A Broad Characterization of Glycogen Storage Disease IV Patients: A Clinical, Genetic, and Histopathological Study.

Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disease caused by variants in the GBE1 gene, which encodes the glycogen branching enzyme (GBE). GSD IV accounts for approximately 3% of all GSD. The phenotype of GSD IV ranges from neonatal death to mild adult-onset disease with variable hepatic, muscular, neurologic, dermatologic, and cardiac involvement. There is a paucity of literature and clinical and dietary management in GSD IV, and liver transplantation (LT) is described to correct the primary hepatic enzyme defect. Objectives: We herein describe five cases of patients with GSD IV with different ages of onset and outcomes as well as a novel GBE1 variant. Methods: This is a descriptive case series of patients receiving care for GSD IV at Reference Centers for Rare Diseases in Brazil and in the United States of America. Patients were selected based on confirmatory GBE1 genotypes performed after strong clinical suspicion. Results: Pt #1 is a Latin male with the chief complaints of hepatosplenomegaly, failure to thrive, and elevated liver enzymes starting at the age of 5 months. Before LT at the age of two, empirical treatment with corn starch (CS) and high protein therapy was performed with subjective improvement in his overall disposition and liver size. Pt #2 is a 30-month-old Afro-American descent patient with the chief complaints of failure to gain adequate weight, hypotonia, and hepatosplenomegaly at the age of 15 months. Treatment with CS was initiated without overall improvement of the symptoms. Pt #3.1 is a female Latin patient, sister to pt #3.2, with onset of symptoms at the age of 3 months with bloody diarrhea, abdominal distention, and splenomegaly. There was no attempt of treatment with CS. Pt #4 is an 8-year-old male patient of European descent who had his initial evaluation at 12 months, which was remarkable for hepatosplenomegaly, elevated ALT and AST levels, and a moderate dilatation of the left ventricle with normal systolic function that improved after LT. Pt #1, #3.2 and #4 presented with high levels of chitotriosidase. Pt #2 was found to have the novel variant c.826G > C p.(Ala276Pro). Conclusions: GSD IV is a rare disease with different ages of presentation and different cardiac phenotypes, which is associated with high levels of chitotriosidase. Attempts of dietary intervention with CS did not show a clear improvement in our case series.

HIF-1alpha-pathway activation in cholangiocytes of patients with biliary atresia: An immunohistochemical/molecular exploratory study.

BACKGROUND: Biliary atresia is a neonatal disease characterized by choledochal obstruction and progressive cholangiopathy requiring liver transplantation in most patients. Hypoxia-ischemia affecting the biliary epithelium may lead to biliary obstruction. We hypothesized that ischemic cholangiopathy involving disruption of the peribiliary vascular plexus could act as a triggering event in biliary atresia pathogenesis. METHODS: Liver and porta hepatis paraffin-embedded samples of patients with biliary atresia or intrahepatic neonatal cholestasis (controls) were immunohistochemically evaluated for HIF-1alpha-nuclear signals. Frozen histological samples were analyzed for gene expression in molecular profiles associated with hypoxia-ischemia. Prospective clinical-laboratory and histopathological data of biliary atresia patients and controls were reviewed. RESULTS: Immunohistochemical HIF-1alpha signals localized to cholangiocytes were detected exclusively in liver specimens from biliary atresia patients. In 37.5% of liver specimens, HIF-1alpha signals were observed in biliary structures involving progenitor cell niches and peribiliary vascular plexus. HIF-1alpha signals were also detected in biliary remnants of 81.8% of porta hepatis specimens. Increased gene expression of molecules linked to REDOX status, biliary proliferation, and angiogenesis was identified in biliary atresia liver specimens. In addition, there was a trend towards decreased GSR expression levels in the HIF-1alpha-positive group compared to the HIF-1alpha-negative group. CONCLUSION: Activation of the HIF-1alpha pathway may be associated with the pathogenesis of biliary atresia, and additional studies are necessary to confirm the significance of this finding. Ischemic cholangiopathy and REDOX status disturbance are putative explanations for HIF-1alpha activation. These findings may give rise to novel lines of clinical and therapeutic investigation in the BA field.

Hypervolemic hyponatremia and transplant-free survival in children with cirrhosis due to biliary atresia.

BACKGROUND: Biliary atresia is the number one cause of cirrhosis and liver transplantation in children. Hyponatremia is the most important electrolytic disturbance observed in decompensated cirrhosis. Studies of hyponatremia in cirrhotic children are scarce and those that exist have defined hyponatremia as serum sodium < 130 mEq/L lasting for at least 7 days. METHODS: We evaluated transplant-free survival (Kaplan-Meier) of children with cirrhosis due to biliary atresia and serum sodium < 130 mEq/L persisting for 1, 2-6, and ≥7 days. This was a single-center, historical cohort that included all patients aged ≤ 18 years on a liver transplantation waiting list. RESULTS: We studied 128 patients. The overall frequency of hyponatremia was 30.5% (39/128). Thirteen patients (10.2%) had hyponatremia when put on the list, and 20.3% developed it during follow-up. The Kaplan-Meier overall transplant-free survival rate was 83.3%. Patients with persistent hyponatremia for at least two days had the lowest transplant-free survival. Glomerular filtration rate (P = .00, RR = 0.96, IC 95% = 0.94-0.99), BMI/age Z-score (P = .02, RR = 0.59, IC 95% = 0.39-0.91), INR (P = .00, RR = 1.43, IC 95% = 1.17-1.74), and serum sodium (P = .04, RR = 0.91, IC 95% = 0.84-0.99) were independently associated with transplant-free survival. We did not observe any difference in mortality prediction after adding sodium to the original PELD score. CONCLUSIONS: We conclude that persistent hyponatremia lasting at least two days may herald poor prognosis for children with cirrhosis due to biliary atresia.

