Is neurodevelopment impaired in Brazilian children with intestinal failure on prolonged parenteral nutrition? A single center study.

PURPOSE: To assess the neurodevelopment outcomes of children younger than 42 months of age with intestinal failure (IF) using prolonged parenteral nutrition (PN) followed by a Pediatric Multidisciplinary Intestinal Rehabilitation Program from a public tertiary hospital in Brazil. METHODS: Bayley III scale was administered in children aged 2 to 42 months with IF and receiving PN for more than 60 days. Composite scores in cognitive, motor, and language domains were analyzed. Developmental delay was defined as a performance 2 standard deviations (SD) below the average at the 3 domains. Association between Bayley III composite scores and clinical variables related to IF were tested. RESULTS: Twenty-four children with median (IQR) age of 17.5 months (9-28.5) were studied, 58.3% were male. Developmental delay was found in 34%, 33% and 27% of the patients in cognitive, motor, and language domains, respectively. There was no significant association between the Bayley-III composite scores and length of hospitalization, prematurity, and number of surgical procedures with anesthesia. CONCLUSION: The study demonstrated impairments in the cognitive, motor and language domains in approximately one-third of young patients with IF on prolonged PN.

Consecutive Liver and Bone Marrow Transplantation for Erythropoietic Protoporphyria: Case Report and Literature Review.

BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare inherited disease of heme biosynthesis resulting in the accumulation of protoporphyrin, characterized by liver failure in a minority of cases. Although liver transplant (LT) is the therapeutic strategy for advanced hepatic disease, it does not correct the primary defect, which leads to recurrence in liver graft. Thus, hematopoietic stem cell transplantation (HSCT) is an approach for treating EPP. METHODS: We aim to describe the first sequential LT and HSCT for EPP performed in Latin America, besides reviewing the present-day literature. RESULTS: The patient, a 13-year-old female with a history of photosensitivity, presented with symptoms of cholestatic and hepatopulmonary syndrome and was diagnosed with EPP. Liver biopsy demonstrated cirrhosis. She was submitted to a successful LT and showed improvement of respiratory symptoms. However, she had disease recurrence on the liver graft. She underwent a myeloablative HSCT using a matched unrelated donor, conditioning with BuCy (busulfan and cyclophosphamide), and GvHD (graft vs. host disease) prophylaxis with ATG (thymoglobulin), tacrolimus and methotrexate. Neutrophil engraftment occurred on D+18. She has presented mixed chimerism, but normalization of PP levels, being 300 days after HSCT, in good state of health and normal liver function. CONCLUSIONS: Consecutive LT and HSCT for EPP is a procedure that has been described in 10 cases in the literature and, even though these patients are a highly diversified population, studies have shown favorable results. This concept of treatment should be considered in patients with established liver disease.

Daily Vitamin D Supplementation Improves Vitamin D Deficiency in Patients With Chronic Liver Disease.

OBJECTIVE: The objective of this article is to evaluate the response to 6000 IU oral cholecalciferol (OC) treatment in children with chronic liver disease (CLD) and 25(OH)D deficiency. METHODS: This historical cohort included non-transplanted CLD patients younger than 18 years old, which were analyzed for serum 25(OH)D, liver function, bone metabolism, Child-Pugh classification, and anthropometry. Patients with 25(OH)D deficiency (defined as 25(OH)D < 20 ng/mL) who received 6000 IU/day of OC were analyzed pre- and post-intervention, and considered responders if 25(OH)D > 20 ng/mL after at least 60 days. We compared clinical and laboratory data from patients with and without 25(OH)D deficiency, responders and nonresponders. RESULTS: We studied 96 patients, of which 57.2% had biliary atresia. The prevalence of 25(OH)D deficiency was 67.7% (65/96). These patients were younger ( P < 0.001), had higher Child-Pugh scores ( P < 0.001), higher levels of total bilirubin (TB) ( P < 0.001), gamma-glutamyl transferase ( P < 0.001), and alkaline phosphatase ( P = 0.002), as well as lower levels of phosphorus ( P = 0.009) compared with patients without 25(OH)D deficiency. The median treatment length was 126 days (70-307 days). At the end of treatment, we observed a higher median of 25(OH)D ( P < 0.001), and lower median of parathyroid hormone (PTH) ( P = 0.023). Nine patients (29%) restored 25(OH)D to normal range; they had lower Child-Pugh score ( P = 0.001), lower TB levels ( P = 0.001), and higher level of phosphorus ( P = 0.003) after treatment. CONCLUSION: Despite an increase in 25(OH)D and decrease in PTH levels, 6000 IU/day of OC was not sufficient to restore 25(OH)D deficiency in most of the patients in this study.

