Canturk Z. Serum levels of hepatoprotective peptide adiponectina in non-alcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2006;18:175-80. 6. Balasubramaniam S, Simons LA, Chang S, Hickie JB. Reduction in plasma cholesterol and increase in biliary cholesterol by a diet rich in n-3 fatty acids in the rat. J Lipid Res. 1985;26:684-9. 7. Brown AM, Baker PW, Gibbons GF. Changes in fatty acid metabolism in rat hepatocytes in response to dietary n-3 fatty acids are associated with changes in the intracellular metabolism and secretion of apoprotein B-48. Lipid Res. 1997;38:469-81. 8. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Non-alcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467-74. 9. Campos FG, Logullo Waitzberg AG, Kiss DR, Waitzberg DL, Habr-Gama A, Gama-Rodrigues J. Diet and colorectal cancer: current evidence for etiology and prevention. Nutr Hosp. 2005;20:18-25. 10. Carvalheira JB, Saad MJ. [Insulin resistance/hiperinsulinemia associated diseases not included in the metabolic syndrome]. Arq Bras Endocrinol Metab. 2006;50:3607. 11. Day CP, James OF. Steatohepatitis a tale of two “hits”? Gastroenterology. 1998;114:842-5. 12. Diehl AM. Lessons from animal models of NASH. Hepatol Res. 2005;33: 138-44.

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13. Farrell GC. Non-alcoholic steatohepatitis: what is it, and why is it important in the Asia-Pacific region? J Gastroenterol Hepatol. 2003;18:124-38. 14. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:s99-112. 15. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewsky R, Burgart LJ, Gores, GJ. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004;40:185-94. 16. Feoli AM, Roehrig C, Rotta LN, Kruger AH, Souza KB, Kessler AM, Renz SV, Brusque AM, Souza DO, Perry ML. Serum and liver lipids in rats and chicks fed with diets containing different oils. Nutrition. 2003;19:789-93. 17. Gaíva MH, Couto RC, Oyama LM, Couto GE, Silveria VL, Roberio EB, Nascimento CM. Polyunsaturated fatty acids-rich diets: effect on adipose tissue metabolism in rats. Br J Nutr. 2001;86:371-7. 18. Gaíva MH, Couto RC, Oyama LM, Couto GE, Silveira VL, Ribeiro EB, Nascimento CM. Diets rich in polyunsaturated fatty acids: effect on hepatic metabolism in rats. Nutrition. 2003;19:144-9. 19. Guidorizzi de Siqueira AC, Cotrim HP, Rocha R, Carvalho FM, Freitas LA, Barreto D, Gouveia L, Landeiro L. Non-alcoholic fatty liver disease and insulin resistance: importance of risk factors and histological spectrum. Eur J Gastroenterol Hepatol. 2005;17:837-41. 20. Hill JO, Peters JC, Lin D, Yakubu F, Greene H, Swift L. Lipid accumulation and body fat distributions is influenced by type of dietary fat fed to rats. Int J Obes Relat Metab Disord. 1993;17:223-36. 21. Hooper L, Summerbell CD, Higgins JP, Thompson RL, Capps NE, Smith GD, Riemersma RA, Ebrahim S. Dietary fat intake and prevention of cardiovascular disease: systematic review. BMJ. 2001;322:757-63. 22. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketors A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40:46-54. 23. Ito M, Suzuki J, Sasaki M, Watanabe K, Tsujioka S, Takahashi Y, Gomori A, Hirose H, Ishihara A, Iwaasa H, Kanatani A. Development of nonalcoholic steatohepatitis model through combination of high-fat diet and tetracycline with morbid obesity in mice. Hepatol Res. 2006;34:92-8. 24. Kamada Y, Takehara T, Hayashi N. Adipocytokines and liver disease. J Gastroenterol. 2008;43:811-22.

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25. Kang H, Greenson JK, Omo JT, Chao C, Peterman D, Anderson L, Foess-Wood, L, Sherbondy, MA, Conjeevaram, HS. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower fat diet in patients with NAFLD. Am J Gastroenterol. 2006;101:2247-53. 26. Machado M, Cortez-Pinto H. Non-alcoholic fatty liver disease and insulin resistance. Eur J Gastroenterol Hepatol. 2005;17:823-6. 27. Matteoni CA, Younossi ZM, Graramlich T, Boparai N, Liu YC, Mc-Cullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413-9. 28. Mauler B, Dubben S, Pawelzik M, Pawelzik D, Weigle DS, Kratz M. Hypercaloric diets differing in fat composition have similar effects on serum leptin and weight gain in female subjects with anorexia nervosa. Nutr Res. 2009;29:1-7. 29. Mehta K, Van Thiel DH, Shah N, Mobarhan S. Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr Rev. 2002;60:289-93. 30. Minehira K, Young SG, Villanueva CJ, Yetukuri L, Oresic M, Hellerstein MK, Farese RV Jr, Horton, JD, Preitner F, Thorens B, Tappy L. Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. J Lipid Res. 2008;49:2038-44. 31. Mori TA, Beilin LJ. Long-chain omega 3 fatty acids, blood lipids and cardiovascular risk reduction. Curr Opin Lipidol. 2001;12:11-7. 32. Moscatiello S, Manini R, Marchesini G. Diabetes and liver disease: an ominous association. Nutr Metab Cardiovasc Dis. 2007;17:63-70.

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33. Oh R. Pratical applications of fish oil (Omega-3 fatty acids) in primary care. J Am Board Fam Pract. 2005;18:28-36. 34. Oudart H, Groscolas R, Calgari C, Nibbelink M, Leray C, Le Maho Y, Malan A. Brown fat thermogenesis in rats fed high-fat diets enriched with n-3 ployunsaturated fatty acids. Int J Obes Metab Disord. 1997;21:955-62. 35. Rustan AC, Nossen JO, Christiansen EN, Drevon CA. Eicosapentaenoic acid reduces hepatic synthesis and secretion of triacylglicerol by decreasing the activity of acyl-coenzyme A:1,2-diacylglycerol acyltransferase. J Lipid Res. 1988;29:1417-26. 36. Sass DA, Chang P, Chopra KB. Nonalcoholic fatty liver disease: a clinical review. Dig Dis Sci. 2005;50:171-80. 37. Shimada M, Kawahara H, Ozaki K, Fukura M, Yano H, Tsuchishima M, Tsutsumi M, Takase S. Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, and serum type IV collagen 7S level to predict the early stage of non-alcoholic steatohepatitis. Am J Gastroenterol. 2007;102:1931-8. 38. Teitelbaum JE, Allan Walker WA. Review: the hole of omega 3 fatty acids in intestinal inflammation. J Nutr Biochem. 2001;12:21-32. 39. Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131:934-45. Received 5/11/2010. Accepted 25/11/2010.

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GASTROENTEROLOGIA EXPERIMENTAL / EXPERIMENTAL GASTROENTEROLOGY

ARQGA/1553

ENDOSCOPIC TREATMENT FOR GASTRIC PERFORATION USING T-tag AND A PLASTIC PROTECTION CHAMBER: a short-term survival study Kiyoshi HASHIBA, Pablo R. SIQUEIRA, Horus A. BRASIL, Marco Aurélio D’ASSUNÇÃO, Daniel MORIBE and Jorge Carim CASSAB ABSTRACT – Context - The endoscopic gastric perforation is a consequence of some endoscopic procedures and now a way to manage abdominal organs. This is the reason why endoscopists are studying a safe endoscopic repair. Objective - To evaluate an endoscopic closure method for the gastric opening in natural orifice transenteric surgery Design - Short-term survival animal study. Methods Ten White Landrace pigs underwent a gastric perforation of 1.8 cm in diameter under general anesthesia. The opening was repaired with stitch assembled in a T-tag anchor placed through the gastric wall with a needle. A plastic transparent chamber, adapted to the endoscope tip protected the abdominal organs from the needle puncture outside the stomach. Six T-tags were placed in most cases and the stitches were tied with a metallic tie-knot, forming three sutures. The animals received liquids in the same operative day. One shoot antibiotic was used. The leakage test was performed with a forceps and by air distention. Results - No complication was detected in the postoperative course. One month later the endoscopy revealed a scar and some suture material was observed in all animals. The antral anterior gastric wall was clear with few adhesions in the laparotomy performed in the same time. The adhesions were intense in an animal in which a cholecystectomy was performed before the repair. Conclusion - The endoscopic repair using T-tag and a protector chamber is feasible, easy to perform and safe. Further studies are needed to show the real value of this kind of procedure. HEADINGS - Endoscopy gastrointestinal. Intestinal perforation. Swine.