Noninvasive Methods of Predicting Large Esophageal Varices in Children With Intrahepatic Portal Hypertension.

OBJECTIVE: Esophageal variceal bleeding is a severe complication of portal hypertension. The standard diagnostic screening test and therapeutic procedure for esophageal varices (EV) is endoscopy, which is invasive in pediatric patients. This study aimed to evaluate the role of noninvasive parameters as predictors of large varices in children with intrahepatic portal hypertension. METHODS: Participants included in this cross-sectional study underwent a screening endoscopy. Variceal size, red marks, and portal gastropathy were assessed and rated. Patients were classified into two groups: Group 1 (G1) with small or no varices and Group 2 (G2) with large varices. The population consisted of 98 children with no history of gastrointestinal (GI) bleeding, with a mean age of 8.9 ±â€Š4.7 years. The main outcome evaluated was the presence of large varices. RESULTS: The first endoscopy session revealed the presence of large varices in 32 children. The best noninvasive predictors for large varices were platelets (Area under the ROC Curve [AUROC] 0.67; 95% CI 0.57-0.78), the Clinical Prediction Rule (CPR; AUROC 0.65; 95% CI 0.54-0.76), and risk score (AUROC 0.66; 95% CI 0.56-0.76). The logistic regression model showed that children with a CPR value under 114 were 8.59 times more likely to have large varices. Risk scores higher than -1.2 also increased the likelihood of large varices (OR 6.09; P = 0.014), as did a platelet count/spleen size z score lower than 25 (OR 3.99; P = 0.043). The combination of these three tests showed a high negative predictive value. CONCLUSIONS: The CPR, the risk score, and the platelet count/spleen size z score could be helpful in identifying cirrhotic children who may be eligible for endoscopy.

Environmental risk factors associated with biliary atresia in Rio Grande do Sul, Brazil

Biliary atresia (BA) seems to be a multifactorial disorder in which environmental factors interact with the patient's genetic constitution. This study aimed to analyze information concerning environmental risk factors associated with BA in southern Brazil. A case-control study with mothers of patients with BA and mothers of patients with cystic fibrosis (CF) was conducted. Inquiry included questions related to exposition to environmental risk factors during the periconceptional and gestational (second and third trimesters) periods. Mothers of BA patients had smoked during pregnancy more frequently in comparison with the mothers of CF patients, but no significant difference was found in a multivariate analysis. There was no between group difference in terms of seasonality, but the multivariate analysis showed a significant difference within the BA group between date of conception in winter compared to other seasons. In conclusion, smoking during pregnancy seemed to increase the risk of BA while date of conception in winter decreased it (AU)

Avaliação nutricional em crianças e adolescentes com cirrose: estudo transversal de duas séries / Nutritional assessment in children and adolescents with cirrhosis: cross-sectional study of two series

Introdução: A cirrose caracteriza-se por uma alteração crônica do parênquima hepático que frequentemente leva à desnutrição em crianças e adolescentes. A intervenção nutricional deve ser feita precocemente, o que requer um cuidadoso acompanhamento desses pacientes. Objetivos: Comparar os resultados da avaliação nutricional de crianças e adolescentes cirróticos realizada em dois períodos de tempo distintos. Métodos: Foram utilizados bancos de dados oriundos de duas pesquisas conduzidas com pacientes pediátricos com cirrose. Após a aplicação de critérios de inclusão e exclusão, 67 crianças e adolescentes foram avaliados em duas séries com intervalo de aproximadamente uma década entre elas. As duas séries tiveram as variáveis antropométricas estatura para idade (E/I) e dobra cutânea tricipital para idade (DCT/I) avaliadas de acordo com os padrões da Organização Mundial de Saúde. A gravidade da doença foi avaliada pelos modelos Pediatric End-stage Liver Disease (PELD)/ Model for End-stage Liver Disease (MELD) e pelo escore Child-Pugh. O nível de significância foi estabelecido em 5%. Resultados: Os resultados da avaliação do estado nutricional dos pacientes nas duas séries não mostraram diferença estatisticamente significativa. Na série 1, 22,6% dos pacientes apresentaram desnutrição, e 27,8% na série 2 (p = 0,955). Conclusões: Podemos concluir que nas duas séries avaliadas, separadas por aproximadamente uma década, o percentual de desnutrição e a gravidade da cirrose se mantiveram estáveis (AU)