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.

Outcomes of the First 54 Pediatric Patients on Long-Term Home Parenteral Nutrition from a Single Brazilian Center.

OBJECTIVES: Data on multidisciplinary programs dedicated to home parenteral nutrition (HPN) in Latin America are limited. This study describes the results of the first multidisciplinary pediatric intestinal rehabilitation program for HPN at a public tertiary hospital in Brazil. METHODS: We retrospectively reviewed patients aged 0-18 years with intestinal failure (IF) who required parenteral nutrition (PN) for >60 days between January/2014 and December/2020. RESULTS: Fifty-four patients were discharged on HPN (15 achieved enteral autonomy, 34 continued on HPN at the end of the study, 1 underwent intestinal transplantation, and 4 died). The median (IQR) age at the study endpoint of patients who achieved enteral autonomy was 14.1 (9.7-19) versus 34.7 (20.4-53.9) months in those who did not achieve enteral autonomy. Overall prevalence of catheter-related thrombosis was 66.7% and catheter-related bloodstream infection rate was 0.39/1000 catheter-days. Intestinal failure-associated liver disease (IFALD) was present in 24% of all patients; none of the patients who achieved enteral autonomy had IFALD. All patients showed significant improvement in anthropometric parameters during the HPN period. The sociodemographic characteristics of the patients' family members were mothers less than 20 years old (7.5%), schooling time more than 10 years (55.5%), and household income between 1 and 3 times the minimum wage (64.8%). The 5-year survival rate for HPN is 90%, and 27.7% of patients achieve enteral autonomy. CONCLUSION: The treatment of pediatric patients with IF followed by a multidisciplinary pediatric intestinal rehabilitation program with HPN is feasible and safe in the Brazilian public health system.

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.

Severity of Ascites Is Associated with Increased Mortality in Patients with Cirrhosis Secondary to Biliary Atresia.

BACKGROUND: Very few prior studies have investigated the presence of ascites as a prognostic factor in children with cirrhosis. To the best of our knowledge, there are no prior studies evaluating the relationship between severity of ascites and patient survival in children with biliary atresia and cirrhosis. AIMS: To evaluate the association between severity of ascites and survival of children with cirrhosis and biliary atresia. METHODS: All children with cirrhosis secondary to biliary atresia evaluated at our institution from 2000 to 2014 were included in this study. Patients were classified into four groups: NA = no ascites; A1 = grade 1 ascites; A2 = grade 2 ascites; and A3 = grade 3 ascites. The primary endpoint of the study was mortality within the first year after patient inclusion. Ninety-day mortality was also evaluated. Prognostic factors related to both endpoints also were studied. RESULTS: One-year patient survival for NA was 97.1%, versus 80.8% for A1, versus 52% for A2, versus 13.6 for A3 (p < 0.001). The presence of ascites increased mortality by 17 times. In the multivariate analysis, clinically detectable ascites (HR 3.14, 95% CI 1.14-8.60, p = 0.026), lower sodium (HR 1.15, 95% CI 1.04-1.27, p = 0.006), higher bilirubin (HR 1.06, 95% CI 1.00-1.12, p = 0.023), and higher PELD score (HR 1.05, 95% CI 1.02-1.08, p = 0.001) were all associated with decreased survival. Lower serum sodium (HR 1.20, 95% CI 1.09-1.32, p < 0.001) and higher PELD score (HR 1.03, 95% CI 1.001-1.063, p = 0.043) were associated with increased 90-day mortality. CONCLUSIONS: Clinically detectable ascites is associated with decreased 1-year survival of children with biliary atresia. These patients should be treated with caution and prioritized for liver transplantation.

Autoimmune hepatitis in 828 Brazilian children and adolescents: clinical and laboratory findings, histological profile, treatments, and outcomes / Hepatite autoimune em 828 crianças e adolescentes brasileiros: achados clínicos e laboratoriais, perfil histológico, tratamentos e resultados