INTRODUCTION

METHODS

Perforation in the gastrointestinal tract during endoscopy is not a rare event. Nowadays the perforation can be a step of the endoscopic procedure, like in some mucosectomy and in natural orifice transenteric surgery (NOTES) procedure. Many techniques were proposed for the repair, but some of them are very complex(9). The use of T-tag seems to be the simplest method and this is, probably, the reason why many studies are made with this device(6, 8). However, the needle insertion in the peritoneal cavity, through the gastrointestinal wall, as proposed in some of them, seems to be dangerous(3, 11, 12). In this presented study a chamber adapted to the endoscope tip was used to protect other abdominal organs during the T-tag anchor placement in order to make an interrupted suture which was applied to close a full-thickness gastric perforation.

This study included 10 farm pigs weighing approximately 30 to 35 kg. No oral food intake was allowed 24 hours before experiments. The animals were got under general anesthesia, ventilated with 100% oxygen and monitored with pulse oximeter. All procedures were performed with the animal in the supine position. The gastric mucosa did not receive previous treatment. The area for NOTES access was chose and guided by transillumination and abdominal digital pressure, a 14-gauge needle was passed through the anterior abdominal wall into the stomach, followed by passage of a guidewire (METII-35-480, Cook Endoscopy, Winston-Salem, NC, USA) through the needle. This wire was captured into the working channel of a conventional gastrointestinal endoscope by means of a biopsy forceps (FB-21K-1, Olympus Latin America, Miami, FL, USA) and then

The following authors report that they have no disclosure relevant to this publication: Pablo R.de Siqueira. Marco Aurélio D’Assunção, Horus A. Brasil, Daniel Moribe. Kiyoshi Hashiba acts as a consultant for Cook Endoscopy Hospital Sírio Libanês Experimental Center and Endoscopic Unit, São Paulo SP, Brazil. Correspondence: Dr. Kiyoshi Hashiba – Rua Dona Adma Jafet, 90 – CEP: 01308-050 – Sao Paulo – SP, Brazil. Email: hashiba@attglobal.net

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the scope and the guide wire were pulled to the mouth. With the stomach partially deflated, a 1.8 cm in diameter, TTS balloon (QD-18x8, Cook Endoscopy) was passed by the working channel over the wire, advanced across the gastric wall and totally inflated in order to dilate the needle puncture. A laparoscopy using a 0o view optical device (26003AEA, Storz, Tuttlingen, Germany) placed into an 11 mm umbilical trocar (30103 MP, Storz, Tuttlingen, Germany), was performed to exclude iatrogenic injury during the peritoneal access. A specially developed plastic chamber (prototype, Cook Endoscopy) is attached to the tip of the conventional gastrointestinal endoscope (GIF-160, Olympus). The chamber has a lateral window that allows the placement of the gastric wall inside (Figures 1 and 2).

Figure 3. After the puncture, the T-tag remains near the gastric serosa in a place at the side of the gastric opening. The endoscope was retrieved, loaded with another T-tag, rotated at the opposite side of the previous puncture and the procedure repeated. So, at the end of these two punctures, two stitches are placed in the side of the gastric perforation (Figure 4). Both stitches are put together with a tie-knot (prototype, Cook Endoscopy) under endoscopic visual control.

FIGURE 3. Endoscopic view of the suture

FIGURE 1. The plastic chamber

FIGURE 4. The T-tag suture

FIGURE 2. Schematic view of the suture

Chamber characteristics: length: 4.2 cm, window: 8 mm in length and 2/3 of the circumference, length distal to the window: 1.5 cm, length from the endoscope tip to the window: 8 mm. The suturing procedure was performed with a T-shaped anchor suture T-tag (prototype, Cook Endoscopy). The suture was loaded into a needle assembled in a narrow plastic tube. The needle is placed at the end of a metal tube and its sharp end remains protected inside the tube, but can be exposed by pushing the metal tube. This set was inserted through the working channel, perforating the wall supported by the chamber as showed on

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The stitches were cut with scissors (FS-3L-1, Olympus), one at a time. At the end of all procedures, a remaining opening was searched using a permanent biopsy forceps (FB-19K-1, Olympus). With the peritoneal cavity totally filled with saline solution, a leakage test was performed with air injected by the endoscope to maximum capacity. The point of failure was defined as the point at which the first sign of air was seen bubbling from the repaired wound. When an air leakage was detected, an endoscopic metallic clip (HX-600-090, Olympus) was placed and the test was repeated. All animals received liquids in the first 12 hours and regular food after that period. One shot of antibiotics (Cefazoline 2 g) was given 2 days postoperatively. One month later, an endoscopic inspection and a laparotomy were performed under the same schedule using general anesthesia. The animals were sacrificed after this second experimental session using embutramide and trimethyllammonium iodide.

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A small piece of gastric tissue with the repair in place was sent for histology. This study was approved by the Hospital Sírio Libanês Institutional Animal Care and Use Committee. RESULTS

The complete opening (1.8 cm in diameter) was achieved in a total time that ranged from 15 to 20 minutes. The transparency of the wall chamber was enough to identify all places. Therefore its insertion in the peritoneal cavity occurred without trauma. In nine animals the complete closure was achieved with three pairs of sutures (Figure 5) and in one pig with three sutures, two clips were placed to close a remaining opening detected by forceps inspection. In one pig only four T-tags were placed and the stitches were put together in a crossing design.

FIGURE 5. The suturing procedure is completed with 3 sutures. The tie knot is clearly seen.

The total time to place one suture with T-tag anchor ranged from 5 to 8 minutes. The animals were monitored clinically until euthanasia and no postoperative complications were detected. The endoscopy revealed a scar in all animals (Figure 6A). Isolated stitches without tie-knots were found in three animals. T-tag anchors were observed in six animals. In eight animals, the laparotomy showed local adhesions of the omentum and the place of the gastric opening was identified (Figure 6B). In the remaining two animals the anterior face of the antrum was not seen due to adherences involving the liver and omentum and they had to be cut. The T-tag, stitches and tie-knot were also not found in the peritoneal cavity. The histology showed an inflammatory process in the submucosa, extending to the muscular layer and serosa, consisting of neutrophils, lymphocytes and histiocytes, together with fibrous and vascular proliferation. In some cases the two portions of sectioned muscular layer were in close proximity, intermixed with inflammatory cells and mild fibrosis. In all animals there was a complete restoration of the mucosal lining (Figure 7).

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FIGURE 6. The repair place scar: Endoscopic (A) and laparoscopic (B) view

FIGURE 7. The histology shows complete restoration of the mucosal lining. DISCUSSION

The occurrence of perforation in endoscopic therapeutic procedures increased the need of an endoscopic method for the repair. Beside the use of clips, many endoscopic methods with this aim are in development(1, 2, 4, 5, 6, 10). Most devices proposed use stitches to make a suture in the gastrointestinal tract wall. The use of T-tags is not new(14). As a matter of fact, the first device used for this aim was not for perforation repair, but to treat gastroesophageal reflux disease(13). In this procedure the stitch must be retrieved to the mouth twice. The use of a T-tag avoids this step of the procedure. However, the insertion of the T-tag through the wall through a needle is a blind procedure. This means that the operator cannot see what the tip of the needle finds when it passes the wall, even with the help of a limitation mechanism to avoid inserting a needle too deeply(3). Sometimes, mainly when the intestine is distended, in the final step of a long procedure, the puncture can reach another organ.

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Hashiba K, Siqueira PR, Brasil HA, D’Assunção MA, Moribe D, Cassab JC. Endoscopic treatment for gastric perforation using T-tag and a plastic protection chamber: a short-term survival study

Experimental studies in gastrointestinal perforation repair showed that this event is not so rare when the perforation is performed with T-tag(1, 2, 4, 5, 6, 7, 10, 12, 13). The idea of using a chamber to protect other abdominal organs seems to be very important when the closure is performed with T-tag(3, 11, 12). One objection raised in relation to the technique presented in this study is the attachment of the gastric wall, in the context of the mucosal surface not by the serosa as is mandatory in surgical rules. As no complication occurred in the animals postoperative course, it would be interesting to know what happens with the T-tag during the repair process. This is the reason why the control approach with endoscopy and laparotomy were performed one month later. It was noticed that, despite the controversial technique applied, the repair was as expected, with few adhesions in most animals. The endoscopic view revealed a scar. Sometimes the material used in the suture was found in the scar site. This suggests that stitches and T-tags migrate to the lumen and are eliminated with residual foods. On the other hand, the histology confirmed the good result observed through endoscopy and laparotomy, including repair of the gastric wall layers.