Introduction: Cirrhosis is characterized by a chronic alteration of the liver parenchyma that often leads to malnutrition in children and adolescents. Nutritional intervention should be performed early, requiring careful follow-up of these patients. Objectives: To compare the nutritional assessment of cirrhotic pediatric patients performed in two separate periods of time. Methods: This research used two different databases originated from studies conducted with pediatric patients with cirrhosis. After applying inclusion and exclusion criteria, 67 children and adolescents were assessed in two series of tests performed within a time range of approximately a decade. Both series had standard deviation score for height-for-age (SDS-H/A), standard deviation score for triceps skinfold-for-age and (SDS-TSF/A), calculated according to the standards established by the World Health Organization. Disease severity was evaluated by the Pediatric End-stage Liver Disease (PELD)/Model for End-stage Liver Disease (MELD) and by the Child-Pugh score. Results were considered significant at p < 0.05. Results: The present study did not find any statistically significant difference for the nutritional status of the researched subjects in any of the series. In the first series, 22.6% of patients were undernourished, compared to 27.8% in the second one (p = 0.955). Conclusions: We can conclude that in both series of tests conducted with an interval of about a decade from each other the percentage of malnutrition and the severity of cirrhosis remained stable (AU)

Hypoxic-ischemic gene expression profile in the isolated variant of biliary atresia.

BACKGROUND: Biliary atresia (BA) includes a sclerosing cholangiopathy whose nature is not fully deciphered. Aiming to evaluate the role of an arteriopathy as an etiologic factor in BA, we investigated hypoxia and the correlated angiogenic response in livers from affected patients. METHODS: Gene expression of the molecular axis: hypoxia-inducible factor (HIF)1a, HIF2a and vascular endothelial growth factor A (VEGFA)/VEGFR1, VEGFR2. Liver biopsy specimens collected at exploratory laparotomy of age-matched patients with isolated, cytomegalovirus IgM-negative BA (n = 32) and intrahepatic cholestasis (IHC, n = 9) were evaluated. RESULTS: We observed higher HIF1a and HIF2a expression in BA than in IHC. Paradoxically, VEGFR2, the main target of VEGFA-induced angiogenesis, was underexpressed in BA, and VEGFA was decreased in most BA patients. Patients with the highest expression of HIFs and the lowest VEGFA and VEGFR2 were essentially the same, indicating hypoxia without the necessary angiogenesis. This group included most BA patients and, except for HIF2a, they were older and presented increased bilirubin serum levels. In the highest HIF2a/lowest VEGFR2 subsets, gene expression of the cytokeratin 19, marker of cholangiocyte phenotype, was decreased. CONCLUSION: This study suggests that hypoxia-ischemia is present in the livers of patients with BA, progresses over time and leads to a decreased cholangiocyte mass.

Serum proinflammatory cytokines and nutritional status in pediatric chronic liver disease.

AIM: To evaluate the nutritional status and its association with proinflammatory cytokines in children with chronic liver disease. METHODS: We performed a cross-sectional study with 43 children and adolescents, aged 0 to 17 years, diagnosed with chronic liver disease. All patients regularly attended the Pediatric Hepatology Unit and were under nutritional follow up. The exclusion criteria were fever from any etiology at the time of enrollment, inborn errors of the metabolism and any chronic illness. The severity of liver disease was assessed by Child-Pugh, Model for End-stage Liver Disease (MELD) and Pediatric End Stage Liver Disease (PELD) scores. Anthropometric parameters were height/age, body mass index/age and triceps skinfold/age according to World Health Organization standards. The cutoff points for nutritional status were risk of malnutrition (Z-score < -1.00) and malnutrition (Z-score < -2.00). Interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α levels were assessed by commercial ELISA kits. For multivariate analysis, linear regression was applied to assess the association between cytokine levels, disease severity and nutritional status. RESULTS: The median (25(th)-75(th) centile) age of the study population was 60 (17-116)-mo-old, and 53.5% were female. Biliary atresia was the main cause of chronic liver disease (72%). With respect to Child-Pugh score, cirrhotic patients were distributed as follows: 57.1% Child-Pugh A, a mild presentation of the disease, 34.3% Child-Pugh B, a moderate stage of cirrhosis and 8.6% Child-Pugh C, were considered severe cases. PELD and MELD scores were only above the cutoff point in 5 cases. IL-6 values ​​were increased in patients at nutritional risk (34.9%) compared with those who were well-nourished [7.12 (0.58-34.23) pg/mL vs 1.63 (0.53-3.43) pg/mL; P = 0.02], correlating inversely with triceps skinfold-for-age z-score (rs = -0.61; P < 0.001). IL-6 levels were associated with liver disease severity assessed by Child-Pugh score (P = 0.001). This association remained significant after adjusting for nutritional status in a linear regression model. CONCLUSION: High IL-6 levels were found in children with chronic liver disease at nutritional risk. Inflammatory activity may be related to nutritional status deterioration in these patients.

