Human induced pluripotent stem cell derived hepatocytes provide insights on parenteral nutrition associated cholestasis in the immature liver.

Parenteral nutrition-associated cholestasis (PNAC) significantly limits the safety of intravenous parenteral nutrition (PN). Critically ill infants are highly vulnerable to PNAC-related morbidity and mortality, however the impact of hepatic immaturity on PNAC is poorly understood. We examined developmental differences between fetal/infant and adult livers, and used human induced pluripotent stem cell-derived hepatocyte-like cells (iHLC) to gain insights into the contribution of development to altered sterol metabolism and PNAC. We used RNA-sequencing and computational techniques to compare gene expression patterns in human fetal/infant livers, adult liver, and iHLC. We identified distinct gene expression profiles between the human feta/infant livers compared to adult liver, and close resemblance of iHLC to human developing livers. Compared to adult, both developing livers and iHLC had significant downregulation of xenobiotic, bile acid, and fatty acid metabolism; and lower expression of the sterol metabolizing gene ABCG8. When challenged with stigmasterol, a plant sterol found in intravenous soy lipids, lipid accumulation was significantly higher in iHLC compared to adult-derived HepG2 cells. Our findings provide insights into altered bile acid and lipid metabolizing processes in the immature human liver, and support the use of iHLC as a relevant model system of developing liver to study lipid metabolism and PNAC.

Impact of parenteral fat composition on cholestasis in preterm infants.

OBJECTIVES: Parenteral nutrition-associated liver disease (PNALD) is frequently detected in neonatal intensive care units. Parenteral lipid emulsion (PLE) content has been implicated in its pathogenesis. We aimed to study the effect on incidence and outcome of PNALD by replacing soy-based PLE with olive oil-based PLE in a population-based group of preterm infants. METHODS: All infants in Stockholm County with gestational age (GA) <30 weeks were included (n = 615). Infants who died before 28 days of age or were referred to or from other regions were excluded (n = 97). PNALD was defined as conjugated serum bilirubin ≥ 30 µmol/L and exceeding 20% of the total fraction on at least 2 occasions. Two different 2-year time periods were compared: before (SOY period) and after (OLIVE period) switching PLE. For each PNALD case, 2 GA-matched controls were randomly identified. RESULTS: PNALD incidence was 14.8% (37/250) in the SOY period and 12.7% (34/268) in the OLIVE period (P = 0.52). The OLIVE infants with PNALD had more risk factors, such as lower GA and longer periods of parenteral nutrition, for developing PNALD than the SOY infants. Nevertheless, treatment during the SOY period was an independent risk factor for PNALD in logistic regression analysis. CONCLUSIONS: Population-based incidence of PNALD is 1 of 7 in preterm infants with GA < 30 weeks. Changing from soy oil to olive oil-based PLE did not decrease the incidence of PNALD significantly. Olive oil-based PLE carries an equal or slightly decreased risk to develop PNALD compared with soy oil-based PLE.

[Use of fish oil lipid emulsions in hospitalized patients under 18 years old with abnormal results in liver tests associated with total parental nutrition]. / Uso de una emulsión lipídica de nutrición parenteral a base de ácidos grasos omega 3 en pacientes menores de 18 años hospitalizados con alteración de las pruebas hepáticas asociada a la nutrición parenteral total.

INTRODUCTION: Prolonged Total Parental Nutrition (TPN) is associated with life-threatening complications in the pediatric population, being cholestasis one of the most important ones. The source of fatty acids, the amount of phytosterols and the dose of lipids in the nutritional support, have been linked to the development of this complication. PURPOSE: To describe the behavior of liver function tests in pediatric patients with TPN where lipid based omega 3 fatty acids (OmegavenR) were used. METHODS: A retrospective research was made in a population of children under 18 years old where omega 3 fatty acids were used for a minimum of 8 days. Patients were initially classified into two groups: cholestasis and abnormal liver tests. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), direct bilirubin (DB) gamma glutamyl transferase (GGT) and alkaline phosphatase (AP) before and after treatment with OmegavenR was evaluated. RESULTS: 33 patients met the inclusion criteria. At the end of treatment with OmegavenR, 82.4% of patients who initially presented cholestasis showed resolution or improvement. The group of patients with abnormal liver tests 18.8% progressed to cholestasis. CONCLUSIONS: Our study suggests that the use of OmegavenR in pediatric patients with TPN and DB ≥ 2 mg/dL, seem to reverse or improve cholestasis while in patients with abnormal liver tests we still don't have clear effect.

