International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

BACKGROUND: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. METHODS: A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. RESULTS: Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients' age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: <1y, 36% (n = 46); 1-10y, 59% (n = 74); 11-16y, 3% (n = 4); and >16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. CONCLUSIONS: Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

Errores innatos del metabolism en un hospital pediátrico. Diferencias sustanciales entre la era pre y postcribado neonatal ampliado / Innate errors of metabolism in a pediatric hospital. Substantial differences between the extended neonatal pre- and post screening era

Introducción. Las aminoacidopatías son enfermedades metabólicas hereditarias (EMH) que sin diagnóstico ni tratamiento precoz pueden producir consecuencias graves, llegando incluso a la muerte. La introducción del programa de cribado neonatal mediante espectrometría de masas en tándem (MS/MS) pretende mejorar el pronóstico. El objetivo del estudio es comparar la evolución clínica de pacientes diagnosticados de aminoacidopatías en fase clínica frente a los resultantes del cribado neonatal. Material y métodos. Estudio descriptivo retrospectivo de pacientes diagnosticados de metabolopatías entre Enero de 2002 y Junio de 2015. El cribado ampliado de EIM mediante MS/MS se está empleando en nuestro centro desde abril de 2010. Resultados. Han sido diagnosticados en nuestra unidad en estos 13 años 245 casos de EMH. Agrupándolos por patologías: 152 trastornos del metabolismo de las proteínas, 27 trastornos del metabolismo de los carbohidratos, 33 trastornos del metabolismo lipídico, 12 enfermedades lisosomales, 2 enfermedades peroxisomales, 4 defectos congénitos de glicosilación de proteínas, 10 casos de enfermedad de Wilson y 5 de deficiencia de alfa-1 antitripsina. Del total de la serie, 19 pacientes son de origen magrebí (7,7%) y un 52 % de sexo femenino. De los casos que debutaron en cuidados intensivos pediátricos la mayoría de los pacientes requirieron apoyo agresivo, incluyendo ventilación mecánica y terapia de eliminación extracorpórea (7 diálisis peritoneal, 6 hemofiltración veno-venosa continua), así como fármacos vasoactivos. De todos los pacientes, sufrieron datos de shock 15 niños, fallo multiorgánico 6, grave insulto neurológico 8, coagulopatía 3 y fallo hepático agudo 3. Discusión. La descompensación aguda de una metabolopatía, como en otros EIM, es una emergencia metabólica que debemos diagnosticar y tratar precozmente, por su elevada morbimortalidad. La instauración del cribado ampliado ha logrado el tratamiento en fase presintomática y la identificación precoz de las descompensaciones agudas, lo cual ha contribuido al descenso de las mismas y a una clara reducción de mortalidad. Hay niños ya diagnosticados por cribado que pueden necesitar ingreso por descompensación y otros sin posibilidad de cribado que pueden requerir ingreso por debut (AU)

Introduction. Amino acid disorders are hereditary metabolic diseases (HMD) that may cause serious consequences, even death, without diagnosis or early treatment. The introduction of the neonatal screening program using tandem mass spectrometry (MS/MS) aims to improve the prognosis. This study has aimed to compare the clinical course of patients diagnosed of amino acid disorders in the clinical phase versus the results of neonatal screening. Material and methods. Retrospective descriptive study of patients diagnosed of metabolic disorders between January 2002 and June 2015. The extended screening of EIM by MS/ MS has been used in our center since April 2010. Results. A total of 245 cases of HMD has been diagnosed in our unit during these 13 years. Grouped by conditions: 152 protein metabolism disorders, 27 carbohydrate metabolism disorders, 33 lipid metabolism disorders, 12 lysosomal diseases, 2 peroxisomal diseases, 4 protein glycosylation congenital defects, 10 cases of Wilson disease and 5 alpha-1 antitrypsin deficiency. Nineteen out of the entire series were of origin Maghreb (7.7%) and 52% were women. Of the cases initiating in pediatric intensive care, most of the patients required aggressive support, including mechanical ventilation and extracorporeal elimination therapy (7 peritoneal dialysis, 6 continuous venovenous hemofiltration) and vasoactive drugs. Fifteen of all the patients suffered shock data, 6 multiorgan failure, 8 severe neurological insult, 3 coagulopathy, and 3 severe liver failure. Discussion. Acute decompensation of a metabolic disorder, as in other EIM is a metabolic emergency that should be diagnosed and treated early, due to its elevated morbidity- mortality. Initiation of extended screening has achieved treatment in the presymptomatic phase and early identification of acute decompensations, which has contributed to their decrease and to a clear reduction of mortality. There are children who have already been diagnosed by screening that may need hospitalization due to decompensations and others without possibility of screening that may require admission due to debut (AU)