Programa de Transplante Hepático Infantil do Hospital de Clínicas de Porto Alegre: resultados dos doze primeiros transplantes hepáticos intervivos / Pediatric liver transplantation program: results of living liver transplantation

Introdução: O Hospital de Clínicas de Porto Alegre (HCPA) é pioneiro na realização de transplante hepático infantil (THI) no RS. A menor oferta de doadores falecidos tem estimulado a realização de transplante hepático (TxH) intervivos. Objetivo: Descrever os resultados do THI intervivos do programa THI-HCPA. Método: Estudo descritivo. Incluídos: receptores de TxH intervivos, 18 anos, ambos os sexos e respectivos doadores, voluntários, ambos os sexos. Excluídos: insufi ciência hepática aguda. Variáveis: receptores: características clínico-demográficas, antropométricas; sorologias para Citomegalovírus (CMV) e Epstein-Barr (EBV); incidência de complicações pós-operatórias, tempo de internação, sobrevida 12 meses; doadores: características clínico-demográficas, sobrevida 12 meses. Todas as cirurgias foram realizadas pelo mesmo cirurgião e os dados, coletados prospectivamente. Estudo aprovado pelo Comitê de Ética em Pesquisa do HCPA (13-0208). Resultados: Doze TxH intervivos incluídos. Idade dos receptores: mediana=2 anos (sexo feminino:7). Espera em lista: 141,4±10,3d. Indicação de TxH: 83,3% atresia biliar. IMC normal: 100%. Child- -Pugh: C:7/12(58%). PELD: mediana=11,9a. Pré-TxH:IgG+CMV (10); IgG+EBV(4); ascite (7); peritonite bacteriana espontânea (3), hiponatremia dilucional (7); encefalopatia hepática (2); varizes esofágicas (4); hemorragia digestiva alta (3). Idade dos doadores: 31,8±8,4a. Sexo feminino=50%; 92% aparentado. Pesos receptor/doador: 19,2±8,9%. Implante do segmento hepático lateral esquerdo: 100%. Tempo de isquemia total: 1,34±0,67h. Duração da cirurgia: 5,94±2,58h. Duração da internação (receptores): 30,6 ± 25,2d. Complicações receptores: vascular (4), biliar (3), steal syndrome (1), small for size (2), sepse (1). Reintervenções cirúrgicas: 5. Tempo de permanência em UTI: mediana=9d. Primo-infecção: CMV (1), EBV (3). Rejeição celular aguda (4). Sobrevida em 1 ano: 76,7%. Tempo de internação(doadores): 8,1±4,0 d. Complicações ao doador: dor pós-operatória (80%). Conclusão: Os nossos resultados se assemelham àqueles da literatura no que se refere à incidência de complicações. A cirurgia tem se mostrado segura para o doador (AU)

Introduction: Hospital de Clínicas de Porto Alegre (HCPA) is a pioneer in conducting child liver transplantation (CLT) in RS. The lower supply of deceased donors has stimulated living liver transplant (LTx). Aim: To describe the results of living CLT in the THI-HCPA program. Methods: A descriptive study that included: LTx recipients from living donor, ≤ 18 years old, both sexes and their donors, volunteers, both sexes; and excluded: acute liver failure. Variables: Receptors: clinical, demographic and anthropometric characteristics, serology for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection, incidence of postoperative complications, length of stay, 12-month survival; Donors: demographic and clinical characteristics, 12-month survival. All surgeries were performed by the same surgeon and the data were collected prospectively. This study was approved by the Research Ethics Committee of the HCPA (13-0208). Results: Twelve LTx from living donors were included. Age of recipients: median = 2 years (female: 7). Waiting in list: 141.4 ± 10.3 d. Indication for liver transplantation: 83.3% biliary atresia. Normal BMI: 100%. Child-Pugh C:7/12 (58%). PELD: median = 11.9a. Pre-LTx: CMV+IgG (10), EBV+IgG (4), ascites (7), spontaneous bacterial peritonitis (3), dilutional hyponatremia (7), hepatic encephalopathy (2), esophageal varices (4), high gastrointestinal bleeding (3). Donor age: 31.8 ± 8.4. Female = 50%, 92% related. Receiver/giver weights: 19.2 ± 8.9%. Implantation of left lateral hepatic segment: 100%. Total ischemic time: 1.34 ± 0.67 h. Length of surgery: 5.94 ± 2.58 h. Duration of hospitalization (receivers): 30.6 ± 25.2 d. Complications in receptors: vascular (4), bile (3), steal syndrome (1), small for size (2), sepsis (1). Surgical re-interventions: 5. Time in ICU: median = 9d. Primary infection: CMV (1), EBV (3). Acute cellular rejection (4). 1-year survival: 76.7%. Length of hospital stay (donors): 8.1 ± 4.0d. Donor complications: postoperative pain (80%). Conclusion: The results resemble those of the literature regarding the incidence of complications. The surgery has been shown to be safe for the donor (AU)

Noninvasive methods for prediction of esophageal varices in pediatric patients with portal hypertension.