Abstract Objective: This large study with a long-term follow-up aimed to evaluate the clinical presentation, laboratory findings, histological profile, treatments, and outcomes of children and adolescents with autoimmune hepatitis. Methods: The medical records of 828 children and adolescents with autoimmune hepatitis were reviewed. A questionnaire was used to collect anonymous data on clinical presentation, biochemical and histological findings, and treatments. Results: Of all patients, 89.6% had autoimmune hepatitis-1 and 10.4% had autoimmune hepatitis-2. The female sex was predominant in both groups. The median age at symptom onset was 111.5 (6; 210) and 53.5 (8; 165) months in the patients with autoimmune hepatitis 1 and autoimmune hepatitis-2, respectively. Acute clinical onset was observed in 56.1% and 58.8% and insidious symptoms in 43.9% and 41.2% of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively. The risk of hepatic failure was 1.6-fold higher for autoimmune hepatitis-2. Fulminant hepatic failure occurred in 3.6% and 10.6% of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively; the risk was 3.1-fold higher for autoimmune hepatitis-2. The gamma globulin and immunoglobulin G levels were significantly higher in autoimmune hepatitis-1, while the immunoglobulin A and C3 levels were lower in autoimmune hepatitis-2. Cirrhosis was observed in 22.4% of the patients; biochemical remission was achieved in 76.2%. The actuarial survival rate was 93.0%. A total of 4.6% underwent liver transplantation, and 6.9% died (autoimmune hepatitis-1: 7.5%; autoimmune hepatitis-2: 2.4%). Conclusions: In this large clinical series of Brazilian children and adolescents, autoimmune hepatitis-1 was more frequent, and patients with autoimmune hepatitis-2 exhibited higher disease remission rates with earlier response to treatment. Patients with autoimmune hepatitis-1 had a higher risk of death.

Resumo Objetivo: Este estudo com acompanhamento de longo prazo visou a avaliar o quadro clínico, os achados laboratoriais, o perfil histológico, os tratamentos e os resultados de crianças e adolescentes com hepatite autoimune. Métodos: Foram analisados os prontuários médicos de 828 crianças e adolescentes com HAI. Foi usado um questionário para coletar os dados anônimos sobre o quadro clínico, os achados bioquímicos e histológicos e os tratamentos. Resultados: De todos os pacientes, 89,6% tinham hepatite autoimune-1 e 10,4% hepatite autoimune-2. O sexo feminino foi predominante nos dois grupos. A idade média no início dos sintomas foi 111,5 (6; 210) e 53,5 (8; 165) meses nos pacientes com hepatite autoimune-1 e hepatite autoimune-2, respectivamente. Foi observado início clínico agudo em 56,1% e 58,8% e sintomas insidiosos em 43,9% e 41,2% dos pacientes com hepatite autoimune-1 e hepatite autoimune-2, respectivamente. A probabilidade de insuficiência hepática foi 1,6 vezes maior para hepatite autoimune-2; 3,6% e 10,6% dos pacientes com hepatite autoimune-1 e hepatite autoimune-2, respectivamente, apresentaram insuficiência hepática fulminante; o risco foi 3,1 vezes maior para hepatite autoimune-2. Os níveis de gamaglobulina e imunoglobulina G foram significativamente maiores nos pacientes com hepatite autoimune-1, ao passo que os níveis de imunoglobulina A e C3 foram menores em pacientes com hepatite autoimune-2; 22,4% dos pacientes apresentaram cirrose e a remissão bioquímica foi atingida em 76,2%. A taxa de sobrevida atuarial foi de 93,0%. Um total de 4,6% pacientes foram submetidos a transplante de fígado e 6,9% morreram (hepatite autoimune-1: 7,5%; hepatite autoimune-2: 2,4%). Conclusões: Nesta grande série clínica de crianças e adolescentes brasileiros, a hepatite autoimune-1 foi mais frequente e os pacientes com hepatite autoimune-2 mostraram maiores taxas de remissão da doença com respostas mais rápidas aos tratamentos. Os pacientes com hepatite autoimune-1 apresentaram maior risco de óbito.

Autoimmune hepatitis in 828 Brazilian children and adolescents: clinical and laboratory findings, histological profile, treatments, and outcomes.