Citrulina plasmática como marcador de pérdida de masa enterocitaria en la enfermedad celíaca en la infancia / Plasma citrulline as a marker of loss of enterocitary mass in coeliac disease in childhood

Introducción: La citrulina plasmática no está incorporada a las proteínas endógenas ni exógenas y constituye un teórico marcador de la atrofia vellositaria. El objetivo del estudio es relacionar los niveles plasmáticos de citrulina y arginina con la severidad de la afectación de la mucosa intestinal en pacientes celiacos. Material y métodos: Estudio transversal de cohortes en niños entre 16 meses y 14 años: 46 con enfermedad celíaca al diagnóstico; 9 celíacos siguiendo dieta sin gluten y 42 controles. Se determina concentración plasmática de aminoácidos, en mmol/L, y variables clínicas y analíticas asociadas. Resultados: No diferencias estadísticamente significativas en IMC, edad o función renal, con ligero incremento de esteatorrea en celíacos. Citrulina, arginina y glutamina plasmáticas significativamente más bajas en los casos (17,7 μmol/l, 38,7 μmol/l, 479,6 μmol/l respectivamente)que en controles (28,9 μmol/l, 56,2 μmol/l, 563,7μmol/l). Citrulina plasmática significativamente más baja en grados avanzados de atrofia (13,8 μmol/l vs 19,7μmol/l, p < 0,05), no así con el resto de aminoácidos. Discusión: La medida postabsortiva de citrulina plasmática constituye buen marcador de reducción de masa enterocitaria en celíacos con atrofia vellositaria; secundariamente disminución también de arginina. Grados bajos de alteración histológica de la biopsia intestinal son suficientes como para diferenciar su citrulina de los controles y además se puede afirmar que grados altos de lesión histológica tienen menor citrulina plasmática que grados bajos (AU)

Introduction: Plasma citrulline is not incorporated in endogenous or exogenous proteins so it is a theoretical marker of villous atrophy. Our aim was to correlate plasma citrulline levels with severity of villous atrophy inceliac patients. Methods: Observational case-control study longitudinal in children 16 month-old to 14 year-old: 48 with untreated celiac disease, 9 celiac children under gluten free diet and 35 non-celiac healthy children. Plasma amino acids concentration is determined, expressed inμmol/L, and so are other clinical and analytical data. Results: No statistically significative difference found in the referring to BMI, age or renal function. Small increase in fecal fat in celiac children. Citrulline, arginine and glutamine are significantly lower in cases (17.7μmol/l, 38.7 μmol/l, 479.6 μmol/l respectively) than in controls(28.9 μmol/l, 56.2 μmol/l, 563.7 μmol/l). Citrulline levels are significantly lower in the severe degrees of atrophy than in mild ones (13.8 μmol/l vs. 19.7 μmol/l, p <0.05), not happening so with rest of amino acids. Summary: Postabsortive mean of plasma citrulline is a good marker of reduction in enterocyte mass in celiac patients with villous atrophy; secondary reduction in plasma arginine too. Just a small histological alteration in intestinal biopsy is enough to differentiate citrulline incases and controls and besides it can be seen that high levels of atrophy present with lower plasma citrulline (AU)

Colectomía en pacientes pediátricos con colitis ulcerosa / Colectomy in paediatric patients with ulcerative colitis

