Associação entre ângulos de fase, estadiamento da fibrose hepática, gravidade da cirrose hepática e da resistência à insulina em portadores de hepatite C

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Dissertação de mestrado apresentada ao Programa de Pós-Graduação “Fisiopatologia em Clínica Médica” como pré-requisito para obtenção do título de mestre.

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BIBLIOTECÁRIA RESPONSÁVEL: ROSEMEIRE APARECIDA VICENTE

Dorna, Mariana de Souza.

Associação entre ângulo de fase, estadiamento da fibrose hepática, gravidade da cirrose hepática e da resistência à insulina de portadores de hepatite C / Mariana de Souza Dorna. – Botucatu : [s. n.], 2012

Dissertação (mestrado) – Universidade Estadual Paulista, Faculdade de Medicina de Botucatu

Orientador: Giovanni Faria Silva Coorientador: Marcos Ferreira Minicucci Capes: 50501038

1. Fígado – Doenças. 2. Hepatite C.

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Resumo... 1

Abstract ... 4

Introdução ... 7

Objetivos ... 14

Casuística e Métodos... 16

Resultados ... 28

Discussão... 46

Conclusões... 53

Referências ... 55

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Tabela 1. Caracterização da amostra segundo dados demográficos e

laboratoriais ...29

Tabela 2. Caracterização da amostra segundo Bioimpedância Elétrica e Dados

Antropométricos...30

Tabela 3. Análise de correlação entre Ângulo de Fase e parâmetros

bioquímicos ...30

Tabela 4. Variáveis demográficas e laboratoriais entre os grupos de fibrose

hepática ...31

Tabela 5. Análise Covariância (ANCOVA) entre Ângulo de Fase, CMB, AMB por

idade e gênero...36

Tabela 6. Distribuição dos pacientes portadores de cirrose hepática, de acordo

com os valores do escore de Child-Pugh B/C ...37

Tabela 7. Regressão Logística para predição de fibrose avançada de acordo

com Ângulo de Fase...38

Tabela 8. Regressão Linear Múltipla para predizer o HOMA-IR...38

Tabela 9. Análise de associação referente à pacientes com vírus C, F4,

classificados segundo o Child...39

Tabela 10. Regressão Logística para análise de Ângulo de Fase como preditor

do aumento da pontuação do escore de Child ...41

Tabela 11. Análises de correlação de pacientes portadores de cirrose hepática

correlacionados com o MELD...42

Tabela 12. Regressão Linear Múltipla para predizer o escore MELD ...42

Tabela 13. Curvas ROC para predição de fibrose em pacientes com vírus da

hepatite C ...44

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Quadro 1. Exames bioquímicos e respectivas metodologias ...19

Quadro 2. Classificação da gravidade da cirrose hepática – critérios de

Child-Pugh (1973) ...20

Quadro 3. Classificação do estadiamento de fibrose de acordo com METAVIR...22

Quadro 4. Classificação do estado nutricional pelo IMC de acordo com a OMS ...23

Quadro 5. Classificação do estado nutricional pelo IMC, para idosos, de acordo

com Lipschitz, 1994...23

Quadro 6. Estado nutricional segundo a Área Muscular do Braço corrigida ...25

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Figura 1. Diferença da Idade entre os grupos de fibrose...32

Figura 2. Valores do Ângulo de Fase entre os grupos de fibrose...32

Figura 3. Valores do HOMA-IR entre os grupos de fibrose ...33

Figura 4. Valores do IMC entre os grupos de fibrose ...33

Figura 5. Valores da CMB entre os grupos de fibrose...34

Figura 6. Valores da AMB entre os grupos de fibrose ...34

Figura 7. AST (n°xLSN) entre os grupos de fibrose ...35

Figura 8. ALT (n°xLSN) entre os grupos de fibrose...35

Figura 9. GGT (n°xLSN) entre os grupos de fibrose...36

Figura 10. Distribuição do número de pacientes portadores de cirrose hepática e com escore de Child B/C...37

Figura 11. Diferença do Colesterol Total entre os pacientes portadores do escore Child A e Child B e C...40

Figura 12. Diferença do LDL-colesterol entre os pacientes portadores do escore Child A e Child B e C...40

Figura 13. Análise de correlação entre MELD e Colesterol Total ...43

Figura 14. Análise de correlação entre MELD e HDL-colesterol ...43

Figura 15. Curva ROC para representação do ponto de corte do Ângulo de Fase, para totalidade da amostra...44

Figura 16. Curva ROC para representação do ponto de corte do Ângulo de Fase, para o sexo feminino ...45

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ƃ: sexo masculino Ƃ: sexo feminino