OBJECTIVE: This large study with a long-term follow-up aimed to evaluate the clinical presentation, laboratory findings, histological profile, treatments, and outcomes of children and adolescents with autoimmune hepatitis. METHODS: The medical records of 828 children and adolescents with autoimmune hepatitis were reviewed. A questionnaire was used to collect anonymous data on clinical presentation, biochemical and histological findings, and treatments. RESULTS: Of all patients, 89.6% had autoimmune hepatitis-1 and 10.4% had autoimmune hepatitis-2. The female sex was predominant in both groups. The median age at symptom onset was 111.5 (6; 210) and 53.5 (8; 165) months in the patients with autoimmune hepatitis 1 and autoimmune hepatitis-2, respectively. Acute clinical onset was observed in 56.1% and 58.8% and insidious symptoms in 43.9% and 41.2% of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively. The risk of hepatic failure was 1.6-fold higher for autoimmune hepatitis-2. Fulminant hepatic failure occurred in 3.6% and 10.6% of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively; the risk was 3.1-fold higher for autoimmune hepatitis-2. The gamma globulin and immunoglobulin G levels were significantly higher in autoimmune hepatitis-1, while the immunoglobulin A and C3 levels were lower in autoimmune hepatitis-2. Cirrhosis was observed in 22.4% of the patients; biochemical remission was achieved in 76.2%. The actuarial survival rate was 93.0%. A total of 4.6% underwent liver transplantation, and 6.9% died (autoimmune hepatitis-1: 7.5%; autoimmune hepatitis-2: 2.4%). CONCLUSIONS: In this large clinical series of Brazilian children and adolescents, autoimmune hepatitis-1 was more frequent, and patients with autoimmune hepatitis-2 exhibited higher disease remission rates with earlier response to treatment. Patients with autoimmune hepatitis-1 had a higher risk of death.

The first episode of spontaneous bacterial peritonitis is a threat event in children with end-stage liver disease.

OBJECTIVE: Studies on native liver survival (NLS) after the first episode of spontaneous bacterial peritonitis (SBP) are rare. Our objective was to evaluate NLS in children up to 1 year after SBP. METHODS: A historical cohort study of 18 children followed after the first episode of SBP was conducted. NLS, in-hospital mortality, causes of death, and rate of multidrug-resistant organisms were reported. RESULTS: Biliary atresia was the most prevalent diagnosis (72.2%); all were Child-Pugh C, and the median age was 1.0 year. The probability of NLS was 77.8, 27.8, and 11.1% at 1, 3 and 6 months, respectively. At 9 months, no child had the native liver. In-hospital mortality was 38.9%, and the main causes of death were septic shock and acute-on-chronic liver failure. Escherichia coli was the predominant organism cultured. Multidrug-resistant organisms were not detected. The cumulative probability of NLS was 77.8% at 1 month, 27.8% at 3 months, and 11.1% at 6 months. At 9-month follow-up, none of children had their native liver. Ascites PMN count cell more than 1000 cells/mm, positive ascites culture, and prolonged international normalized ratio reached a significant value as predictive factors of NLS and were selected for multivariate analysis. We did not identify independent predictors of survival. CONCLUSION: Development of SBP was a late event in children and had a high effect on NLS.

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.

Variability index of tacrolimus serum levels in pediatric liver transplant recipients younger than 12 years: Non-adherence or risk of non-adherence?

MLVI has been used to assess adherence. To determine the MLVI in children <12 years of age at transplantation and to identify demographic correlates and consequences for the graft. This is a retrospective study of 50 outpatients (4.0 ± 3.5 years), at least 13-month post-liver transplantation. The outcomes evaluated were MLVI, ALT > 60 IU/L, ACR, death, and graft loss. We analyzed demographic and socioeconomic characteristics, indication for transplantation, and type of donor. Student's t test and the chi-square test were used. Statistical significance was set at P ≤ .05. Seventy-two percent were infants or preschoolers, 62% biliary atresia. Seventy-four percent of the mothers had middle-school education, and 54% of the families had an income ≤3632.4 US$/y. Twenty-two (44%) patients had a MLVI ≥ 2 SD; this was more prevalent in families with higher incomes (P = .045). ALT levels > 60 IU/L were more common in MLVI ≥ 2 SD group (P = .035). ACR episodes were similar between groups (P = 1.000). No patient died or lost the graft. MLVI ≥ 2 SD may be an indicator of the risk of medication non-adherence.

Neonatal Liver Failure and Congenital Cirrhosis due to Gestational Alloimmune Liver Disease: A Case Report and Literature Review.

Neonatal liver failure (NLF) is a major cause of neonatal morbidity and mortality, presenting as acute liver failure and/or congenital cirrhosis. Many affected patients show antenatal signs of fetal injury. There are several causes of NLF and early diagnosis is mandatory to elucidate the etiology and determine a specific treatment or the best management strategy. Gestational alloimmune liver disease associated with neonatal hemochromatosis (GALD-NH) is a rare but potentially treatable cause of NLF. It should be considered in any neonate with fetal signs of disease and postnatal signs of liver failure with no other identifiable causes. GALD-NH is often diagnosed late and patients are therefore referred late to specialized centers, delaying treatment. This case highlights the consequences of late diagnosis and treatment of GALD-NH and emphasizes the importance of a high grade of suspicion of this disease in order to refer the patient to a specialized center soon enough to perform the appropriate treatment.

