Análise multivariada de variáveis relacionadas ao fluxo biliar e sobrevida pós-Kasai em pacientes com atresia biliar / Multivariate analysis of biliary flow-related factors and post-kasai survival in biliary atresia patients

ABSTRACT BACKGROUND: Biliary atresia represents the most common surgically treatable cause of cholestasis in newborns. If not corrected, secondary biliary cirrhosis invariably results. OBJECTIVE: To evaluate, through multivariate analysis, the prognostic factors associated with the presence of biliary flow and survival with the native liver following Kasai portoenterostomy. METHODS: The study analyzed data from 117 biliary atresia patients who underwent portoenterostomy and had suitable histological material for evaluation. A logistic regression model was used to assess the presence of biliary flow. Survival was investigated through Kaplan-Meier curves and Cox-adjusted models. RESULTS: One third of patients achieved biliary flow and the median age at surgery was 81 days. Age at surgery, albumin, postoperative complications, biliary atresia structural malformation (BASM), liver architecture, larger duct diameter at porta hepatis, and cirrhosis (Ishak score) were the initial variables for the multivariate analysis. Age at surgery >90 days was the only variable associated with the absence of biliary drainage. Survival analysis revealed that the absence of biliary flow (P<0.0001), age at surgery >90 days (P=0.035), and the presence of BASM (P<0.0001), alone, could predict death or need for liver transplantation. Multivariate analysis demonstrated that the absence of biliary flow (P<0.0001 hazard ratio [HR] 6.25, 95% confidence interval [CI] 3.19-12.22) and the presence of BASM (P=0.014 HR 2.16, 95% CI 1.17-3.99) were associated with lowest survival with the native liver. CONCLUSION: Age at surgery >90 days was associated with absence of biliary flow. The presence of biliary drainage and the absence of structural malformations are cornerstone features for higher survival rates with the native liver.

RESUMO CONTEXTO: A atresia biliar representa a principal causa de colestase tratada cirurgicamente durante o período neonatal. Se a criança não for operada, ela evolui invariavelmente para cirrose biliar secundária. OBJETIVO: Avaliar, através de análise multivariada, os fatores prognósticos associados à presença de fluxo biliar e à sobrevida com fígado nativo após a realização da portoenterostomia de Kasai. MÉTODOS: O estudo analisou 117 pacientes com atresia biliar submetidos à portoenterostomia e com material histológico adequado para avaliação. O modelo de regressão logística foi utilizado para avaliar a presença de fluxo biliar. Sobrevida foi estudada através das curvas Kaplan-Meier e ajuste do modelo de Cox. RESULTADOS: Um terço dos pacientes obteve fluxo biliar e a mediana de idade à cirurgia foi de 81 dias. Idade à cirurgia, albumina, complicação pós-operatória, BASM (do inglês, biliary atresia structural malformation), arquitetura hepática, diâmetro do maior canalículo no porta hepatis e cirrose, segundo o escore de Ishak, foram as variáveis iniciais da análise multivariada. Idade à cirurgia maior que 90 dias de vida foi a única variável associada à ausência de drenagem biliar. A análise de sobrevida mostrou que as variáveis: ausência de fluxo biliar (P<0,0001), idade à cirurgia maior que 90 dias (P=0,035) e presença de BASM (P<0,0001), isoladamente, predizem morte ou necessidade de transplante hepático. Na análise multivariada, ausência de fluxo biliar (P<0,0001 HR:6,25 [IC95% 3,19; 12,22]) e presença de BASM (P=0,014 HR:2,16 [IC95% 1,17; 3,99]) mostraram-se associadas, com significância estatística, a menor sobrevida com fígado nativo. CONCLUSÃO: Idade à cirurgia maior que 90 dias foi identificada como fator de risco independente para ausência de fluxo biliar. Além disso, a presença de drenagem biliar e a ausência de malformações estruturais da atresia biliar são variáveis fundamentais para a maior sobrevida com fígado nativo.