Introducción: La Nutricion Parental Total (NPT) prolongada esta asociada con complicaciones potencialmente mortales en la poblacion pediatrica como lo es la colestasis. Dentro del soporte nutricional, la fuente de acidos grasos, el contenido de fitoesteroles y la dosis de lipidos se han relacionado con el desarrollo de esta complicacion. Objetivo: Describir el comportamiento de las pruebas hepaticas en pacientes pediatricos con NPT en quienes se uso lipidos a base de acidos grasos omega 3 (omegavenR). Métodos: Estudio retrospectivo, en menores de 18 anos con tratamiento intravenoso por minimo 8 dias con acidos grasos omega 3. Los pacientes fueron inicialmente clasificados en dos grupos: colestasis y alteracion de pruebas hepaticas. Se evaluo el comportamiento de la transaminasa glutamico oxalacetica (TGO), transaminasa glutamico piruvica (TGP), bilirrubina total (BT), bilirrubina directa, gama glutamil transferasa (GGT) y fosfatasa alcalina (FA) antes y despues del tratamiento con omegaven R. Resultados: 33 pacientes cumplieron los criterios de inclusion. Al finalizar la administracion de omegavenR, 82,4% de los pacientes que presentaron inicialmente colestasis mostraron resolucion o mejoria. En el grupo de pacientes con alteracion de pruebas hepaticas 18,8% progresaron a colestasis. Conclusiones: Nuestro estudio sugiere que el uso de omegaven R en pacientes pediatricos con NPT y BD ≥ 2 mg/dL, parece revertir o mejorar la colestasis, mientras que en pacientes con alteracion de pruebas hepaticas aun no se tiene claro su efecto.

Uso de una emulsión lipídica de nutrición parenteral a base de ácidos grasos omega 3 en pacientes menores de 18 años hospitalizados con alteración de las pruebas hepáticas asociada a la nutrición parenteral total / Use of fish oil lipid emulsions in hospitalized patients under 18 years old with abnormal results in liver tests associated with total parental nutrition

Introducción: La Nutrición Parental Total (NPT) prolongada está asociada con complicaciones potencialmente mortales en la población pediátrica como lo es la colestasis. Dentro del soporte nutricional, la fuente de ácidos grasos, el contenido de fitoesteroles y la dosis de lípidos se han relacionado con el desarrollo de esta complicación. Objetivo: Describir el comportamiento de las pruebas hepáticas en pacientes pediátricos con NPT en quienes se usó lípidos a base de ácidos grasos omega 3 (omegaven®). Métodos: Estudio retrospectivo, en menores de 18 años con tratamiento intravenoso por mínimo 8 días con ácidos grasos omega 3. Los pacientes fueron inicialmente clasificados en dos grupos: colestasis y alteración de pruebas hepáticas. Se evaluó el comportamiento de la transaminasa glutámico oxalacética (TGO), transaminasa glutámico pirúvica (TGP), bilirrubina total (BT), bilirrubina directa, gama glutamil transferasa (GGT) y fosfatasa alcalina (FA) antes y después del tratamiento con omegaven®. Resultados: 33 pacientes cumplieron los criterios de inclusión. Al finalizar la administración de omegaven®, 82,4% de los pacientes que presentaron inicialmente colestasis mostraron resolución o mejoría. En el grupo de pacientes con alteración de pruebas hepáticas 18,8% progresaron a colestasis. Conclusiones: Nuestro estudio sugiere que el uso de omegaven® en pacientes pediátricos con NPT y BD ≥ 2 mg/dL, parece revertir o mejorar la colestasis, mientras que en pacientes con alteración de pruebas hepáticas aun no se tiene claro su efecto (AU)

Introduction: Prolonged Total Parental Nutrition (TPN) is associated with life-threatening complications in the pediatric population, being cholestasis one of the most important ones. The source of fatty acids, the amount of phytosterols and the dose of lipids in the nutritional support, have been linked to the development of this complication. Purpose: To describe the behavior of liver function tests in pediatric patients with TPN where lipid based omega 3 fatty acids (Omegaven®) were used. Methods: A retrospective research was made in a population of children under 18 years old where omega 3 fatty acids were used for a minimum of 8 days. Patients were initially classified into two groups: cholestasis and abnormal liver tests. Levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), direct bilirubin (DB) gamma glutamyl transferase (GGT) and alkaline phosphatase (AP) before and after treatment with Omegaven® was evaluated. Results: 33 patients met the inclusion criteria. At the end of treatment with Omegaven®, 82.4% of patients who initially presented cholestasis showed resolution or improvement. The group of patients with abnormal liver tests 18.8% progressed to cholestasis. Conclusions: Our study suggests that the use of Omegaven® in pediatric patients with TPN and DB ≥ 2 mg/dL, seem to reverse or improve cholestasis while in patients with abnormal liver tests we still don't have clear effect (AU)