Introducción: No son frecuentes los estudios descritos sobre fallo del tratamiento médico en colitis ulcerosa (CU) que conduce a la realización de colectomía. Material y métodos: Estudio retrospectivo desde 1984 hasta 2009 de pacientes diagnosticados de CU, menores de 14 años, sometidos a colectomía por falta de respuesta al tratamiento. Se clasifica en función de la cirugía en colectomía urgente y en electiva. Resultados: Colectomía efectuada en 14 pacientes pediátricos, el 26,9% del total de pacientes diagnosticados de CU. Edad al diagnóstico 7,8±4,0 años, inferior a 10 años en 8 casos y por debajo de 5 años en 5 pacientes. Todos los casos diagnosticados con menos de 5 años fueron colectomizados antes del sexto mes tras el diagnóstico. Se realiza una colectomía electiva en 5/14 y urgente en 9/14. Las complicaciones surgidas se dividen en precoces, por debajo de los 30 días tras colectomía, y tardías, pasado el primer mes. El tratamiento farmacológico en los casos de colectomía urgente abarca metilprednisolona por vía intravenosa (100%), tacrolimus por vía oral (55,5%), ciclosporina por vía oral/intravenoso (33,3%) einfliximab (33,3%). Los casos correspondientes a colectomía electiva corresponden al periodo1985-1998. Conclusiones: La influencia de la edad es determinante en el pronóstico. Todos los menores de5 años diagnosticados de CU terminaron colectomizados. La indicación de colectomía urgente fue realizada tras falta de respuesta al tratamiento con corticoide por vía intravenosa en combinación con potente agente inmunomodulador (tacrolimus, ciclosporina, infliximab). Los casos correspondientes a colectomía electiva sucedieron en el período anterior a 1999, cuando la terapéutica con fármacos de segunda línea era muy infrecuente, con lo que la remisión era excepcional (AU)

Introduction: There are not many studies published in the literature on failure of medical treatment in Ulcerative Colitis (UC) that leads to colectomy. Patients and methods: Retrospective study of patients under 14 years diagnosed with UC from1984 to 2009, who underwent colectomy due to lack of response to medical treatment. They are divided into urgent or elective surgery. Results: Colectomy performed in 14 paediatric patients (26.9% of total UC patients). Age at diagnosis 7.8±4.0 years, 8 of them younger than 10 years and 5 younger than 5 years. All cases diagnosed on patients less than 5 years of age required colectomy in the first 6 months after diagnosis. Elective colectomy was performed on 5/14 and urgent surgery in 9/14. The reported complications were divided into early (first 30 days after colectomy) and late. Pharmacological treatment in cases with urgent colectomy included methylprednisolone (100%), oral tacrolimus (55.5%), oral/intravenous cyclosporine (33.3%) and infliximab (33.3%). Cases of elective colectomy were all in the 1985—1998 period. Conclusions: The influence of age is a key factor for prognosis. All patients less than 5 year old ended up with colectomy. The main indication for urgent surgery was lack of response to treatment with intravenous steroids combined with a potent immunomodulator (tacrolimus, cyclosporine, infliximab). All cases of elective colectomy were performed before 1999, when second line medical treatment was very uncommon, making remission unlikely (AU)

Predicción de lesión histológica intestinal en pacientes pediátricos con enfermedad celíaca / Prediction of intestinal histological lesions in paediatric patients with coeliac disease