Paracrine Effects of Bone Marrow Mononuclear Cells in Survival and Cytokine Expression after 90% Partial Hepatectomy.

Acute liver failure is a complex and fatal disease. Cell-based therapies are a promising alternative therapeutic approach for liver failure due to relatively simple technique and lower cost. The use of semipermeable microcapsules has become an interesting tool for evaluating paracrine effects in vivo. In this study, we aimed to assess the paracrine effects of bone marrow mononuclear cells (BMMC) encapsulated in sodium alginate to treat acute liver failure in an animal model of 90% partial hepatectomy (90% PH). Encapsulated BMMC were able to increase 10-day survival without enhancing liver regeneration markers. Gene expression of Il-6 and Il-10 in the remnant liver was markedly reduced at 6 h after 90% PH in animals receiving encapsulated BMMC compared to controls. This difference, however, was neither reflected by changes in the number of CD68+ cells nor by serum levels of IL6. On the other hand, treated animals presented increased caspase activity and gene expression in the liver. Taken together, these results suggest that BMMC regulate immune response and promote apoptosis in the liver after 90% PH by paracrine factors. These changes ultimately may be related to the higher survival observed in treated animals, suggesting that BMMC may be a promising alternative to treat acute liver failure.

Encapsulated platelets modulate kupffer cell activation and reduce oxidative stress in a model of acute liver failure.

Acute liver failure (ALF) is characterized by massive hepatocyte cell death. Kupffer cells (KC) are the first cells to be activated after liver injury. They secrete cytokines and produce reactive oxygen species, leading to apoptosis of hepatocytes. In a previous study, we showed that encapsulated platelets (PLTs) increase survival in a model of ALF. Here, we investigate how PLTs exert their beneficial effect. Wistar rats submitted to 90% hepatectomy were treated with PLTs encapsulated in sodium alginate or empty capsules. Animals were euthanized at 6, 12, 24, 48, and 72 hours after hepatectomy, and livers were collected to assess oxidative stress, caspase activity, and gene expression related to oxidative stress or liver function. The number of KCs in the remnant liver was evaluated. Interaction of encapsulated PLTs and KCs was investigated using a coculture system. PLTs increase superoxide dismutase and catalase activity and reduce lipid peroxidation. In addition, caspase 3 activity was reduced in animals receiving encapsulated PLTs at 48 and 72 hours. Gene expression of endothelial nitric oxide synthase and nuclear factor kappa B were elevated in the PLT group at each time point analyzed. Gene expression of albumin and factor V also increased in the PLT group. The number of KCs in the PLT group returned to normal levels at 12 hours but remained elevated in the control group until 72 hours. Finally, PLTs modulate interleukin (IL) 6 and IL10 expression in KCs after 24 hours of coculture. In conclusion, these results indicate that PLTs interact with KCs in this model and exert their beneficial effect through reduction of oxidative stress that results in healthier hepatocytes and decreased apoptosis. Liver Transplantation 22 1562-1572 2016 AASLD.

Encapsulated Whole Bone Marrow Cells Improve Survival in Wistar Rats after 90% Partial Hepatectomy.

Background and Aims. The use of bone marrow cells has been suggested as an alternative treatment for acute liver failure. In this study, we investigate the effect of encapsulated whole bone marrow cells in a liver failure model. Methods. Encapsulated cells or empty capsules were implanted in rats submitted to 90% partial hepatectomy. The survival rate was assessed. Another group was euthanized at 6, 12, 24, 48, and 72 hours after hepatectomy to study expression of cytokines and growth factors. Results. Whole bone marrow group showed a higher than 10 days survival rate compared to empty capsules group. Gene expression related to early phase of liver regeneration at 6 hours after hepatectomy was decreased in encapsulated cells group, whereas genes related to regeneration were increased at 12, 24, and 48 hours. Whole bone marrow group showed lower regeneration rate at 72 hours and higher expression and activity of caspase 3. In contrast, lysosomal-ß-glucuronidase activity was elevated in empty capsules group. Conclusions. The results show that encapsulated whole bone marrow cells reduce the expression of genes involved in liver regeneration and increase those responsible for ending hepatocyte division. In addition, these cells favor apoptotic cell death and decrease necrosis, thus increasing survival.

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)

ERK 1/2 activation does not contribute to increased survival mediated by bone marrow cells after 90% partial hepatectomy in Wistar rats

We investigated the influence of bone marrow cells upon activation of ERK 1/2 in an animal model of 90% PH. Phosphorylated ERK 1/2 was evaluated by western blot. No differences were found between the groups. Thus, increased survival does not appear to be mediated by ERK 1/2 activation (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.