Avaliação e suporte nutricional na criança com colestase / Nutrition assessment and support of children with cholestasis

A colestase acomete 65% dos pacientes pediátricos com hepatopatia, sendo responsável por várias consequências clínicas, como: retenção hepática de substâncias excretadas pela bile, lesão hepática progressiva, má-absorção intestinal de gorduras e vitaminas lipossolúveis, anorexia e esteatorreia. Há risco subestimado de desnutrição nesses pacientes, que está associada a grande morbidade. Para classificar os pacientes quanto ao estado nutricional, usam-se os índices de avaliação do crescimento. Porém, considerando a condição clínica do paciente, que pode incluir visceromegalias e ascite, os índices que utilizam o peso na análise podem ser imprecisos. Nesses casos, o uso das medidas de pregas cutâneas e da circunferência braquial leva a avaliações mais fidedignas. O paciente com colestase exige suporte nutricional para compensar a má-absorção e possível desnutrição. Esse suporte inclui: aporte calórico elevado,ingestão proteica em níveis que não se induza hiperamonemia, oferta de ácidos graxos majoritariamente de cadeia média, suplementação de vitaminas lipossolúveis (A,D, E e K) e alguns minerais. Adequado suporte nutricional pode evitar a progressão rápida da doença hepática, facilitar o processo de cicatrização, aumentar a função imunológica, além de prevenir várias consequências da deficiência de uma variedade de micro ou macronutrientes que pode ocorrer na colestase...

Cholestasis affects 65% of pediatric patients with liver disease and it is responsible for several clinical consequences such as liver retention of substances excreted in bile, progressive liver damage, intestinal malabsorption of fats and fat-soluble vitamins, anorexia, and steatorrhea. There is an underestimated risk of malnutrition in these patients, whichis associated with high morbidity. Indexes of growth evaluation are used to classify patients according to their nutritional status. However, considering the clinical condition of the patient, which may include increase of some organs?s size and ascites, the indices that use weight in the analysis may be inaccurate. In these cases, the use of measures of skinfold thickness and arm circumference leads to more reliable evaluations. The patient with cholestasis requires nutritional support to compensate the malabsorption and possible malnutrition. This support includes: caloric intake higher than usual, protein intake at levels which do not induce hyperammonemia, an offer of fatty acids predominantly mediumchain (absorbed independently from the action of micellar bile acids), supplementation of fat-soluble vitamins (A, D, E and K) and some minerals. An adequate nutritional support can avoid the fast progression of liver disease, facilitate the healing process, and enhance immune function, besides of preventing many consequences from the deficiency of a variety of micro or macronutrients which may happens in cholestasis...

Do patients with lymphoedema cholestasis syndrome 1/Aagenaes syndrome need dietary counselling outside cholestatic episodes?

BACKGROUND & AIMS: Patients with lymphoedema cholestasis syndrome 1/Aagenaes Syndrome need a fat reduced diet when cholestatic. We wanted to assess the need for dietary counselling outside cholestatic episodes, and hypothetized that no counselling was needed. METHODS: Fifteen patients above 10 years of age without symptoms of cholestasis were compared with a sex and age matched control group. Diet from a four-day weighed record and blood samples were compared between the two groups and with general Norwegian recommendations. RESULTS: The patients had a similar diet to the healthy controls, except for statistically significant lower intake of energy from total fat (p=0.04) and saturated fat (0.02), and fish (0.05). The patients met the dietary recommendations for macronutrients, except for saturated fat, monounsaturated fat, refined sugar and fibre. Supplements were needed to meet the micronutrient recommendations. Patients had a significantly lower serum level of alpha-tocopherol (0.01) compared with the control group, and the serum 25-OH D level was below reference ranges. CONCLUSIONS: The patients would benefit from counselling on fat quality, carbohydrates including fibre intake, and individual needs for vitamins D and E. To secure serum 25-OH D and alpha-tocopherol levels within reference ranges, regular examinations to determine the need for supplementary vitamins D and E are recommended.