In conclusion, the protection chamber represents an improvement in the T-tag suture for an opening in the gastric wall. When an opening represents an acceptable event, a full-thickness resection of the gastric wall could be an option for endoscopic mucosal resection or SMD, techniques that are time-consuming, expensive and very often followed by pneumoperitoneum. It would be a possibility when gastric wall limited resection was indicated, such as in selected cases of GIST, avoiding a laparotomy or a laparoscopic procedure. ACKNOWLEDGMENTS

We thank Ms. Alvamar Helena de Campos Andrade Lamparelli for the manuscript revision and Mr Vihar Surti, Senior Research Engineer, Cook Endoscopy, Winston-Salem, NC, for the development of the set for the suturing procedure. The endoscope system and other devices were kindly provided for the study by Olympus Latinamerica, Miami, FL, USA, and Cook Endoscopy, Winston Salem, NC, USA

Hashiba K, Siqueira PR, Brasil HA, D’Assunção MA, Moribe D, Cassab JC. Tratamento endoscópico para perfuração gástrica por sutura utilizando dispositivos em T associados à câmara plástica protetora: estudo com curto tempo de sobrevida. Arq Gastroenterol. 2011; 48(2): 159-62. RESUMO – Contexto - A perfuração gástrica pode ser consequência de alguns procedimentos endoscópicos, atualmente, produzida intencionalmente para acesso a alguns órgãos com o advento da cirurgia transluminal endoscópica por orifícios naturais. Esta é a razão para que os endoscopistas estudem uma maneira segura de reparar estas lesões por via endoscópica. Objetivo - Avaliar um novo método de fechamento das perfurações gástricas utilizadas para acesso ao NOTES. Modelo de estudo - Pesquisa em modelos animais com curto tempo de sobrevida. Método - Dez porcos da raça White Landrace, foram submetidos a perfuração gástrica de 1,8 cm, monitorizados e sob anestesia geral. A abertura gástrica foi reparada com dispositivo especial constituído por agulha em forma de T montada com fio (T-tag), inserida, por via endoscópica, nas bordas do ferimento perfurando a parede gástrica e fixando-se a ela como uma âncora. Uma câmara plástica protetora, especialmente desenvolvida, foi adaptada à ponta do endoscópio para proteção dos órgãos subjacentes. Seis T-tags foram inseridos na maioria dos casos e os pontos foram amarrados e fixados com auxílio de outro dispositivo metálico de contenção do nó denominado “tie-knot”, formando três suturas. Um teste de vazamento do tipo manobra do borracheiro era realizado ao término do procedimento. Os animais recebiam líquido no pós-operatório imediato. Foi usada profilaxia antibiótica. Resultados - Não houve complicações. Um mês depois, a endoscopia de controle revelou cicatriz e alguns restos de sutura. A laparotomia, feita no mesmo tempo, revelou poucas aderências na face anterior do antro. Conclusão - O reparo endoscópico com T-tags e câmara protetora parece ser efetiva, fácil e segura. Estudos maiores e com maior tempo são necessários para confirmar estes resultados e a utilidade deste procedimento DESCRITORES - Endoscopia gastrointestinal. Perfuração intestinal. Suínos.

REFERENCES 1. 2.

3.

4.

5.

6.

7.

8.

Bergström M, Ikeda K, Swain P, Park PO. Transgastric anastomosis by using flexible endoscopy in a porcine model (with video). Gastrointest Endosc. 2006;65:307-12. Fritscher-Ravens A, Mosse CA, Mills TN, Mukherjee D, Park PO, Swain P. A through-the-scope device for suturing and tissue approximation under EUS control. Gastrointest Endosc. 2002;56:737-42. Ikeda K, Fritscher-Ravens A, Mosse A, Mills T, Tajiri H, Swain CP. Endoscopic full-thickness resection with sutured closure in a porcine model. Gastrointest Endosc. 2005;62:122-9. Ikeda K, Tajiri H. Evaluation of bifurcated double T-bar suturing device for effective closure of gastric perforation in ex vivo porcine models – aimed at clinical application of NOTES [abstract]. Gastrointest Endosc. 2008;67:AB116. Pham BV, Raju GS, Ahmed I, Brinning D, Chung S, Cotton P, Gostout CJ, Hawes RH, Kalloo AN, Kantsevov SV, Pasricha PJ. Immediate endoscopic closure of colon perforation by using a prototype endoscopic suturing device: feasibility and outcome in a porcine model (with video). Gastrointest Endosc. 2006;64:113-9. Rahmani EY, Freeman L, Sherman S, Chiorean MV, Selzer DJ. New method of gastric incision closure in NOTES: short term survival study. Gastrointest Endosc. 2008;67:AB121. Raju GS, Fritscher-Ravens A, Rothstein R, Swain P, Gelrud A, Ahmed I, Gomez G, Winny M, Sonnanstine T, Bergström M, Park PO. Endoscopic closure of colon perforation compared to surgery in a porcine model: a randomized controlled

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13. 14.

trial (with video). Gastrointest Endosc. 2008;68:324-32. Rothstein RI, Bowman H, Zwolinski A, Swain P. Randomized testing optimizing parameters for flexible endoscopic suturing in the stomach using T-tag suture fasteners. Gastrointest Endosc. 2008;67:AB120. Sclabas GM, Swain P, Swanstrom LL. Endoluminal methods for gastrotomy closure in natural orifice transenteric surgery (NOTES). Surg Innov. 2006;13:23-30. Shaik SN, Fernandez-Esparrach G, Thompson CC. Use of a nitinol crown prototype for gastrostomy closure: evaluation in an ex vivo porcine model [abstract]. Gastroenterology 2008;134:A105-A106. Sumiyama K, Gostout CJ, Rajan E, Bakken TA, Deters JL, Knipschield MA. Endoscopic full-thickness closure of large gastric perforations by use of tissue anchors. Gastroiontest Endosc. 2007;65:134-9. Sumiyama K, Gostout CJ, Rajan E, Bakken TA, Knipschield MA, Chung S, Cotton PB, Hawes RH, Kalloo NA, Kantsevoy SV, Pasricha PJ. Transgastric cholecystectomy: transgastric accessibility to the gallblader improved with SEMF method and a novel multibending therapeutic endoscope. Gastrointest Endosc. 2007;65:1028-34. Swain P. Park P, Mills T. Bard EndoCinch: the device, the technique and preclinical studies. Gastrointest Endosc Clin N Am. 2003;13:75-88. Wu TK, Pietrocola D, Welch HF. New method of percutaneous gastrostomy using anchoring devices. Am J Surg. 1987;153:230-2. Received 4/5/2010. Accepted 20/10/2010.

v. 48 – no.2 – abr./jun. 2011


COMUNICAÇÃO BREVE / BRIEF COMMUNICATON

ARQGA/1554

CELIAC DISEASE SCREENING IN PATIENTS WITH SCLERODERMA Renato NISIHARA1, Shirley Rosa UTIYAMA1, Pedro Ming AZEVEDO2 and Thelma Larocca SKARE2 ABSTRACT - Both celiac disease and scleroderma have autoimmune etiology and affect the bowel causing diarrhea. As an association of autoimmune disease in a single individual is not rare, it is important to know if a patient with scleroderma may also have celiac disease. To analyze this we studied 105 scleroderma patients and 97 volunteers for IgA-EmA by indirect immunofluorescence assay. We could not find a higher prevalence of this autoantibody in scleroderma patients. The authors conclude that there is no need to screen scleroderma patients with diarrhea for celiac disease unless there is a clear clinical indication for this. HEADINGS - Celiac disease. Scleroderma, systemic.