Introducción: Los marcadores séricos son de gran utilidad como indicadores de enfermedad celíaca (EC), si bien la biopsia intestinal sigue siendo el patrón oro para establecer el diagnóstico. La positividad de los anticuerpos antitransglutaminasa tisular humana de clase IgA (AATGt-IgA) y los anticuerpos antiendomisio IgA (AAE-IgA) se correlaciona con histología intestinal patológica. La atrofia vellositaria (Marsh 3) representa una característica fundamental para el diagnóstico de EC. El tipo correspondiente a Marsh 2 (hiperplasia críptica) es debatido como lesión propia de la EC. Objetivo: Comprobar el nivel de AATGt-IgA que corresponda a un valor predictivo positivo (VPP) de lesión histológica de 100% para el diagnóstico de EC. Material y métodos: Serie de 120 pacientes menores de 14 años sin déficit de IgA sometidos a biopsia intestinal con serología positiva tanto a AATGt-IgA como AAE-IgA. Para los AATGt- IgA según recomendación del fabricante se consideran valores positivos cifras ≥ 16 U/ml. Se establece el VPP de AATGt-IgA a diferentes puntos de corte. Resultados: La distribución de los hallazgos histológicos en relación con el punto de corte de AATGt-IgA pone de manifiesto el mayor número de lesiones patológicas a medida que aumenta los valores de AATGt-IgA. Con valores del punto de corte por encima de 7,5-10,6 se corresponde con Marsh 2 2,1% y Marsh 3 93,4%; por encima de 10,6 veces el punto de corte, todas las biopsias se catalogan como Marsh 3 (100%). El VPP considerando solo las lesiones Marsh 3 alcanza bajo valor (55%) con serología positiva a AATGt-IgA con valores comprendidos entre 16 y 67 U/ml (1 a 4,2 x punto de corte), y elevado valor (92%) para las concentraciones entre 68 y 118 U/ml (4,3 a 7,4 x punto de corte), y para los casos con 69-170 U/ml (7,5 a 10,6 x punto de corte) (93%). Por encima de 170 U/ml (> 10,6 x punto de corte) el VPP es 100%. Conclusiones: El uso de valores superiores al punto de corte recomendado lógicamente debe mejorar aún más la especificidad del test y su VPP. En el 31,6% de los pacientes con positividad para AATGt-IgA y AAE-IgA (38/120) hubiera sido posible diagnosticar la enfermedad sin biopsia intestinal al contar con VPP de 100%. Como existen diversos kits comerciales con distintos puntos de corte, no es posible la estandarización de los resultados, por lo que hay que ser muy cautos para establecer recomendaciones basadas en los valores de AATGt-IgA (AU)

Introduction: Serological markers are of great interest in coeliac disease (CD), although intestinal biopsy is still the gold standard for establishing the diagnosis. Tissue transglutaminase IgA antibodies (AATGt-IgA) and antiendomysial antibodies IgA (AAE-IgA) are closely correlated to intestinal damage observed in biopsies. Villous atrophy (Marsh 3) plays a major role in CD diagnosis. Marsh 2 stage (crypt hyperplasia) as a CD marker is still under debate. Objective: To ascertain an AATGt-IgA level that corresponds to a positive predictive value (PPV) of 100% for a histological CD diagnosis. Material and methods: A series of 120 patients younger than 14 years, non- IgA deficient, whounderwent an intestinal biopsy and were positive for both serological markers (AATGt-IgA andAAE-IgA). For AATGt-IgA, according to the manufacturer’s recommendations, a value greaterthan 16 IU/mL is considered as a positive value. The PPV of AATGt was determined for different cut-off points. Results: The histological findings distribution is directly correlated to the AATGt-IgA cut-off point. When the cut-off point is set above 7.5-10.6 times the commercial reference value, there is a 2.1% of Marsh 2 lessions and 93.4% of Marsh 3; above 10.6 times the reference value, all biopsies where Marsh 3 (100%). The PPV that considers Marsh 3 is (93.4%). The PPV, for considering Marsh 3 is low (55%) when AATGt-IgA serology is positive with levels between 16and 67 IU/ml (1-4.2 times the cut-off point) and a higher value (92%) for concentrations between68 and 118 IU/ml (4.3-7.4 times) and for cases with 69-170 IU/ml (7.5-10.6 times); above 170IU/ml (>10.6 times) PPV is 100% (AU)

[Prediction of intestinal histological lesions in paediatric patients with coeliac disease]. / Predicción de lesión histológica intestinal en pacientes pediátricos con enfermedad celíaca.