Indicaciones y uso de la nutrición parenteral en pediatría / Parenteral nutrition in infants and children

La nutrición parenteral (NP) es la administración intravenosa de nutrientes a pacientes que no pueden tolerar una cantidad suficiente de alimentación enteral y que están malnutridos o en riesgo de estarlo. El desarrollo de la técnica ha estado íntimamente ligado a su uso en niños desde las primeras experiencias clínicas a mediados de 1960. Desde entonces se ha convertido en una pieza clave en el tratamiento de niños gravemente enfermos, o en el postoperatorio de grandes cirugías abdominales así como en el tratamiento de los recién nacidos pretérmino de muy bajo peso. Los avances en las soluciones de macro y micronutrientes, el mejor conocimiento de los requerimientos, así como las mejoras en accesos venosos y cuidado de los mismos han permitido disminuir el número de complicaciones, aunque todavía son frecuentes. En aquellos niños en lo que la duración de la NP se prevé prolongada y que tienen una situación clínica estable, lo más conveniente es incluir al niño en un programa de nutrición parenteral domiciliaria (NPD). Se revisan en este artículo las indicaciones del uso de la NP, las características de los accesos venosos, los requerimientos de nutrientes y la composición de la solución de NP, así como aspectos relacionados con la técnica de la NP. De forma más breve, se repasan también las complicaciones más habituales, su abordaje diagnóstico y terapéutico. Por último se dan unas pautas precisas sobre la monitorización de la NP y se señalan las características de los programas de NPD (AU)

Nutrition management in chronic liver disease.

Liver has a central role in nutritional homeostasis and any liver disease leads to abnormalities in nutrient metabolism and subsequent malnutrition. All children with chronic liver disease (CLD) must undergo a periodic nutritional assessment--medical history, anthropometry esp. skinfold thickness and mid-arm circumference, and biochemical estimation of body nutrients. Nutritional rehabilitation is catered to the individual child but generally the caloric intake is increased to 130% of RDA by adding glucose polymers and/or MCT oil (coconut oil) with essential fatty acid supplementation (sunflower oil). The enteral route is preferred and occasionally nasogastric and/or nocturnal feeding are required to ensure an adequate intake. Proteins rich in branched chain amino acids are given in moderation (2-3 gm/kg/day) in compensated cirrhotics unless encephalopathy occurs when protein restriction may be necessary (1 gm/kg/day). Fat-soluble vitamins are supplemented in large quantities esp. in cholestasis along with other vitamins and minerals. Dietary therapy is the mainstay of management of some metabolic liver diseases and may be curative in disorders like galactosemia, fructosemia and glycogen storage disorders. Pre and postoperative nutritional support is an important factor in improving survival after liver transplantation.

Nutrición parenteral total ciclada en niños

El soporte nutricional con nutrición parenteral total (NPT) ha permitido que la sobrevida de muchos niños con disfunción intestinal sea mayor. la gama de disfunción y enfermedad hepática grave relacionada con el uso de la NPT ha emergido como consecuencia del uso de NPT por tiempo prolongado. La colestasis intrahepática, es uno de los problemas más frecuentes y ocacionalmente graves asociados con NPT prolongada. La NPT ciclada (NPT) referida también como intermitente o discontínua, disminuye la incidencia de complicaciones provocadas por NPT prolongada. Muchas ventajas teóricas y prácticas sicológicas por el uso de la NPTC han sido descritas. Este artículo describe las indicaciones, las deferencias maneras de ciclar, la monitori-zación y las complicaciones por la adminis-tración de NPTC en niños.

Essential fatty acid deficiency associated with the use of a medium-chain-triglyceride infant formula in pediatric hepatobiliary disease.

Serum phospholipid fatty acid patterns were determined by gas chromatography in four infants with hepatobiliary disease receiving a formula with a high content of medium-chain-triglyceride (MCT) oil. All four infants demonstrated signs of essential fatty acid deficiency, characterized by decreased arachidonic acid and increased palmitoleic and oleic acids. All had substantial concentrations of the pathologic triene 5,8,11-eicosatrienoic acid. Three of four had decreased linoleic acid concentrations and abnormal ratios of triene to tetraene (5,8,11-eicosatrienoic acid: arachidonic acid), greater than 0.38. One patient may have experienced growth failure due to abnormal essential fatty acid status. Infants with the potential for fat malabsorption should only receive MCT-oil feedings with well above the generally recommended requirements for linoleic acid (3% of total caloric intake).