INTRODUCTION

Aggregation of autoimmune diseases is frequently observed in clinical practice. There is no clear cut explanation for this although it is noted that autoimmune diseases may share a genetic background. In addition, an exposure to a common etiological trigger agent is also possible(1). Celiac disease (CD) is a chronic, inflammatory and immunological mediated gluten-dependent enteropathy disease that occurs in genetically susceptible individuals(2). It appears in association with other organ specific autoimmune diseases such as thyroiditis, diabetes mellitus, dermatitis herpetiformis, autoimmune miocarditis, Addison disease, autoimmune hepatitis and primary biliary cirrhosis, etc(2). CD is also associated albeit occasionally with systemic autoimmune disorders such as connective tissue disorders(1). In this context, Sjögren syndrome is probably the connective tissue disease that bears the more convincing data. Iltanen et al.(1) studying 34 Sjogren’s syndrome patients found that 14.7% had CD, a prevalence of 30 to 40 fold higher than observed in the normal population. It is known that Sjögren’s syndrome shares the HLA DQ2 and DQ8 haplotype with CD. On the other hand, no association has been found with rheumatoid arthritis(1). Association of CD with polymyositis is less studied and described in case reports(1); as CD is a common disease, this relationship may be coincidental. In scleroderma (SSc), association with CD is controversial. Luft et al.(3) studying IgA antitissue transglutaminase antibody (anti-tTG) in 30 SSc patients found that 2 (7%) of them had this antibody against (2/40) 4% of normal population (P = NS). Rosato et

al.(4) analyzing 50 SSc patients found a prevalence of anti-tTG in 5/50 of their patients although only 4 (8% of the total sample) had biopsy proven CD a value that is higher than in normal population. SSc is associated with diarrhea due to loss of peristalsis by fibrous involvement of smooth muscle and intraluminal bacterial overgrowth and the clinical findings of diarrhea and malabsorption mimics CD(5). Nevertheless, the treatment of these two entities is completely different, which emphasized the need for a correct differential diagnosis. Nowadays, endomysium antibodies (IgA-EmA) are currently regarded as the most sensitive and specific immunologic marker of CD(2). IgA-EmA as well as anti-tissue transglutaminase (anti-tTG) has allowed evaluating the potential risk for CD in individuals with suggestive symptoms and in high risk populations. IgA-EmA antibody has over 90% specificity and sensibility for CD diagnosis. The titer of these antibodies is related to the degree of intestinal atrophy and symptoms severity(2). In this context we studied 105 scleroderma patients from Southern Brazil for the presence of EmA-IgA antibodies. METHODS

One hundred and five scleroderma patients were included in this study. In this sample 7.6% were male and 92.3% female; mean age of 43.2 years and mean disease duration of 7.7 years. In this sample, 36/105 (34.2%) had diffuse scleroderma; 9/105 (8.5%) had the mixed form (SSc plus myositis), 1 (0.9%) was sine scleroderma and 59/105 (56.2%) had the limited form (CREST syndrome).

Financial source: none Conflict of interests: none 1 Immunopathology Laboratory, Hospital de Clínicas;2 Rheumatology Unit Hospital Evangélico, Curitiba, PR, Brazil. Correspondence: Dr. Thelma L. Skare – Rua João Alencar Guimarães, 796 – 80310-420 – Curitiba, PR, Brasil. E-mail: tskare@onda.com.br

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Nisihara R, Utiyama SR, Azevedo PM, Skare TL. Celiac disease screening in patients with scleroderma

After formal consenting, blood was collected and the serum aliquoted and stored at -80o C until performing tests. As control, we studied 97 healthy volunteers from the same geographical region matched for age and sex. Tests for IgA-EmA were performed by indirect immunofluorescence assay, using human umbilical cord as substract and fluorescein conjugated goat anti-human IgA (GMK, Porto Alegre, RS, Brazil) as conjugate. Positive and negative controls were included in each test battery (Figure 1).

FIGURE 1. A - Negative IgA-EmA in cryostatic section of human umbilical chord (400X). B - Positive IgA-EmA in cryostatic section of human umbilical chord (400X) RESULTS

All samples, patients and controls were negative for IgA-EmA. DISCUSSION

Crypt hyperplasia, villous atrophy and intra epithelial lumphocytic infiltration are the main pathological characteristics

of CD. CD patients classically develop prolonged diarrhea, abdominal pain and weight loss, iron or folate deficiency, osteoporosis, chronic fatigue, milk intolerance, dental problems, neuropathy, dementia and failure to thrive. Subclinical forms are quite common; it is not rare that CD patients with minor gastroenterological symptoms are misdiagnosed as having irritable bowel disease or that CD diagnosis is only detected after the investigation of iron deficiency anemia or low bone mass (osteoporosis/osteopenia)(2). Bowel disease is the second most common involvement in scleroderma, next to skin, and has a high variable severity. Fibrous infiltration of small bowel results in dilated and often atonic loops that loose their propulsive function. Bacterial overgrowth causes damage of mucous layer causing malabsorption and malnutrition(5). In our study we could not prove association of SSc and CD. Our results are in contrast with those from Rosato et al.(4). Differences in genetic background may be one explanation for this finding. Although the prevalence of CD in our geographical region is the same as worldwide (0.3% to 0.5%)(2), we do not have enough knowledge of the genetic background of scleroderma Brazilian patients. One more data to be taken into account is that our sample had a small proportion of generalized SSc form – that was the only form associated with CD in the previously cited study. Sample size may be another explanation for the discordant results. SSc is a quite rare disorder, affecting 286 per million population and CD, as already mentioned, is a very common one. In this context multicentric studies with larger samples may answer this question. Concluding, in our sample of 105 Brazilian patients there is no detected association between scleroderma and IgA-EmA presence.

Nisihara R, Utiyama SR, Azevedo PM, Skare TL. Triagem para doença celíaca em pacientes com esclerodermia. Arq Gastroenterol. 2011;48(2):163-4. RESUMO - Tanto a esclerodermia como a doença celíaca são doenças de autoimunidade que causam diarreia. Como o agrupamento de doenças autoimunes em único indivíduo não é raro, é importante saber se um individuo com esclerodermia tem maiores chances de ter ou não doença celíaca. Para isso, estudaram-se 105 pacientes com esclerodermia e 97 controles saudáveis para o anticorpo EmA IgA. Não foi possível detectar presença aumentada de EmA IgA em pacientes com esclerodermia. Conclui-se que não existe necessidade de busca ativa de doença celíaca em pacientes com esclerodermia e diarreia, a menos que existam evidências clínicas claras da doença. DESCRITORES - Doença celíaca. Escleroderma, sistêmico.

REFERENCES 4. 1. 2. 3.

Iltanen S, Collin P, Korpela M, Holm K, Partanem J, Polvi A, Mäki M. Celiac disease and markers of celiac disease latency in patients with primary Sjögren’s syndrome. Am J Gastroenterol. 1999;94:1042-6. Kotze LM. Doença celíaca. In: Coelho JCU, editor. Aparelho Digestivo Clínica e Cirurgia. 3ª ed. São Paulo: Atheneu; 2005. v.2, p. 703-24. Luft LM, Barr SG, Martin LO, Chan EK, Fritzler MJ. Autoantibodies to tissue transglutaminase in Sjögren’s syndrome and related rheumatic diseases. J

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5.

Rheumatol. 2003;30:2613-9. Rosato E, De Nitto D, Rossi C, Libanori V, Donato G, Di Tola M, Pisarri S, Salsano F, Picarelli A. High incidence of celiac disease in patients with systemic sclerosis. J Rheumatol. 2009;36:965-9. Varga J. Systemic sclerosis: epidemiology, pathology and pathogenesis. In: Klippel JH, Stone J, Crofford LJ, White PH, editors. Primer on rheumatic diseases. 13th ed. Atlanta: Springer Science-Business Media LLC; 2008. p.351-8. Received 26/4/2010. Accepted 15/10/2010.