AIM: To evaluate clinical and laboratory parameters for prediction of bleeding from esophageal varices (EV) in children with portal hypertension. METHODS: Retrospective study of 103 children (mean age: 10.1 ± 7.7 years), 95.1% with intrahepatic portal hypertension. All patients had no history of bleeding and underwent esophagogastroduodenoscopy for EV screening. We recorded variceal size (F1, F2 and F3), red-color signs and portal gastropathy, according to the Japanese Research Society for Portal Hypertension classification. Patients were classified into two groups: with and without EV. Seven noninvasive markers were evaluated as potential predictors of EV: (1) platelet count; (2) spleen size z score, expressed as a standard deviation score relative to normal values for age; (3) platelet count to spleen size z score ratio; (4) platelets count to spleen size (cm) ratio; (5) the clinical prediction rule (CPR); (6) the aspartate aminotransferase to platelet ratio index (APRI); and (7) the risk score. RESULTS: Seventy-one children had EV on first endoscopy. On univariate analysis, spleen size, platelets, CPR, risk score, APRI, and platelet count to spleen size z score ratio showed significant associations. The best noninvasive predictors of EV were platelet count [area under the receiver operating characteristic curve (AUROC) 0.82; 95%CI: 0.73-0.91], platelet: spleen size z score (AUROC 0.78; 95%CI: 0.67-0.88), CPR (AUROC 0.77; 95%CI: 0.64-0.89), and risk score (AUROC 0.77; 95%CI: 0.66-0.88). A logistic regression model was applied with EV as the dependent variable and corrected by albumin, bilirubin and spleen size z score. Children with a CPR < 114 were 20.7-fold more likely to have EV compared to children with CPR > 114. A risk score > -1.2 increased the likelihood of EV (odds ratio 7.47; 95%CI: 2.06-26.99). CONCLUSION: Children with portal hypertension with a CPR below 114 and a risk score greater than -1.2 are more likely to have present EV. Therefore, these two tests can be helpful in selecting children for endoscopy.

Peritonite bacteriana espontânea: novas perspectivas / Spontaneuous bacterial peritonitis: new perspectives

A peritonite bacteriana espontânea (PBE) é uma das infecções mais frequentes no paciente cirrótico, estando associada à alta morbi-mortalidade. Descrita desde a metade dos anos de 1960, diretrizes recentemente publicadas apontam para o surgimento de novos conceitos relacionados à patogênese, ao diagnóstico e ao tratamento da PBE, motivo desta revisão. Dentre os principais aspectos discutidos destacam-se o conceito de translocação bacteriana patológica e a identificação de polimorfismos genéticos associados ao desenvolvimento da PBE, este último sugerindo a existência de um fator de risco adicional para a infecção. Os critérios diagnósticos e terapêuticos são revisados, sendo enfatizada a crescente ocorrência de resistência bacteriana naqueles pacientes que desenvolvem PBE nosocomial, situação na qual é sugerida uma abordagem terapêutica específica. Discute-se finalmente, as atuais indicações de profilaxia primária e secundária. Quando pertinente, serão também apresentados os aspectos relacionados à PBE que acomete o paciente pediátrico (AU)

Spontaneous bacterial peritonitis (SBP) is one of the most common infections in cirrhotic patients and is associated with high morbidity and mortality. Described since the mid-1960s, recently published guidelines point to the emergence of new concepts related to the pathogenesis, diagnosis and treatment of SBP, subject of this review. The main aspects discussed include the concept of pathological bacterial translocation and identification of genetic polymorphisms associated with the development of SBP, the latter suggesting the existence of an additional risk factor for infection. The diagnostic and therapeutic criteria are reviewed, with an emphasis on the increasing occurrence of bacterial resistance in patients who develop nosocomial SBP, in which case a specific therapeutic approach is suggested. Finally we discuss the current indications for primary and secondary prophylaxis. Where relevant, SBP-related aspects affecting the pediatric patient will also be presented (AU)

Intestinal permeability assessed by 51Cr-EDTA in rats with CCl4 - induced cirrhosis.

CONTEXT: The straight relationship between cirrhosis and impaired intestinal barrier has not been elucidated yet. OBJECTIVES: To verify (51)Cr-EDTA-intestinal permeability in rats with CCl(4)-induced cirrhosis and controls. METHOD: Fifty male Wistar rats weighing 150-180 g were separated in three groups: 25 animals received CCl(4) 0.25 mL/kg with olive oil by gavage with 12 g/rat/day food restriction for 10 weeks (CCl(4)-induced cirrhosis); 12 received the same food restriction for 10 weeks (CCl(4)-non exposed). Other 13 rats received indomethacin 15 mg/kg by gavage as positive control of intestinal inflammation. RESULTS: The median (25-75 interquartile range) (51)Cr-EDTA-IP values of cirrhotic and CCl(4)-non exposed rats were 0.90% (0.63-1.79) and 0.90% (0.60-1.52) respectively, without significant difference (P = 0.65). Animals from indomethacin group showed (51)Cr-EDTA-IP, median 7.3% (5.1-14.7), significantly higher than cirrhotic and CCl(4)-non exposed rats (P<0.001). CONCLUSION: This study showed the lack of difference between (51)Cr-EDTA-intestinal permeability in rats with and without cirrhosis. Further studies are necessary to better clarify the relationship between intestinal permeability and cirrhosis.