IL-6, TNF-α, IL-10, and nutritional status in pediatric patients with biliary atresia / IL-6, TNF-α, IL-10 e estado nutricional em pacientes pediátricos com atresia biliar

Abstract Objectives: The objective of the present study is to evaluate whether IL-6, TNF-α, IL-10 are associated with nutritional status in patients with cirrhosis secondary to biliary atresia and compare to healthy controls. Methods: The parameters used for nutritional assessment were the standard deviation scores of height-for-age and of triceps skinfold thickness-for-age. The severity of cirrhosis was evaluated using the Child-Pugh score and PELD/MELD. Serum cytokines were measured using Cytometric Bead Array flow cytometry. Results: IL-6, TNF-α, and IL-10 were significantly higher in the cirrhosis group when compared with the control group (2.4 vs. 0.24 (p < 0.001), 0.21 vs. 0.14 (p = 0.007), and 0.65 vs. 0.36 (p = 0.004), respectively. IL-6 and IL-10 were positively correlated with disease severity (0.450 [p = 0.001] and 0.410; [p = 0.002], respectively). TNF-α did not show a significant correlation with disease severity (0.100; p = 0.478). Regarding nutritional evaluation, IL-6 was negatively correlated with the standard deviation score of height-for-age (−0.493; p < 0.001) and of triceps skinfold thickness-for-age (−0.503; p < 0.001), respectively. IL-10 exhibited a negative correlation with the standard deviation score of height-for-age (−0.476; p < 0.001) and the standard deviation score of triceps skinfold thickness-for-age (−0.388; p = 0.004). TNF-α did not show any significance in both anthropometric parameters (−0.083 (p = 0.555) and −0.161 (p = 0.253). Conclusion: The authors suggest that, in patients with cirrhosis secondary to biliary atresia, IL-6 could be used as a possible supporting biomarker of deficient nutritional status and elevated IL-10 levels could be used as a possible early-stage supporting biomarker of deteriorating nutritional status.

Resumo Objetivos: Avaliar se há associações entre a IL-6, o TNF-α, a IL-10 e a estado nutricional em pacientes com cirrose secundária a atresia biliar e comparar com controles saudáveis. Métodos: Os parâmetros usados na avaliação nutricional foram desvio padrão de estatura para a idade e espessura da prega cutânea do tríceps para a idade. A gravidade da cirrose foi avaliada por meio da classificação de Child-Pugh e do PELD/MELD. As citocinas no soro foram medidas por citometria de fluxo - técnica de Cytometric Bead Array. Resultados: A IL-6, o TNF-α e a IL-10 foram significativamente maiores no grupo de cirrose em comparação com o grupo de controle [2,4 em comparação com 0,24 (p < 0,001)], [0,21 em comparação com 0,14 (p = 0,007)] e [0,65 em comparação com 0,36 (p = 0,004)], respectivamente. A IL-6 e a IL-10 demonstraram correlação positiva com a gravidade da doença (0,450; p = 0,001) e (0,410; p = 0,002), respectivamente. O TNF-α não mostrou relevância na gravidade da doença (0,100; p = 0,478). Com relação à avaliação nutricional, a IL-6 demonstrou correlação negativa com o desvio padrão de estatura para a idade (−0,493; p < 0,001) e o desvio padrão de espessura da prega cutânea do tríceps para a idade (−0,503; p < 0,001), respectivamente. A IL-10 demonstrou correlação negativa com o desvio padrão de estatura para a idade (−0,476; p < 0,001) e o desvio padrão de espessura da prega cutânea do tríceps para a idade (−0,388; p = 0,004), respectivamente. O TNF-α não mostrou relevância em ambos os parâmetros antropométricos [(−0,083; p = 0,555); (−0,161; p = 0,253)]. Conclusão: Assim, sugerimos que, em pacientes com cirrose secundária a atresia biliar, IL-6 pode ser usado como um possível biomarcador de suporte do estado nutricional deficiente e níveis aumentados de IL-10 podem ser usados como um possível biomarcador de suporte, em fase inicial, de deterioração do estado nutricional.