v. 48 – no.2 – abr./jun. 2011


Pantozol® Comprimidos Revestidos 20 mg e 40 mg pantoprazol sódico sesquiidratado USO ADULTO Apresentação e composição: embalagens com 2,7, 14, 28, 42 e 56 comprimidos gastroresistentes, na concentração de 20 mg por comprimido de pantoprazol (na forma de pantoprazol sódico sesquiidratado) e na concentração de 40 mg por comprimido de pantoprazol (na forma de pantoprazol sódico sesquiidratado). Indicações: Pantozol® 20 mg: tratamento das lesões gastrointestinais leves. Alívio dos sintomas gastrointestinais que dependam da secreção ácido-gástrica. Gastrites ou gastroduodenites agudas ou crônicas e dispepsias não-ulcerosas. Tratamento da doença por refluxo gastroesofágico sem esofagite, das esofagites leves e na manutenção de pacientes com esofagite de refluxo cicatrizada, prevenindo as recidivas. Profilaxia das lesões agudas da mucosa gastroduodenal induzidas por medicamentos como os antiinflamatórios não-hormonais. Pantozol® 40 mg: tratamento da úlcera péptica duodenal, úlcera péptica gástrica e das esofagites por refluxo moderada ou grave. Para as esofagites leves, recomenda-se o uso de Pantozol® 20 mg. Tratamento da Síndrome de Zollinger Ellison e outras doenças que levam a uma produção exagerada de ácido pelo estômago Para erradicação do Helicobacter pylori, com a finalidade de redução da taxa de recorrência de úlcera gástrica ou duodenal causadas por este microorganismo. Neste caso, deve ser associado a dois antibióticos adequados. Este medicamento está indicado para: Para as esofagites leves, recomenda-se o uso de Pantozol® 20 mg. Para erradicação do Helicobacter pylori,(bactéria responsável pela formação de úlceras) com a finalidade de redução da taxa de recorrência de úlcera gástrica ou duodenal causadas por este microorganismo. Neste caso, deve ser associado a dois antibióticos adequados Contra-indicações: Pantozol® não deve ser usado em casos de hipersensibilidade conhecida aos componentes da fórmula e, assim como outros IBPs, não deve ser co-administrado com atazanavir. Pantozol® 40 mg não deve ser administrado, em terapia combinada para erradicação do Helicobacter pylori, a pacientes com disfunção hepática ou renal de moderada a grave, uma vez que não existe experiência clínica sobre a eficácia e a segurança da terapia combinada nesses pacientes. Precauções e advertências: antes de se iniciar o tratamento, é necessário que se exclua a possibilidade de úlcera gástrica maligna e doenças malignas do esôfago, já que o tratamento com Pantozol® pode aliviar os sintomas e retardar o diagnóstico. Em pacientes com disfunção hepática grave (insuficiência hepática), as enzimas hepáticas devem ser regularmente monitoradas durante o tratamento com Pantozol®, se houver aumento nos valores enzimáticos, o tratamento deve ser descontinuado. Assim como os outros inibidores da secreção ácida, o medicamento pode reduzir a absorção da vitamina B12 (cianocobalamina) devido à hipocloridria ou acloridria. Esse fato deve ser considerado em terapia por tempo prolongado em pacientes com reserva baixa de vitamina B12 ou com fatores de risco de absorção reduzida de vitamina B12. Em terapia de longo prazo, especialmente quando o tratamento exceder 1 ano, os pacientes devem ser mantidos sob acompanhamento regular. Pacientes que não responderem ao tratamento após 4 semanas deverão ser investigados. Pantozol® 40 mg: não está indicado em distúrbios gastrointestinais leves, como por exemplo na dispepsia n. Quando prescrito dentro de uma terapia combinada, as instruções de uso de cada uma das drogas devem ser seguidas Interações medicamentosas: Pantozol® pode alterar a absorção de medicamentos cuja biodisponibilidade seja dependente do pH do suco gástrico, como por exemplo o cetoconazol. Isso se aplica, também, aos medicamentos ingeridos pouco tempo antes de Pantozol®. IBPs, incluindo o pantoprazol, não devem ser co-administrados com atazanavir. Pantoprazol é extensivamente metabolizado no fígado. Inicialmente ocorre desmetilação e oxidação a sulfonas pelas sub enzimas CYP2C19 e CYP3A4 do citocromo P 450 (Fase I do metabolismo). Como conseqüência da baixa afinidade do pantoprazol e de seus metabólitos, o hidroxipantoprazol e o hidroxipantoprazol sulfona pelas enzimas do citocromo P 450, seu potencial de interação na Fase I é limitado, o que permite que a droga saia rapidamente do retículo endoplasmático e seja subseqüentemente transferida para o citoplasma para ser conjugada com sulfato, na Fase II do metabolismo. Esta baixa afinidade resulta em predominância do metabolismo no sistema de conjugação (Fase II) que, ao contrário do sistema P 450, não é saturável e conseqüentemente não interativa. Esta etapa independe do sistema enzimático citocromo P 450. A interação entre pantoprazol e outras substâncias metabolizadas na Fase I do metabolismo não pode, em princípio, ser excluída. Nos estudos sobre interações medicamentosas conduzidos até o momento, onde foram analisados os substratos de todas as famílias do citocromo P450 envolvidas no metabolismo de drogas no homem, verificou-se que pantoprazol não afeta a farmacocinética ou a farmacodinâmica da carbamazepina, cafeína, diazepam, diclofenaco, digoxina, etanol, glibenclamida, metoprolol, naproxeno, nifedipina, fenitoína, piroxicam, teofilina, e contraceptivos orais. A ingestão de antiácidos não interfere na absorção do pantoprazol. Pantozol® não aumenta a excreção urinária dos marcadores de indução, ácido D-glucarídico e 6 ß-hidroxicortisol. Da mesma forma, as drogas investigadas não influenciaram a farmacocinética do pantoprazol. Embora, em estudos clínicos farmacocinéticos, não tenha sido observada, nenhuma interação durante a administração concomitante à femprocumona ou à varfarina, foram observados, no período de pós comercialização, alguns casos isolados de alterações no INR (tempo de protrombina do paciente/ média normal do tempo de protrombina)ISI nessas situações. Conseqüentemente, em pacientes que estão sendo tratados com os anticoagulantes cumarínicos, é recomendada a monitorização do tempo de protrombina / INR, após o início, término ou durante o uso irregular de pantoprazol. Não existe interação na administração concomitante de antiácidos. Estudos de interação farmacocinética em humanos, nos quais o pantoprazol foi administrado simultaneamente aos antibióticos claritromicina, metronidazol e amoxicilina, não demonstraram nenhuma interação clinicamente siginificante.

Reações adversas: Distúrbios gastrointestinais: ocasionalmente foram relatados casos de dor abdominal, diarréia, constipação ou flatulência. Houve raros relatos de náusea e vômito. Distúrbios do sistema nervoso: ocasionalmente pode ocorrer o aparecimento de cefaléia. Têm sido relatados raros casos de vertigem ou distúrbios visuais (visão turva). Distúrbios do tecido cutâneo e subcutâneo: reações alérgicas como prurido e exantema foram ocasionalmente relatados. Urticária e angioedema foram relatados em casos isolados. Distúrbios hepato-biliares: aumento de enzimas hepáticas (transaminases, γ-GT) em casos isolados. Em casos raros ocorreu dano hepatocelular severo conduzindo à icterícia com ou sem insuficiência hepática. Distúrbios músculo-esqueléticos e do tecido conjuntivo: mialgia, em casos isolados, que regrediu com o término do tratamento. Distúrbios psiquiátricos: depressão mental, em casos isolados, que regrediu com o término do tratamento. Distúrbios gerais: febre e edema periférico, em casos isolados, que regrediram com o término do tratamento. Distúrbios metabólicos: aumento de triglicérides em casos individuais. Distúrbios no sistema imune: o tratamento com pantoprazol pode levar, em casos isolados, à reações anafiláticas, incluindo o choque anafilático. Posologia: Pantozol® 20 mg: Recomenda-se 1 comprimido de Pantozol® 20 mg ao dia. A duração do tratamento fica à critério médico e dependente da indicação. Na maioria dos pacientes, o alívio dos sintomas é rápido. Na esofagite por refluxo leve, um tratamento de 4 a 8 semanas é, em geral, suficiente. Os sintomas recorrentes poderão ser controlados administrando-se 1 comprimido de Pantozol® 20 mg ao dia, quando necessário (“on demand”). A mudança para terapia contínua deve ser considerada nos casos em que os sintomas não puderem ser devidamente controlados sob terapia “on demand”. Em pacientes com insuficiência renal, a dose diária de 40 mg não deve ser ultrapassada. Em caso de redução intensa da função hepática, a dose de 1 comprimido de 20 mg ao dia não deve ser ultrapassada. Quando administrado por longos prazos, recomenda-se a manutenção da dose de 1 comprimido de Pantozol ® 20 mg ao dia, aumentando-se para 40 mg de pantoprazol ao dia em casos de reincidência. Após a melhora, a dose pode ser reduzida novamente para 20 mg de pantoprazol. Em terapia de longo prazo, especialmente quando o tratamento exceder 1 ano, os pacientes devem ser mantidos sob acompanhamento regular. Pantozol® pode ser administrado antes, durante ou após o café da manhã. Pantozol® 40 mg: A posologia habitualmente recomendada para obtenção da cicatrização da úlcera péptica gastroduodenal e da esofagite por refluxo é de 1 comprimido de 40 mg ao dia, antes, durante ou após o café da manhã. Úlceras duodenais normalmente cicatrizam completamente em 2 semanas. Para úlceras gástricas e esofagite por refluxo um período de tratamento de 4 semanas é, geralmente, adequado. Em casos individuais, pode ser necessário estender o tratamento para 4 semanas (úlcera duodenal) ou para 8 semanas (úlcera gástrica e esofagite por refluxo). Em casos isolados de esofagite de refluxo, úlcera gástrica ou úlcera duodenal, a dose diária pode ser aumentada para 2 comprimidos ao dia, particularmente nos casos de pacientes refratários a outros medicamentos antiulcerosos. Nos casos de úlcera gástrica ou duodenal associadas à infecção por Helicobacter pylori, a erradicação da infecção é obtida através da terapia combinada com dois antibióticos, motivo pelo qual se recomenda o uso de Pantozol® em jejum nesta condição. Qualquer uma das seguintes combinações de Pantozol® com antibióticos são recomendadas, de acordo com o padrão de resistência da bactéria: a) 1 comprimido de Pantozol® 40 mg duas vezes ao dia + 1000 mg de amoxicilina duas vezes ao dia + 500 mg de claritromicina duas vezes ao dia b) 1 comprimido de Pantozol® 40 mg duas vezes ao dia + 500 mg de metronidazol duas vezes ao dia + 500 mg de claritromicina duas vezes ao dia c) 1 comprimido de Pantozol® 40 mg duas vezes ao dia + 1000 mg de amoxicilina duas vezes ao dia + 500 mg de metronidazol duas vezes ao dia A duração da terapia combinada para erradicação da infecção por Helicobacter pylori é de 7 dias, podendo ser prolongada por até 14 dias (até o máximo de 14 dias). Se após esse período, for necessário tratamento adicional com Pantozol® (por exemplo, em função da persistência da sintomatologia) para garantir a cicatrização completa da úlcera, a posologia recomendada para úlceras gástricas e duodenais deve ser observada.Em pacientes idosos ou com insuficiência renal, a dose diária de 1 comprimido de 40 mg não deve ser ultrapassada. A não ser na terapia combinada para erradicação do Helicobacter pylori, onde pacientes idosos também devem receber, durante uma semana, a dose usual de 2 comprimidos ao dia (80 mg de Pantozol®/dia). Em caso de redução intensa da função hepática a dose deve ser ajustada para 1 comprimido de 40 mg a cada dois dias ou 1 comprimido de 20 mg ao dia. O tratamento não deve ser superior a 8 semanas, uma vez que são restritas as experiências a longo prazo. Para o tratamento da Síndrome de Zollinger-Elisson e outras condições patológicas hipersecretórias, os pacientes devem iniciar o tratamento com dose diária de 80 mg (2 comprimidos de Pantozol® 40 mg). Em seguida, a dose pode ser alterada para uma dose maior ou menor conforme necessário, utilizando medidas de secreção de ácido gástrico como parâmetro. Doses diárias acima de 80 mg devem ser divididas e administradas duas vezes ao dia (2 comprimidos de Pantozol® 40 mg por dia). Aumentos temporários da dose diária para valores acima de 160 mg de pantoprazol são possíveis, mas não devem ser utilizados por períodos que se prolonguem além do necessário para controlar devidamente a secreção ácida. A duração do tratamento da Síndrome de Zollinger-Elisson e outras condições patológicas hipersecretórias não é limitada e deve ser adaptada conforme necessidade clínica. O prazo de validade está impresso na embalagem do produto. A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. MEDICAMENTO SOB PRESCRIÇÃO. Registro MS - 1.0639.0182 PT20_0207_0909 / PT40_0207_0909