Intestinal permeability assessed by 51Cr-EDTA in rats with CCl4 - induced cirrhosis / Permeabilidade intestinal ao 51-Cr-EDTA em ratos com cirrose induzida por CCl4

CONTEXT: The straight relationship between cirrhosis and impaired intestinal barrier has not been elucidated yet. OBJECTIVES: To verify 51Cr-EDTA-intestinal permeability in rats with CCl4-induced cirrhosis and controls. METHOD: Fifty male Wistar rats weighing 150-180 g were separated in three groups: 25 animals received CCl4 0.25 mL/kg with olive oil by gavage with 12 g/rat/day food restriction for 10 weeks (CCl4-induced cirrhosis); 12 received the same food restriction for 10 weeks (CCl4-non exposed). Other 13 rats received indomethacin 15 mg/kg by gavage as positive control of intestinal inflammation. RESULTS: The median (25-75 interquartile range) 51Cr-EDTA-IP values of cirrhotic and CCl4-non exposed rats were 0.90 percent (0.63-1.79) and 0.90 percent (0.60-1.52) respectively, without significant difference (P = 0.65). Animals from indomethacin group showed 51Cr-EDTA-IP, median 7.3 percent (5.1-14.7), significantly higher than cirrhotic and CCl4-non exposed rats (P<0.001). CONCLUSION: This study showed the lack of difference between 51Cr-EDTA-intestinal permeability in rats with and without cirrhosis. Further studies are necessary to better clarify the relationship between intestinal permeability and cirrhosis.

CONTEXTO: A relação direta entre cirrose e alterações na barreira intestinal ainda não foi devidamente esclarecida. OBJETIVO: Verificar a permeabilidade intestinal ao 51Cr-EDTA em ratos com cirrose induzida por tetracloreto de carbono (CCl4) e controles. MÉTODO: Cinquenta ratos Wistar machos pesando 150-180 g foram separados em três grupos: 25 animais receberam CCl4 0,25 mL/kg diluído em óleo de oliva por gavagem com restrição dietética de 12 g/rato/dia por 10 semanas (grupo cirrose induzida por CCl4); 12 receberam a mesma restrição dietética por 10 semanas (grupo não exposto ao CCl4). Outros 13 ratos receberam indometacina 15 mg/kg por gavagem como controle positivo de inflamação intestinal. RESULTADOS: A mediana (intervalo interquartil 25-75) dos valores de permeabilidade intestinal ao 51Cr-EDTA dos grupos cirrose induzida por CCl4 e não exposto ao CCl4 foram 0,90 por cento (0,63-1,79) e 0,90 por cento (0,60-1,52), respectivamente, sem significância estatística (P = 0,65). Os animais do grupo indometacina apresentaram uma mediana de permeabilidade intestinal ao 51Cr-EDTA de 7,3 por cento (5,1-14,7), sendo significativamente maior do que os grupos cirrose induzida por CCl4 e não exposto ao CCl4 (P<0,001). CONCLUSÃO: Este estudo não demonstrou diferenças entre a permeabilidade intestinal ao 51Cr-EDTA em ratos com e sem cirrose. Mais estudos são necessários para melhor esclarecer a relação entre a permeabilidade intestinal e cirrose.

Terapia nutricional em crianças e adolescentes com cirrose: uma visão atual / Nutritional therapy in children and adolescents with cirrhosis: current status

A anorexia e o hipermetabolismo são aspectos clínicos importantes em crianças com cirrose. Embora muitas das complicações da cirrose sejam semelhantes àquelas encontradas em adultos, a etiologia e a história natural da progressão da doença e o tratamento clínico em pacientes pediátricos podem ser significativamente diferentes. As alterações metabólicas da doença hepática crônica agravada pela anorexia e desnutrição podem ter implicações negativas no crescimento e desenvolvimento infantil. Crianças com cirrose de evolução progressiva são frequentemente desnutridas e, no entanto, os métodos comumente empregados para avaliação nutricional têm uso limitado nestes pacientes. Mesmo que a importância do estado nutricional sobre o prognóstico destes pacientes seja clara, poucos estudos sobre a terapia nutricional nas hepatopatias da infância têm sido realizados. A avaliação nutricional em crianças com cirrose hepática deve incluir uma completa história clínica e dietética, medidas antropométricas e parâmetros laboratoriais. A recomendação nutricional na cirrose infantil pode variar de acordo com o estado nutricional, idade e quadro clínico. Como a doença hepática crônica em crianças pode impactar significativamente sobre o estado nutricional e consequentemente no crescimento e desenvolvimento, o objetivo deste artigo é revisar os aspectos clínicos e fisiopatológicos envolvidos no diagnóstico e manejo nutricional da cirrose hepática em pacientes pediátricos.