Nutritional status of patients with biliary atresia and autoimmune hepatitis related to serum levels of vitamins A, D and E / Estado nutricional de pacientes com atresia biliar e hepatite autoimune e relação com os níveis séricos de vitaminas A, D e E

CONTEXT: Chronic liver disease may induce to malabsorption of lipids and fat-soluble vitamins, leading to injury of nutritional status. OBJECTIVES: To evaluate the nutritional status of pediatric-age patients with autoimmune hepatitis and biliary atresia related to serum levels of vitamins A, D and E and the disease severity. METHODS: This controlled transverse study, evaluated the patients with autoimmune hepatitis and biliary atresia and a reference group paired by sex and age. The patients underwent anthropometric evaluation, alimentary inquiry and determination of serum levels of vitamins A, D and E by high performance liquid chromatography. The Mann-Whitney test, Spearman correlation coefficients and variance analysis (ANOVA) were utilized for data treatment, regarding significant difference if P<0.05. RESULTS: The highest nutritional deficit was observed in patients with biliary atresia, mainly with cholestasis. The serum levels of vitamins A and E for the reference group changed as a function of age. The serum levels of vitamins A, D and E were higher in reference group than in patients with biliary atresia and autoimmune hepatitis together or separately. There were not difference in the serum levels of vitamins A, D and E between biliary atresia groups with cholestasis and without cholestasis. It was verified correlation between weight/age, triceps skinfold thickness, subscapular skinfold thickness, midarm circumference, midarm fat area values and vitamin A serum levels, as well as between all anthropometric indicators and vitamin E in patients with autoimmune hepatitis and biliary atresia. CONCLUSION: The patients with biliary atresia and cholestasis presented the highest nutritional injury. The patients with biliary atresia and autoimmune hepatitis presented lower serum levels of vitamins A, D and E that in control group. There is a directly proportional correlation between vitamin serum levels, mainly vitamin E, and all anthropometric...

CONTEXTO: As doenças hepáticas crônicas podem induzir à má absorção de lipídios e vitaminas lipossolúveis e levar ao comprometimento do estado nutricional. OBJETIVOS: Avaliar o estado nutricional e relacionar com os níveis séricos de vitaminas (A, D e E) e a gravidade da doença em pacientes com atresia biliar e hepatite autoimune na faixa etária pediátrica. MÉTODOS: O estudo foi transversal controlado e foram avaliados os pacientes com hepatite autoimune e atresia biliar e um grupo controle pareado por sexo e idade. Foi realizada avaliação antropométrica, aplicação do inquérito alimentar e determinação dos níveis séricos das vitaminas A, D e E pela técnica de cromatografia líquida de alta eficiência. Foram empregados os testes de Mann-Whitney, o coeficiente de correlação de Spearman e análise de variância (ANOVA), sendo considerada diferença significativa se P<0,05. RESULTADOS: O déficit nutricional mais grave foi observado nos pacientes com atresia biliar, principalmente com colestase. Em relação às vitaminas, no grupo controle, constatou-se que os níveis séricos das vitaminas A e E variaram com a idade. Os níveis séricos das vitaminas A, D e E foram maiores no grupo controle em relação aos pacientes com atresia biliar e hepatite autoimune em conjunto ou separadamente. Verificou-se a correlação do peso/idade, prega cutânea tricipital, prega cutânea subescapular, circunferência braquial, área adiposa braquial com a vitamina A e de todos os indicadores antropométricos com a vitamina E nos pacientes com hepatite autoimune e atresia biliar em conjunto. CONCLUSÕES: Os pacientes com atresia biliar e colestase apresentaram o maior comprometimento nutricional. Os pacientes com atresia biliar e hepatite autoimune possuíram menores níveis séricos das vitaminas A, D e E do que o grupo controle. Existe uma correlação diretamente proporcional, principalmente da vitamina E com todos as variáveis antropométricas do grupo de AB e HAI em conjunto.

Insulin-like growth factor-1 (IGF-1) in children with postoperative biliary atresia: a cross-sectional study.