Pantozol® Grânulos pantoprazol sódico sesquiidratado USO ADULTO Apresentação e composição: Envelopes contendo grânulos gastro-resistentes em embalagens com 2 ou 28 unidades. Cada envelope contém 40 mg de pantoprazol, na forma de pantoprazol sódico sesquiidratado. Indicações: Tratamento da úlcera duodenal, úlcera gástrica e das esofagites de refluxo moderada ou grave. Para as esofagites leves, recomenda-se o uso de Pantozol® 20 mg, comprimidos revestidos. Na erradicação do Helicobacter pylori com a finalidade de evitar a recorrência de úlcera gástrica ou duodenal causadas por este microorganismo. Neste caso, deve ser associado a dois antibióticos adequados (vide modo de usar). Tratamento da Síndrome de Zollinger-Ellison e de outras doenças que produzem ácido em excesso no estômago . Tratamento intermitente de sintomas graves ou moderados, como pirose, regurgitação, dor ou desconforto na região superior do abdômen, de acordo com a necessidade. ���������������������������������������������������������������������� produto não ������������������������������������������������������������ deve ser usado por indivíduos que apresentem hipersensiContra-indicações: O bilidade conhecida ao pantoprazol ou aos demais componentes da fórmula. Assim como outros IBPs, não deve ser coadministrado com atazanavir. Não deve ser administrado, em terapia combinada para erradicação do Helicobacter pylori, a pacientes com disfunção hepática ou renal de moderada a grave, uma vez que não existe experiência clínica sobre a eficácia e a segurança da terapia combinada nesses pacientes. Este medicamento é contraindicado para menores de 12 anos. Precauções e advertências: Pantozol® 40 mg grânulos não está indicado para distúrbios gastrintestinais leves, como por exemplo a dispepsia não-ulcerosa. Quando prescrito dentro de uma terapia combinada, as instruções de uso de cada um dos fármacos devem ser seguidas. Na presença de qualquer sintoma de alarme (como significante perda de peso não intencional, vômitos recorrentes, disfagia, hematêmese, anemia ou melena) e quando houver suspeita ou presença de úlcera gástrica, deve ser excluída a possibilidade de malignidade, já que o tratamento com pantoprazol pode aliviar os sintomas e retardar o diagnóstico. Casos os sintomas persistam apesar de tratamento adequado, investigações adicionais devem ser consideradas. Em pacientes com disfunção hepática grave (insuficiência hepática), as enzimas hepáticas devem ser regularmente monitoradas durante o tratamento com Pantozol® 40 mg grânulos, se houver aumento nos valores enzimáticos, o tratamento deve ser descontinuado. Pacientes com síndrome de Zollinger-Ellison e outras condições hipersecretoras patológicas que necessitam terapia por longo prazo, o uso de pantoprazol , assim como de todos os medicamentos bloqueadores de ácido, pode reduzir a absorção de vitamina B12 (cianocobalamina) devido a hipo ou acloridia. Deve-se considerar este fato caso sejam observados sintomas clínicos respectivos. Uso na gravidez e lactação: Categoria “B” de risco para a gravidez: Este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do cirurgião-dentista. Interferência em testes de laboratório: Em alguns poucos casos isolados, detectou-se alterações no tempo de coagulação durante o uso de pantoprazol. Desta forma, em pacientes tratados com anticoagulantes cumarínicos, recomenda-se a monitoração do tempo de coagulação após início, final ou durante o tratamento com pantoprazol. Pacientes idosos: Em pacientes idosos, a dose diária de 40 mg não deve ser ultrapassada, a não ser na terapia combinada para erradicação do Helicobacter pylori, na qual pacientes idosos também devem receber, durante uma semana, a dose usual de 2 envelopes ao dia (2 x envelopes / dia). Pacientes com insuficiência hepática: Em pacientes com insuficiência hepática grave, a dose deve ser reduzida para 40 mg de pantoprazol em dias alternados. Nestes pacientes, os níveis de enzimas hepáticas devem ser monitorados durante a terapia com pantoprazol; caso ocorra uma elevação destes níveis, o tratamento com pantoprazol deve ser descontinuado. Pacientes com insuficiência renal: A dose diária de 40 mg de pantoprazol (1 envelope) não deve ser ultrapassada. Interações medicamentosas: Pantoprazol pode alterar a absorção de medicamentos cuja biodisponibilidade seja dependente do pH do suco gástrico, como por exemplo o cetoconazol. Isto se aplica também a medicamentos ingeridos pouco tempo antes de Pantozol® 40 mg grânulos. Os IBPs, incluindo o pantoprazol, não devem ser coadministrados com atazanavir. A interação entre pantoprazol e outras substâncias metabolizadas pelas enzimas CYP2C19 e CYP3A4 do citocromo P 450 não pode, em princípio, ser excluída. Entretanto, nenhuma interação clinicamente significativa foi observada nos estudos específicos com um grande número de medicamentos ou compostos, como carbamazepina, cafeína, diazepam, diclofenaco, digoxina, etanol, glibenclamida, metoprolol, naproxeno, nifedipina, fenitoína, piroxicam, teofilina, e contraceptivos orais. Não existe interação na administração concomitante de antiácidos. Nos estudos sobre interações medicamentosas conduzidos até o momento, onde foram analisados os substratos de todas as famílias do citocromo P450 envolvidas no metabolismo de drogas no homem, verificou-se que pantoprazol não afeta a farmacocinética ou a farmacodinâmica da carbamazepina, cafeína, diazepam, diclofenaco, digoxina, etanol, glibenclamida, metoprolol, naproxeno, nifedipina, fenitoína, piroxicam, teofilina, e contraceptivos orais. Pantoprazol não aumenta a excreção urinária dos marcadores de indução, ácido D-glucarídico e 6 ß-hidroxicortisol. Da mesma forma, as drogas investigadas não influenciaram a farmacocinética do pantoprazol. Embora, em estudos clínicos farmacocinéticos, não tenha sido observada, nenhuma interação durante a administração concomitante com femprocumona ou com varfarina, foram observados, no período pós-comercialização, alguns casos isolados de alterações no INR (tempo de protrombina do paciente/média normal do tempo de protrombina)ISI nessas situações. Consequentemente, em pacientes que estão sendo tratados com anticoagulantes cumarínicos, é recomendada a monitorização do tempo de