Anorexia and hypermetabolism are disorders of paramount importance in children with cirrhosis. Although many complications caused by cirrhosis in children are similar to those found in adults, the etiologic spectrum and natural history of this disease progression and its clinical management in pediatric patients may be significantly different. The metabolic changes caused by chronic liver disease aggravated by anorexia and malnutrition can affect child growth and development. Malnutrition is common in children with cirrhosis and the methods commonly used for their nutritional assessment are limited. Although the importance of the nutritional status on the prognosis of these patients is clear, there are few studies about nutritional therapy in children with cirrhosis. Nutritional assessment in children with liver cirrhosis should include full clinical and nutritional history, anthropometric measurements, and laboratory parameters. The nutritional recommendation for cirrhosis in children may vary depending on age and nutritional and clinical status. Because chronic liver disease in children may have a significant impact on nutritional status, growth, and development, the objective of this study is to review the clinical and pathophysiological aspects involved in the diagnosis and nutritional management of liver cirrhosis in children.

Desnutrição calórico-proteica do tipo kwashiorkor desencadeada por alergia à proteína do leite de vaca / Kwashiorkor-type malnutrition due to cow's milk protein allergy

A enteropatia induzida por proteína alimentar, uma das formas de apresentação de hipersensibilidade alimentar, tem na alergia à proteína do leite de vaca a causa mais comum dessa síndrome. Ocorre comumente em lactentes, e o diagnóstico depende de uma anamnese minuciosa associada a uma resposta clínica favorável à retirada do antígeno. No presente relato, paciente do sexo feminino de 1 ano e 8 meses, interna para investigação de desnutrição calórico-proteica grave com história de vômitos, diarreia sanguinolenta e perda ponderal pronunciada a partir dos 8 meses de idade. Amamentação exclusiva no primeiro mês de vida e fórmula láctea do segundo ao quarto mês; desde então, com leite de vaca integral. Na admissão, chorosa, irritada, emagrecida, desidratada, cabelos despigmentados e quebradiços, em anasarca e com hepatomegalia. Exames laboratoriais revelaram anemia megaloblástica, leucocitose e hipoalbuminemia. Hipóteses diagnósticas: doença celíaca, fibrose cística e alergia à proteína do leite de vaca. Realizada endoscopia digestiva alta com biópsia: discreto aumento de eosinófilos na lâmina própria em mucosa gástrica e duodenal e esofagite crônica discreta com raros eosinófilos intraepiteliais. Teste do suor negativo. Estabelecido o diagnóstico de alergia à proteína do leite de vaca desencadeando um quadro de desnutrição calórico-proteica grave do tipo kwashiorkor e iniciada dieta com hidrolisado proteico. A alergia à proteína do leite de vaca é uma apresentação clínica frequente de alergia alimentar em lactentes e pré-escolares, sendo as repercussões gastrintestinais e nutricionais significativas nessa faixa etária. Dessa forma, o diagnóstico de alergia à proteína do leite de vaca deve ser considerado em pacientes com desnutrição calórico-proteica, uma vez que a desnutrição primária, por ingestão insuficiente, tenha sido excluída.

Dietary protein-induced enteropathy is one of the presentations of food allergy, and cow's milk protein allergy (CMPA) is its most common cause, frequently affecting infants. Diagnosis depends on thorough history associated with favorable clinical response to the antigen with drawal. This case report describes the case of a twenty-month-old female patient admitted to investigate protein-energy malnutrition (PEM) with severe vomiting, bloody diarrhea and significant weight loss since eight months of age. She was breastfed during the first month of life, receiving infant formula up to the fourth month and, since then, whole cow's milk. At admission, the patient was very irritable, crying, angry, dehydrated, with severe weight loss, brittle and depigmented hair, edema and hepatomegaly. Laboratory tests showed megaloblastic anemia, leukocytosis and hypoalbuminemia. Diagnostic hypotheses: celiac disease, cystic fibrosis and CMPA. Esophagogastroduodenoscopy with biopsy showed slight increase in intra-epithelial eosinophils in the duodenum and chronic mild esophagitis with rare eosinophil infiltrate. Sweat test was negative. Diagnosis of kwashiorkor-type malnutrition triggered by CMPA was made, and hydrolyzed protein diet was started with favorable clinical outcome. CMPA is a prevalent clinical presentation of food allergy in infants and preschool children, and nutritional consequences are also important in these age groups. Therefore, CMPA diagnosis should always be considered in patients with PEM, provided the primary malnutrition secondary to insufficient food intake is excluded.

[Eosinophilic esophagitis in 29 pediatric patients]. / Esofagite eosinofílica em 29 pacientes pediátricos.