[The effect of a diet enriched with food fibers and polyunsaturated fatty acids on the composition of the lipid components in the enterohepatic circulation system in rabbits with cholestasis]. / Vliianie ratsiona, obogashchennogo pishchevymi voloknami i polinenasyshchennymi zhirnymi kislotami, na sostav lipidnykh komponentov v sisteme pechenochno-kishechnoi tsirkuliatsii u krolikov pri kholestaze.

In experiments on rabbits that had undergone partial constriction of the choledochus, the development of calculous hepatocholecystitis was observed in a half of the operated on animals. No biliary calculi were detected in the animals that received the ration enriched with food vegetable fibres, beta-sitosterol and linoleic polyunsaturated fatty acids after similar operations.

Pitfalls in diagnosing galactosemia: false negative newborn screening following red blood cell transfusion.

Newborn galactosemia screening programs using the fluorescence spot test to detect red cell galactose-1-phosphate uridyltransferase activity are prone to inaccuracy if the screened infants have received blood transfusions. We describe an infant with galactosemia who received packed red cell transfusions in the first few days of life and was misdiagnosed after an initial positive screening test result. Although the patient was thought to have cytomegaloviral hepatitis, a percutaneous liver biopsy helped direct the evaluation toward identifying the galactosemia carrier state in both parents. This case report illustrates the need for careful consideration of the patient's history of transfusion of blood products when evaluating newborn screening results.

Short- and long-term vitamin A treatment in children with cholestasis.

Newborns have limited reserve supplies of vitamin A. Infants with chronic cholestasis are in a precarious nutritional state because of their limited ability to build these stores even though the vitamin is present in their diet. In this study, we investigated liver concentrations of vitamin A in 30 children with extrahepatic biliary atresia. We demonstrate that correction of the deficiency occurs after intramuscular administration of a water-miscible solution of retinyl palmitate (100,000 IU, or 30 mg retinol equivalent). Furthermore, we evaluated the effect of vitamin A injections on liver and blood concentrations in nine children with chronic cholestasis over a 1-y period. We conclude this treatment is efficient and is well tolerated.

A dietary regimen alters hepatocyte plasma membrane lipid fluidity and ameliorates ethinyl estradiol cholestasis in the rat.

A dietary regimen which induces hepatic fatty acyl desaturase activities increases the lipid fluidity of hepatocyte plasma membranes, both in normal rats and in animals treated with ethinyl estradiol to produce cholestasis. In the cholestatic animals the fluidity change is accompanied by a significant increase in bile flow rate of approx. 33%.

[Change in the exocrine function of the liver after cholecystectomy under the influence of diet therapy]. / Izmenenie vneshnesekretornoi funktsii pecheni u bol'nykh posle kholetsistéktomii pod vliianiem dietoterapii.

In patients with sustained cholecystectomy the content of the basic bile components (cholesterol, cholic acid, total phosphorus) was measured. The cholate-cholesterol coefficient, enabling it to a certain degree to evaluate the lithogeneity of the bile, was calculated. The cholesterol concentration in the serum and bile was contrasted. A total of 104 patients were examined at different post-operative periodss and it was found that in 70 per cent of them the bile was not oversaturated with cholesterol. Two variants of the No. 5 diet were used--the sparing and fatty, differing in the amount of fat and carbohydrates. Under the effect of the No. 5 sparing diet a reduced serum cholesterol concentration was noted along with a noticeable rise of the cholic acid content in the bile with a not too brusque rise of the cholesterol level therein, which led to an increase of the cholate-cholesterol coefficient. Against the background of the treatment with a No. 5 fat diet in evidence was a diminution of the serum cholesterol content, a clearcut fall in the cholesteroland cholic acid concentration in the bile with a continuing fairly high cholate-chole sterol coefficient.

[Controlled trial with ACTH and corticosteroids in patients with cholestatic viral hepatitis]. / Ricerca controllata con ACTH e corticosteroidi in pazienti affetti da epatite virale ad impronta colostatica

Comparison was made between synthetic ACTH (tetracosactide), betamethasone and a normal paradigm (dietary management with glucose solutions, detoxicants and vitamins) over a period at least of 21 days in 27 patients with cholostatic viral hepatitis. Assessment of the clinical and laboratory parameters by means of both covariance and multivariance analysis showed that hormonal therapy offered no significant advantages with respect to the basic treatment protocol.