protrombina/INR após o início, término ou durante o uso irregular de pantoprazol. Estudos de interação farmacocinética em humanos, administrando-se pantoprazol sódico simultaneamente aos antibióticos claritromicina, metronidazol ou amoxicilina, não demonstraram nenhuma interação clinicamente significativa. Reações adversas: Podem ocorrer as seguintes reações adversas com o uso do produto: Reações comuns (ocorrem entre 1% e 10% dos pacientes que utilizam este medicamento): dor abdominal, diarréia, constipação, flatulência, cefaléia. Reações incomuns (ocorrem entre 0,1% e 1% dos pacientes que utilizam este medicamento): náusea/vômito, vertigem, distúrbios visuais (visão turva), reações alérgicas como prurido e exantema. Reações raras (ocorrem entre 0,01% e 0,1% dos pacientes que utilizam este medicamento): boca seca, artralgia, depressão, alucinação, desorientação e confusão mental, especialmente em pacientes predispostos; agravamento destes sintomas se pré-existentes. Reações muito raras (ocorrem em menos de 0,01% dos pacientes que utilizam este medicamento): leucopenia, trombocitopenia, edema periférico, dano hepatocelular grave levando a icterícia com ou sem insuficiência hepática, reações anafiláticas, incluindo choque anafilático, aumento nos níveis de enzimas hepáticas (transaminases, γ-GT), aumento nos níveis de triglicerídios, elevação da temperatura corporal, mialgia, nefrite intersticial, reações dermatológicas graves como síndrome de Stevens Johnson, eritema multiforme, síndrome de Lyell, fotossensibilidade, urticária e angioedema. Posologia: Tratamento da esofagite de refluxo moderada ou grave: A posologia habitualmente recomendada é de 40 mg (um envelope) uma vez ao dia, 30 minutos antes do café da manhã. Em casos isolados, a dose diária pode ser aumentada para 2 envelopes ao dia (80 mg de pantoprazol), particularmente nos casos de pacientes refratários a outros medicamentos antiulcerosos. Para a esofagite de refluxo, um período de tratamento de 4 semanas é, geralmente, adequado. Em casos individuais, quando não for suficiente, pode ser necessário estender o tratamento por mais 4 semanas para se obter cicatrização. Os sintomas recorrentes poderão ser controlados administrando-se o conteúdo de 1 envelope de Pantozol® 40 mg grânulos ao dia, quando necessário (“on demand”). A mudança para terapia contínua deve ser considerada nos casos em que os sintomas não puderem ser devidamente controlados sob terapia “on demand”. Tratamento da úlcera gástrica ou duodenal: A posologia habitualmente recomendada é de 40 mg (um envelope) uma vez ao dia, 30 minutos antes do café da manhã. Em casos isolados, a dose diária pode ser aumentada para 2 envelopes ao dia (80 mg de pantoprazol), particularmente nos casos de pacientes refratários a outros medicamentos antiulcerosos. Para o tratamento de úlceras gástricas, um período de tratamento de 4 semanas é, geralmente, adequado. Em casos individuais, pode ser necessário estender o tratamento por mais 4 semanas. Úlceras duodenais normalmente cicatrizam completamente em 2 semanas. Caso um período de tratamento de 2 semanas não seja suficiente, a cicatrização pode ser obtida na maioria dos casos com mais 2 semanas de terapia. Erradicação do H. pylori em combinação dois antibióticos apropriados: Nos casos de úlcera gástrica ou duodenal associadas à infecção por Helicobacter pylori, a erradicação da infecção é obtida através da terapia combinada com dois antibióticos. Qualquer uma das seguintes combinações de Pantozol® 40 mg grânulos com antibióticos são recomendadas, de acordo com o padrão de resistência da bactéria: a) 1 envelope de Pantozol® 40 mg grânulos duas vezes ao dia + 1000 mg de amoxicilina duas vezes ao dia + 500 mg de claritromicina duas vezes ao dia b) 1 envelope de Pantozol® 40 mg grânulos duas vezes ao dia + 500 mg de metronidazol duas vezes ao dia + 500 mg de claritromicina duas vezes ao dia c) 1 envelope de Pantozol® 40 mg grânulos duas vezes ao dia + 1000 mg de amoxicilina duas vezes ao dia + 500 mg de metronidazol duas vezes ao dia A duração da terapia combinada para erradicação da infecção por Helicobacter pylori é de 7 dias, podendo ser prolongada até o máximo de 14 dias. Se após esse período, for necessário tratamento adicional com monoterapia com Pantozol® 40 mg grânulos (por exemplo, em função da persistência da sintomatologia) para garantir a cicatrização completa da úlcera, a posologia recomendada para úlceras gástricas e duodenais deve ser observada. Caso a terapia combinada não seja uma opção (por exemplo, se o paciente tiver teste de H. pylori negativo), devem ser aplicadas as recomendações posológicas para monoterapia. Síndrome de Zollinger-Ellison e outras condições hipersecretoras patológicas: Para o tratamento de longo-prazo da síndrome de Zollinger-Ellison e de outras condições hipersecretoras patológicas, os pacientes devem iniciar com uma dose diária de 80 mg de pantoprazol (2 envelopes). Depois disso, a dose deve ser titulada (para baixo ou para cima) como necessário utilizando-se as mensurações de secreção de ácido gástrico como guia. Doses superiores a 80 mg/dia devem ser divididas e administradas em duas tomadas. Um aumento temporário da dose acima de 160 mg de pantoprazol é possível, mas não deve ser usada por períodos maiores do que o necessário para o controle adequado da secreção ácida. A duração do tratamento na síndrome de Zollinger-Ellison e em outras condições hipersecretoras patológicas não é limitado e deve ser mantido de acordo com as necessidades clínicas. O prazo de validade está impresso na embalagem do produto. A PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. MEDICAMENTO SOB PRESCRIÇÃO. Registro MS - 1.0639.0182 PZGR_1107_0510_P


3,5g

Devolve o movimento natural do intestino

1,2


PlantaBen® contém fibras

Contém fibras 100% vegetais:

3,5

70%

Grande capacidade de retenção hídrica

6

fibra solúvel

4

30%

7

fibra insolúvel

• •

Aumenta o peso da massa fecal Acelera o trânsito intestinal

4

8

Pode ser utilizado por períodos prolongados Normaliza o ritmo do intestino de maneira fisiológica 9

2,3


solúveis e insolúveis.

3,4

Contém fibras solúveis

Contém fibras insolúveis

3,5g

Gomaguar

10,11

Polímero sintético

12,13

3,5g

Devolve o movimento natural do intestino

1,2


3,5g Devolve o movimento natural do intestino

APRESENTAÇÕES

Caixas com 10 e 30 envelopes3 1,2

• Pó solúvel efervescente3 • Sabor artificial de laranja3 • Não contém açúcar3

POSOLOGIA*

3

1 a 3 envelopes ao dia

Referências bibliográficas: 1) Slavin JL. Position of the American Dietetic Association: health implications of dietary fiber. J Am Diet Assoc. 2008;108(10):1716-31. 2) Wasserman MS et al. Consenso Latinoamericano de estreñimiento crónico [The Latin-American consensus on chronic constipation]. Gastroenterol Hepatol. 2008;31(2):59-74. 3) Plantaben® [Bula]. São Paulo. Nycomed Pharma. 4) Moreno LA et al. Psyllium fibre and the metabolic control of obese children and adolescent. J Physiol Biochem. 2003;59(3):235-42. 5) Dhar MK et al. Plantago ovata: genetic diversity, cultivation, utilization and chemistry. Plant Genetic Res. 2005;3:252-63. 6) Yu LL, Lutterodt H, Cheng Z. Beneficial health properties of psyllium and approaches to improve its functionalities. Adv Food Nutr Res. 2009;55:193-220. 7) Singh B. Psyllium as therapeutic and drug delivery agent. Int J Pharma. 2007;334:1-14. 8) Spiller RC. Pharmacology of dietary fibre. Pharmacol Ther. 1994;62(3):407-27. 9) Oliver SD. The long-term safety and tolerability of ispaghula husk. J R Soc Health. 2000;120(2):107-11. 10) Benefiber. [Bula] São Paulo: Novartis. 11) Fibermais. [Bula]. São Paulo: Nestlé. 12) Muvinor. [Bula]. São Paulo: Libbs. 13) Benestare. [Bula]. São Paulo: Medley.