Å: ângulo de fase

Alb: albumina

ALT: alanina aminotransferase

AMB-c: área muscular do braço corrigida

ANCOVA: Análise de Covariância

AST: aspartato aminotransferase

AUC_{: área under the curve} (área sob a curva) BIA: bioimpedância elétrica

BT: bilirrubinas totais

CB: circunferência braquial

CH: cirrose hepática

CHC: carcinoma hepatocelular

CMB: circunferência muscular do braço

Curva ROC: Receiver Operating Characteristic

Cut-off: ponto de corte

DPOC: doença pulmonar obstrutiva crônica

E: estatura

EH: encefalopatia hepática

F: fibrose

GGT: gama-glutamil transferase

HCFMB: Hospital das Clínicas da Faculdade de Medicina de Botucatu

HDL-c: HDL-colesterol

HIV: vírus da imunodeficiência adquirida

HOMA-IR_{: Homeostasis Mode of Assessment of Insulin Resistence} IC: intervalo de confiância

ICC: insuficiência cardíaca congestiva

IMC: índice de massa corporal

IRC: insuficiência renal crônica

LDL-c: LDL-colesterol

MELD_{: Model for End-Stage Liver Disease}

n°xLSN: número de vezes do limite superior de normalidade

OMS: Organização Mundial de Saúde

OR: Odds Ratio PA: peso atual

R: resistência

RI: resistência à insulina

RNI: razão de normalidade internacional

RVS: resposta virológica sustentada

TCLE: Termo de Consentimento Livre e Esclarecido

TGL: triglicerídeos

WHO: _{World Health Organization} (OMS) Xc: reactância

Z: impedância

CEP: Comitê de Ética em Pesquisa

CT: colesterol total

DC: dobra cutânea triciptal

Gtp: genótipo

UNESP: Universidade Estadual Paulista – “Júlio de Mesquita Filho”

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Estado Nutricional

Desnutrido Método de avaliação

Nutrido

Leve/Moderado Grave AMBc Percentil >15 Percentil entre 5 e 15 Percentil < 5

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Tabela 1&DUDFWHUL]DomRGDDPRVWUDVHJXQGRGDGRVGHPRJUiILFRVHODERUDWRULDLV

Dados Valores (n=108)

Idade (anos) 51,3 ±12,1 Masculino, % (nº) 56,48 (61) Genótipo 1, % (nº) 76,85 (83)

HOMA-IR 2,7 (1,69 - 4,96) CT (g/dL) 159,4 ±34,38

LDL-c (g/dL) 84,8 ±29,14 HDL-c (g/dL) 50,7 ±18,5

TGL(g/dL) 102 (75 – 142) AST (n°xLSN) 1,23 (0,80 – 1,85) ALT (n°xLSN) 1,17 (0,75 – 1,79) GGT (n°xLSN) 1,41 (0,82 – 2,69)

Dados expressos em proporção, média, desvio-padrão, mediana e percentis 25 e 75 e n°xLSN (número de vezes do limite superior de normalidade).

HOMA-IR: Homeostasis Mode of Assessment of Insulin Resistence ; CT: Colesterol Total; LDL-c: LDL colesterol; HDL-c: HDL colesterol; TGL: Triglicerídeos; AST: Aspartato Aminotransferase ALT: Alanina Aminotransferase; GGT: Gama-Glutamil Transferase.

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Dados Valores (n=108)

Ângulo de Fase (graus) 6,34 ±0,86 IMC (Kg/m²) 26,1 ± 4,5

CB (cm) 32,8 ± 3,9 CMB (cm) 25,72 (23,59 – 28,14) AMB (mm²) 43,58 (36,76 – 52,36)

DC (mm) 20 (13 – 27)

Dados expressos em média, desvio-padrão, mediana e percentis 25 e 75.

IMC: Índice de Massa Corporal; CB: Circunferência do Braço; CMB: Circunferência Muscular do Braço; AMB: Área Muscular do Braço; DC: Dobra Cutânea Triciptal.

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Variáveis Coeficiente de _{correlação (r)} Valor de p

CT (g/dL) -0,113 0,024

LDL (g/dL) -0,019 0,84 HDL (g/dL) -0,180 0,07 TG (g/dL) +0,052 0,60 AST (nºxLSN) -0,278 0,004

ALT (nºxLSN) -0,050 0,60 GGT (nºxLSN) -0,227 0,02

CT: Colesterol Total; LDL: LDL-colesterol; HDL: HDL-colesterol; TGL: Triglicerídeos; AST: Aspartato Aminotransferase; ALT: Alanina Aminotransferase; GGT: Gama-Glutamil Transferase; nºxLSN: número de vezes do limite superior de normalidade.