BACKGROUND: Eosinophilic esophagitis is a recently described entity with esophageal symptoms like gastroesophageal reflux disease and significant esophageal eosinophilic infiltration. AIM: To present our clinical series of 29 children with eosinophilic esophagitis, describing the clinical and diagnostic features, treatment and outcome. METHODS: We describe 29 patients (22 boys), 1-18 years-old, with 20 eosinophils per high-power field in esophageal biopsy specimens and absence of eosinophilic inflammation in the stomach and duodenum. Evaluation of the clinical, endoscopic and histologic findings, treatment and outcome was undertaken. RESULTS: The most common presenting symptoms included vomiting in 15 patients (52%) and abdominal pain in 11 patients (38%). Children under the age of 4 years presented with feeding disorder and failure to thrive. Patients between 5 and 8 years of age presented commonly with abdominal pain or symptoms that may be associated with reflux (heartburn and/or vomiting). Patients over the age of 8 presented most often with abdominal pain, dysphagia and occasional food impaction. Endoscopic features included vertical furrowing in 14 patients (48%), whitish papules in 12 (41%), corrugated rings in 2 patients (7%) and esophageal erosions in 3 patients (10%). In seven patients endoscopy was normal (24%). Treatment included swallowed fluticasone propionate in 19 patients and restriction diet in 7 patients. Patients who returned for follow-up had either improvement or remission of symptoms. After treatment, endoscopic biopsies were repeated in 11 patients, and a significant decrease in esophageal eosinophil counts was observed. CONCLUSIONS: The diagnosis of eosinophilic esophagitis must be considered when symptoms of reflux do not respond to conventional treatment. Upper gastrointestinal endoscopy must be complemented by a detailed analysis of histologic findings and eosinophil counts.

Esofagite eosinofílica em 29 pacientes pediátricos / Eosinophilic esophagitis in 29 pediatric patients

RACIONAL: A esofagite eosinofílica é uma entidade recentemente descrita, caracterizada por sintomas esofágicos, semelhantes aos da doença por refluxo gastroesofágico e importante eosinofilia esofágica. OBJETIVO: Apresentação de 29 pacientes com esofagite eosinofílica, discutindo as características clínicas, diagnóstico, tratamento e evolução. MÉTODOS: Foram identificados 29 pacientes (22 do sexo masculino) com idade entre 1 e 18 anos, nos quais as biopsias de esôfago demonstraram contagem de 20 ou mais eosinófilos/campo de grande aumento, sem infiltração eosinofílica em antro e/ou duodeno. Avaliaram-se as manifestações clínicas, achados endoscópicos e histológicos, tratamento e evolução. RESULTADOS: Os sintomas mais freqüentes foram vômitos em 15 pacientes (52 por cento) e dor abdominal em 11 (38 por cento). Os pacientes com idade inferior a 4 anos apresentavam recusa alimentar e baixo peso. Os com idades entre 5 e 8 anos apresentavam predominantemente dor abdominal e/ou pirose e/ou vômitos. Os pacientes com mais de 8 anos apresentavam dor abdominal, disfagia e/ou impactação alimentar eventual. Os achados endoscópicos incluíram estrias verticais em 14 pacientes (48 por cento), pontilhado branco em 12 (41 por cento), anéis circulares em 2 (7 por cento) e esofagite erosiva em 3 (10 por cento). Em sete pacientes a endoscopia foi normal (24 por cento). O tratamento incluiu fluticasona tópica em 19 pacientes e restrição dietética em 7. Os pacientes acompanhados apresentaram resposta favorável ao tratamento, com melhora ou remissão dos sintomas. Onze pacientes que foram submetidos a endoscopia de controle pós-tratamento apresentaram diminuição significativa do número de eosinófilos no esôfago. CONCLUSÕES: A esofagite eosinofílica deve ser considerada quando há sintomas de refluxo, que não respondem ao tratamento habitual. Os exames endoscópicos devem ser acompanhados de biopsias com análise detalhada do número de eosinófilos.

BACKGROUND: Eosinophilic esophagitis is a recently described entity with esophageal symptoms like gastroesophageal reflux disease and significant esophageal eosinophilic infiltration. AIM: To present our clinical series of 29 children with eosinophilic esophagitis, describing the clinical and diagnostic features, treatment and outcome. METHODS: We describe 29 patients (22 boys), 1-18 years-old, with 20 eosinophils per high-power field in esophageal biopsy specimens and absence of eosinophilic inflammation in the stomach and duodenum. Evaluation of the clinical, endoscopic and histologic findings, treatment and outcome was undertaken. RESULTS: The most common presenting symptoms included vomiting in 15 patients (52 percent) and abdominal pain in 11 patients (38 percent). Children under the age of 4 years presented with feeding disorder and failure to thrive. Patients between 5 and 8 years of age presented commonly with abdominal pain or symptoms that may be associated with reflux (heartburn and/or vomiting). Patients over the age of 8 presented most often with abdominal pain, dysphagia and occasional food impaction. Endoscopic features included vertical furrowing in 14 patients (48 percent), whitish papules in 12 (41 percent), corrugated rings in 2 patients (7 percent) and esophageal erosions in 3 patients (10 percent). In seven patients endoscopy was normal (24 percent). Treatment included swallowed fluticasone propionate in 19 patients and restriction diet in 7 patients. Patients who returned for follow-up had either improvement or remission of symptoms. After treatment, endoscopic biopsies were repeated in 11 patients, and a significant decrease in esophageal eosinophil counts was observed. CONCLUSIONS: The diagnosis of eosinophilic esophagitis must be considered when symptoms of reflux do not respond to conventional treatment. Upper gastrointestinal endoscopy must be complemented by a detailed analysis of histologic findings and eosinophil...