Março/2011

Plantaben® Plantago ovata (Ispaghula husk) Indicações: Plantaben® é indicado tanto na diarréia como na constipação intestinal. Adicionalmente, auxilia na redução dos níveis de açúcar e de colesterol do sangue. Também pode ser utilizado para complementar a ingestão diária de fibras. Plantaben® é indicado também para: Doenças que evoluem com alternância de episódios de diarréia e constipação intestinal (intestino irritável, diverticulose; Regulação da evacuação em pacientes portadores de ânus artificial (colostomia); Constipação intestinal crônica habitual ou decorrente da permanência no leito após operações cirúrgicas, por alterações de dieta, viagens ou tratamentos prolongados com laxantes potentes; Diarréias de origem funcional e como adjuvante em casos de doença de Crohn; Hemorróidas, fissuras anais ou abscesso anal, com redução da dor de defecação e facilitação da evacuação das fezes; Os casos de ingestão insuficiente de fibras. Como Plantaben® não contém estimulantes da motilidade ou irritantes da mucosa intestinal, pode ser utilizado por pessoas que são alérgicas a estas substâncias ou em casos em que não há contra-indicação específica. Registro MS - 1.0639.0205. PLPO_0202_0910_VP.

*Posologia para adultos e crianças acima de 12 anos.

a persistirem os sintomas, o médico deverá ser consultado.

NÃO USE ESTE MEDICAMENTO EM CASO DE DOENÇAS INTESTINAIS GRAVES. Nycomed Pharma Ltda. Rua do Estilo Barroco, 721 - 04709-011 - São Paulo - SP Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes. Material destinado exclusivamente a profissionais habilitados a prescrever e/ou dispensar medicamentos. Plantaben® – marca registrada MADAUS S.A.


Certos momentos pedem que você fique sentado. E sem nenhum desconforto. Alívio rápido da dor e CICATRIZAÇÃO das lesões anorretais.1,2

Referências: 1. Espinosa DJ. Revisión analítica de estudios multicentricos con policresuleno en patologia hemorroidal. Acta Gastroentestinal Latinoamericana. 2000; 30(3): 177− 186. 2. Arnold K, Abele I, Auel H. Multicenter clinical study of a new non−steroid preparation in proctology. Arzneimittel−Forschung Drug Res.1976;26(1):95−9. 3. Seppaner J, Mattinen P. Salo H. Experience of the topical use of Faktu ointment in the treatment of various conditions and postoperative wounds in the anorectal region. Diagnosis. 1979; 4: 449−452. 4. Proctyl® [Bula]. São Paulo: Nycomed Pharma. PR00_0807_0808

Indicações: hemorroidas, fissuras anais, pruridos e eczemas anais. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO PROCTYL® É UM MEDICAMENTO. SEU USO PODE TRAZER RISCOS. PROCURE O MÉDICO E O FARMACÊUTICO. LEIA A BULA. EM CASO DE DÚVIDAS LIGUE GRATUITAMENTE

SAC:0800-77100345

www.nycomed.com.br

Nycomed Pharma Ltda. Rua do Estilo Barroco, 721 - CEP 04709-011 - São Paulo - SP Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes. Material exclusivo para a classe médica.

Março/2011

Registro MS − 1.0639.0111


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om arado c dos2 p m o c ndo imi ido qua g de 30 compr m i r p m por co 100m *Custo ção de Siilif* enta a apres

Contraindicações: hipersensibilidade conhecida aos componentes da fórmula. Interaçõesmedicamentosas:osestudosrealizadosnãodemonstraraminterações medicamentosas com nenhum dos seguintes tratamentos concomitantemente prescritos: hipoglicemiantes orais, anticoagulantes e digitálicos. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. Este material é destinado aos profissionais de saúde habilitados a prescrever ou dispensar tais produtos. Fevereiro/2011.


No Tratamento da Sii

Preço é um fator importante para adesão ao tratamento 1

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O nosso tratamento para o alívio da dor abdominal do seu paciente.3,4

A o M c i é m ô n o c e

*

ado com s2 r a p m o c o quando 30 comprimid o d i m i r e p d por com 100mg *Custo ção de Siilif* enta a apres

Contraindicações: hipersensibilidade conhecida aos componentes da fórmula. Interaçõesmedicamentosas:osestudosrealizadosnãodemonstraraminterações medicamentosas com nenhum dos seguintes tratamentos concomitantemente prescritos: hipoglicemiantes orais, anticoagulantes e digitálicos. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. Este material é destinado aos profissionais de saúde habilitados a prescrever ou dispensar tais produtos. Fevereiro/2011.

comprimidos

Também nas apresentações: • 50mg com 30 comprimidos • 100mg com 30 comprimidos

Referências bibliográficas: 1) Sabaté E (org.) Adherencia a los tratamientos a largo plazo: pruebas para la acción. [online]. Organización Mundial de la Salud. 2004 [acesso em 23 nov. 2010]. Disponível em: http://www.paho.org/Spanish/ad/dpc/nc/adherencia-largo-plazo.pdf. 2) Revista Kairos, nov. 2010. 3) Guslandi M. Profilo farmacologico clinico del pinaverio bromuro. Minerva Med. 1994;85:179-85. 4) Siilif*[Bula]. São Paulo: Nycomed Pharma. SIILIF* - brometo de pinavério - USO ADULTO - Apresentações e composição: Comprimido revestido de 50 mg em embalagens com 30 unidades. Comprimido revestido de 100 mg em embalagens com 10, 30 e 60 unidades. Indicações: Tratamento sintomático da dor ou desconforto abdominal, dos distúrbios da frequência ou consistência das evacuações (constipação ou diarréia) e da distensão abdominal, decorrentes dos transtornos funcionais do intestino (SII). Tratamento sintomático das dores decorrentes dos transtornos funcionais das vias biliares. Preparação de enemas opacos. Contraindicações: hipersensibilidade conhecida aos componentes da fórmula. Precauções e advertências: É desaconselhável a utilização do brometo de pinavério durante a gravidez. Além disso, deve-se observar a presença de bromo, cuja administração no final da gravidez pode causar alterações neurológicas no recém-nascido (hipotonia, sedação). Em função da falta de estudos, recomenda-se não utilizar o brometo de pinavério durante a lactação. Interações medicamentosas: os estudos realizados não demonstraram interações medicamentosas com nenhum dos seguintes tratamentos concomitantemente prescritos: hipoglicemiantes orais, anticoagulantes e digitálicos. Reações adversas: foram relatados, raramente, alguns casos de alterações digestivas leves e casos isolados de reações cutâneas, algumas do tipo alérgico. Raramente pode haver agravamento da constipação e epigastralgia. Em casos de erupção cutânea, é conveniente interromper a administração do medicamento. Posologia: recomenda-se a administração de 1 comprimido de 50 mg, 3 ou 4 vezes ao dia, ou 1 comprimido de 100 mg, 2 vezes ao dia (manhã e noite). Excepcionalmente, a posologia pode ser aumentada para 6 comprimidos de 50 mg ou 3 comprimidos de 100 mg ao dia. Os comprimidos devem ser deglutidos inteiros, sem mastigar, com um pouco de água, imediatamente antes ou durante as refeições. Na preparação de enemas opacos, a posologia é de 2 comprimidos diários de 100 mg ou 4 comprimidos diários de 50 mg, nos 3 dias anteriores ao exame. MEDICAMENTO SOB PRESCRIÇÃO. MS - Registro MS – 1.0639.0254. SICO_NSPC_1209 Material de distribuição exclusiva à classe médica. Nycomed Pharma Ltda. Rua do Estilo Barroco, 721 - 04709-011 - São Paulo - SP. Mais informações poderão ser obtidas diretamente com o nosso Departamento Médico ou por meio de nossos representantes. * Marca Depositada.

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6052309 – RX REV. ARQUIVOS GASTRO ED. 02/2011

Arquivos de Gastroenterologia • Volume 48 • Número 2 • 2011 • p.89-166

Publication of the Brazilian Institute for Studies and Research in Gastroenterology and others Specialities - IBEPEGE

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número

abril/junho 2011 volume 48

Instituto Brasileiro de Estudos e Pesquisas de Gastroenterologia e outras Especialidades - IBEPEGE Brazilian Institute for Studies and Research in Gastroenterology and others Specialities Colégio Brasileiro de Cirurgia Digestiva - CBCD Brazilian College of Digestive Surgery Sociedade Brasileira de Motilidade Digestiva - SBMD Brazilian Digestive Motility Society Federação Brasileira de Gastroenterologia - FBG Brazilian Federation of Gastroenterology Sociedade Brasileira de Hepatologia Brazilian Hepatology Society Sociedade Brasileira de Endoscopia Digestiva Brazilian Digestive Endoscopy Society

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