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Tabela 4 9DULiYHLV GHPRJUiILFDV H ODERUDWRULDLV HQWUH RV JUXSRV GH ILEURVH

KHSiWLFD

Variáveis

Fibrose 0 a 2

(42)

Fibrose 3 e 4

(66)

Valor de p

Idade (anos) 45,4 ± 11,5 55,0 ± 11,1 <0,001 Masculino,% (n) 57,1 (24) 56,1 (37) 0,93 Genótipo 1, % (n) 73,8 (31) 78,8 (52) 0,61 Ângulo de Fase (graus) 6,67 ± 0,82 6,13 ± 0,84 0,001

HOMA-IR 2,1 (1,3-2,9) 4,14 (2,1-6,3) <0,001

CT (g/dL) 159,9 ± 35,6 158,4 ± 33,7 0,83 LDL(g/dL) 83,8 ± 30,0 85,3 ± 29,0 0,80 HDL (g/dL) 53,3 ± 17,5 47,5 ± 18,4 0,11 TG (g/dL) 92,0(71,0-122,5) 111,0(79,3-146,5) 0,10 IMC (Kg/m²) 25,1 ± 4,5 26,9 ± 4,5 0,05 CB (cm) 32,1 ± 3,7 33,2 ± 4,12 0,14 CMB (cm) 24,7(22,8-27,9) 26,5(24,2-28,2) 0,04

AMB (mm²) 40,4(32,7-49,6) 45,6(39,3-53,8) 0,02

DC (mm) 22,0(12,0-30,0) 20,0(13,0-26,0) 0,84 AST (n°xLSN) 0,84(0,60-1,35) 1,47(1,0-2,11) <0,001

ALT (n°xLSN) 0,99(0,59-1,47) 1,38(0,77-1,89) 0,04

GGT (n°xLSN) 0,86(0,53-2,20) 1,65(1,14-2,96) <0,001 Dados expressos em proporção, média, desvio-padrão, mediana e percentis 25 e 75 e nºxLSN (número de vezes do limite superior de normalidade).

HOMA-IR: Homeostasis Mode of Assessment of Insulin Resistence ; CT: Colesterol Total; LDL-c: LDL colesterol; HDL-c: HDL colesterol; TG: Triglicerídeos; AST: Aspartato Aminotransferase; ALT: Alanina Aminotransferase; GGT: Gama-Glutamil Transferase; IMC: Índice de Massa Corporal; CB: Circunferência do Braço, CMB: Circunferência Muscular do Braço; AMB: Área Muscular do Braço; DC: Dobra Cutânea Triciptal.

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p < 0,001

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0 1 2 3 4 5

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Variáveis

Fibrose 1 ou 2

(42)

Fibrose 3 ou 4

(66)

Valor de p

Ângulo de Fase (graus) 6,48 ± 0,11 6,25 ± 0,09 0,108 CMB (cm) 25,36 ± 0,49 26,63 ± 0,38 0,048

AMB (mm²) 43,14 ± 2,13 49,30 ± 1,67 0,030 Dados apresentados em média ± erro padrão.

CMB: Circunferência Muscular do Braço; AMB: Área Muscular do Braço.

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Paciente Ascite EH BT Alb RNI Child

1 1 1 2 3 1 B8

2 1 1 1 1 3 B7

3 2 1 2 1 1 B7

4 2 1 1 2 1 B7

5 2 2 3 2 1 C10

6 1 1 2 2 1 B7

7 1 2 1 2 1 B7

8 1 1 1 3 1 B7

9 1 1 1 3 1 B7

10 1 1 2 2 1 B7

EH: Encefalopatia Hepática; BT: Bilirrubinas Totais; Alb: Albumina; RNI: Razão de Normalidade Internacional

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Odds Ratio 95% IC Valor de p Ângulo de Fase 0,428 0,246 – 0,744 0,003

Ângulo de Fase# 0,332 0,122 – 0,904 0,031 # Ajustado por gênero, idade, HOMA, HDL e AST

HOMA-IR: Homeostasis Mode of Assessment of Insulin Resistence; HDL-c: HDL colesterol; AST: Aspartato Transaminase;

IC= Intervalo de Confiança

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Coeficiente Erro padrão Valor de p

Sexo O,979 0,637 0,12

Idade (anos) 0,026 0,027 0,354

Ângulo de Fase (graus) -0,373 0,422 0,38

CT (g/dL) -0,006 0,008 0,41

*R²= 0,0518 CT: Colesterol Total; HOMA-IR: Homeostasis Mode of Assessment of Insulin Resistence

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Variáveis Child A (39)

Child B ou C (10)

Valor de p

Idade (anos) 55,0 ± 9,7 60,1 ± 13,4 0,18 Masculino,% (nº) 59,0 (23) 50,0 (5) 0,73 Genótipo 1, % (nº) 69,2 (27) 90,0 (9) 0,41