Biliary atresia is the leading cause of chronic infantile cholestasis which eventually leads to cirrhosis. Re-establishment of biliary drainage by Kasai portoenterostomy and liver transplantation for end-stage liver disease has favorably altered the clinical outcome. However, growth failure, one of the major complications of chronic liver disease, remains a major problem. The aim of the study is to evaluate growth, nutritional status and serum growth factor IGF-1 in children with biliary atresia after Kasai operation and at comparing these data between the groups with successful and unsuccessful operation. Fifty-four children with postoperative biliary atresia were evaluated for their clinical outcome, height, blood biochemistry related nutritional status and serum IGF-1. Height and serum IGF-1 were expressed as standard deviation score (SDS) to minimize the influence of age. With 44.4% of the enrolled patients the operation had been unsuccessful and jaundice persisted. The mean age of children with jaundice in comparison with the jaundice free groups was not significantly different (42.0 and 49.9 months, p = 0.458). In jaundice-free patients, hematocrit, serum albumin, calcium and phosphorus were normal and significantly higher. In the successful Kasai group, the height SDS and serum IGF-1 SDS were within the normal range and significantly higher (height SDS 0.2 +/-1.0 vs. -0.9 +/- 1.2, p < 0.01 and IGF-1 SDS 0.5 +/- 2.2 vs. -1.3 +/- 1.0, p < 0.01). The mean IGF-1 SDS in the failed Kasai group was less than -1. Children with good outcome of postoperative biliary atresia showed better growth, better nutritional status and higher serum IGF-1 levels when compared to those with unsuccessful operation.

Association of serum levels of tissue inhibitors of metalloproteinase-1 with clinical outcome in children with biliary atresia.

The purpose of this study was to determine the possible role of serum levels of tissue inhibitors of metalloproteinase-1 (TIMP-1) in the pathogenesis of the progressive inflammation and fibrosis in biliary atresia (BA). Serum concentrations of TIMP-1 were measured in 57 BA patients and 15 healthy controls using commercially available enzyme-linked immunosorbent assays. The mean ages of the BA patients and the controls were 6.1 +/- 0.6 and 6.7 +/- 1.1 years, respectively. The patients were categorized into two groups according to their clinical outcomes: patients with jaundice (total bilirubin > or = 2 mg/dl) and patients without jaundice (total bilirubin < 2 mg/dl). In our study, serum levels of TIMP-1 were significantly higher in the BA patients than in healthy subjects (4.8 +/- 0.4 vs. 3.5 +/- 0.3 ng/ml, respectively; p < 0.05). Additionally, serum levels of TIMP-1 significantly increased in the BA patients with jaundice in comparison to those without jaundice (6.3 +/- 0.7 vs. 3.1 +/- 0.3 ng/ml, respectively; p = 0.001). Patients with persistent jaundice had lower levels of albumin but had greater levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma glutamyl transpeptidase compared with patients without jaundice. Furthermore, patients with portal hypertension (PH) had higher TIMP-1 levels than those without PH (5.3 +/- 0.4 vs. 1.9 +/- 0.3 ng/ml, respectively; p < 0.001). It is concluded that serum levels of TIMP-1 increased in patients with BA. The significant increase in TIMP-1 levels is related to the presence of PH and the severity of jaundice. The elevated TIMP-1 levels may reflect the degree of hepatic fibrosis and development of PH. The data suggest that TIMP-1 may play a role in the pathophysiology of post-Kasai BA.

Prevalence of hepatitis A virus infection in children with biliary atresia.

This study aimed at identifying the prevalence of hepatitis A virus (HAV) infection in children with biliary atresia (BA). Blood samples were collected from children with BA whom had undergone portoenterostomy and attended the pediatric liver clinic, King Chulalongkorn Memorial Hospital between May 2002 and May 2003. Seventy-seven patients, 45 females and 32 males, ages ranging from 0.2-19 years (mean +/- SD = 5.9 +/- 4.6 years) were enrolled in the study. The HAV seropositivity rate of patients aged <10 years and > or =10 years were 13.1% and 25%, respectively. The seropositivity rate of patients with favorable outcomes (total bilirubin level < or =2 mg/dl) and unfavorable outcome (total bilirubin level >2 mg/dl) were 17.5% and 13.5%, respectively, which were not statistically different (p = 0.6). Children suffering from BA with failed portoenterostomy are at risk of developing severe liver damage at an early age. In these patients a superimposed acute liver infection due to a hepatitis virus, including HAV, may affect liver function and lead to particularly severe disease. The effectiveness of HAV immunization in this particular group of children merits further study.