Ângulo de Fase

(graus) 6,3 (5,8-6,7) 5,8 (4,2-6,7) 0,23

HOMA-IR 3,96 (2,01-5,79) 4,99 (2,46-7,75) 0,42 CT (g/dL) 162,4 ± 32,1 128,2 ± 18,3 0,002

LDL (g/dL) 88,8 ± 27,3 68,1 ± 21,5 0,03 HDL (g/dL) 45,1 ± 13,2 36,7 ± 20,2 0,12 TG (g/dL) 130,0(92,0-157,0) 95,5(75,0-200,0) 0,46 IMC (Kg/m²) 26,9 ± 4,7 26,9 ± 3,5 0,97 CB (cm) 33,2 ± 4,1 33,5 ± 4,5 0,84 CMB (cm) 26,1 ± 3,0 27,1 ± 4,4 0,40 AMB (mm²) 47,3 ± 13,8 51,5 ± 16,8 0,42 DC (mm) 20,0(15,0-26,8) 20,5(11,0-23,0) 0,68 AST (nºxLSN) 1,58(1,14-2,72) 1,53(1,41-2,14) 1,00 ALT (nºxLSN) 1,46 ± 0,96 1,37 ± 0,77 0,79 GGT (nºxLSN) 1,97(1,09-3,39) 1,48(1,18-3,49) 0,76

Dados expressos em proporção, media, desvio-padrão, mediana e percentis 25 e 75 e nºxLSN (número de vezes do limite superior de normalidade).

HOMA-IR: Homeostasis Mode of Assessment of Insulin Resistence; CT: Colesterol Total; LDL: LDL-colesterol; HDL: HDL-colesterol; TG: Triglicerídeos; IMC: Índice de Massa Corporal; CB: Circunferência do Braço; CMB: Circunferência Muscular do Braço; DC: Dobra Cutânea Triciptal; AST: Aspartato Aminotransferase; ALT: Alanina Aminotransferase ; GGT: Gama-Glutamil Transferase

6IWYPXEHSW

Child A

C

o

lesterol t

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tal

(mg/dL)

0 50 100 150 200

Child B e C

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Child A

LD

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0 20 40 60 80 100 120 140

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# Ajustado para gênero, idade e AST

CT: Colesterol Total; AST: Aspartato Aminotransferase; IC: Intervalo de Confiança

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Variáveis Coeficiente de

correlação (r) Valor de p Idade (anos) 0,13 0,38 Ângulo de Fase (graus) 0,05 0,73

HOMA-IR 0,245 0,09 CT (g/dL) -0,420 0,003

LDL (g/dL) -0,255 0,08 HDL (g/dL) -0,368 0,01

TG (g/dL) -0,134 0,37

IMC (kg/m²) 0,166 0,25

CB (cm) 0,026 0,86

CMB (cm) 0,139 0,34

AMB (mm²) 0,072 0,62

DC (mm) -0,191 0,19

AST (nºxLSN) 0,176 0,23 ALT (nºxLSN) -0,065 0,66 GGT (nºxLSN) -0,227 0,12

HOMA-IR: Homeostasis Mode of Assessment of Insulin Resistence; CT: Colesterol Total; LDL: LDL-colesterol; HDL: HDL-colesterol; TG: Triglicerídeos; IMC: Índice de Massa Corporal; CB: Circunferência do Braço; CMB:

Circunferência Muscular do Braço; AMB: Área Muscular do Braço; DC: Dobra Cutânea Triciptal; AST: Aspartato Aminotransferase; ALT: Alanina

Aminotransferase; GGT: Gama-Glutamil Transferase; nºxLSN: número de vezes do limite superior de normalidade.

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Coeficiente Erro padrão Valor de p

Gênero 1,789 0,880 0,048

Idade (anos) 0,113 0,046 0,018

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4 6 8 10 12 14 16 18 20

Col est er ol to ta l (m g/ dL ) 80 100 120 140 160 180 200 220 240 260

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Variável AUC Erro _padrão 95% IC Cut-off Sensibili. Especifici. Valor p

Å total

(n=108) 0,676 0,055 0,579-0,763 ” 6,4 62,12% 69,05% 0,001 Å ƃ

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(n=47) 0,737 0,077 0,588- 0,854 ” 6,4 82,76% 61,11% 0,002 Curva ROC: Receiver Operating Characteristic; AUC: Área sobre a curva; IC: Intervalo

de Confiança; CUT-off: ponto de corte; ƃ: sexo masculino; Ƃ: sexo feminino; Å: Ângulo de Fase

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Ângulo de Fase população geral

0 20 40 60 80 100

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Ângulo de Fase sexo masculino

0 20 40 60 80 100

0 20 40 60 80 100

100-Especificidade

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0 20 40 60 80 100

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