INTRODUCTION: Serological markers are of great interest in coeliac disease (CD), although intestinal biopsy is still the gold standard for establishing the diagnosis. Tissue transglutaminase IgA antibodies (AATGt-IgA) and antiendomysial antibodies IgA (AAE-IgA) are closely correlated to intestinal damage observed in biopsies. Villous atrophy (Marsh 3) plays a major role in CD diagnosis. Marsh 2 stage (crypt hyperplasia) as a CD marker is still under debate. OBJECTIVE: To ascertain an AATGt-IgA level that corresponds to a positive predictive value (PPV) of 100% for a histological CD diagnosis. MATERIAL AND METHODS: A series of 120 patients younger than 14 years, non- IgA deficient, who underwent an intestinal biopsy and were positive for both serological markers (AATGt-IgA and AAE-IgA). For AATGt-IgA, according to the manufacturer's recommendations, a value greater than 16 IU/mL is considered as a positive value. The PPV of AATGt was determined for different cut-off points. RESULTS: The histological findings distribution is directly correlated to the AATGt-IgA cut-off point. When the cut-off point is set above 7.5-10.6 times the commercial reference value, there is a 2.1% of Marsh 2 lessions and 93.4% of Marsh 3; above 10.6 times the reference value, all biopsies where Marsh 3 (100%). The PPV that considers Marsh 3 is (93.4%). The PPV, for considering Marsh 3 is low (55%) when AATGt-IgA serology is positive with levels between 16 and 67 IU/ml (1-4.2 times the cut-off point) and a higher value (92%) for concentrations between 68 and 118 IU/ml (4.3-7.4 times) and for cases with 69-170 IU/ml (7.5-10.6 times); above 170 IU/ml (>10.6 times) PPV is 100%. CONCLUSION: The use of values higher than the recommended cut-off point must logically improve specificity and PPV. In 31.6% patients positive for AATGt-IgA and AAE-IgA (38/120) it would have been possible to diagnose the disease without intestinal biopsy as of the PPV was 100%. It is not possible to standardise results as there are different commercial kits with variable cut-off points, so we must be cautious when setting recommendations based on AATGt-IgA.

[Colectomy in paediatric patients with ulcerative colitis]. / Colectomía en pacientes pediátricos con colitis ulcerosa.

INTRODUCTION: There are not many studies published in the literature on failure of medical treatment in Ulcerative Colitis (UC) that leads to colectomy. PATIENTS AND METHODS: Retrospective study of patients under 14 years diagnosed with UC from 1984 to 2009, who underwent colectomy due to lack of response to medical treatment. They are divided into urgent or elective surgery. RESULTS: Colectomy performed in 14 paediatric patients (26.9% of total UC patients). Age at diagnosis 7.8±4.0 years, 8 of them younger than 10 years and 5 younger than 5 years. All cases diagnosed on patients less than 5 years of age required colectomy in the first 6 months after diagnosis. Elective colectomy was performed on 5/14 and urgent surgery in 9/14. The reported complications were divided into early (first 30 days after colectomy) and late. Pharmacological treatment in cases with urgent colectomy included methylprednisolone (100%), oral tacrolimus (55.5%), oral/intravenous cyclosporine (33.3%) and infliximab (33.3%). Cases of elective colectomy were all in the 1985-1998 period. CONCLUSIONS: The influence of age is a key factor for prognosis. All patients less than 5 year-old ended up with colectomy. The main indication for urgent surgery was lack of response to treatment with intravenous steroids combined with a potent immunomodulator (tacrolimus, cyclosporine, infliximab). All cases of elective colectomy were performed before 1999, when second line medical treatment was very uncommon, making remission unlikely.

[Plasma citrulline as a marker of loss of enterocitary mass in coeliac disease in childhood]. / Citrulina plasmática como marcador de pérdida de masa enterocitaria en la enfermedad celíaca en la infancia.

INTRODUCTION: Plasma citrulline is not incorporated in endogenous or exogenous proteins so it is a theoretical marker of villous atrophy. Our aim was to correlate plasma citrulline levels with severity of villous atrophy in celiac patients. METHODS: Observational case-control study longitudinal in children 16 month-old to 14 year-old: 48 with untreated celiac disease, 9 celiac children under gluten free diet and 35 non-celiac healthy children. Plasma amino acids concentration is determined, expressed in µmol/L, and so are other clinical and analytical data. RESULTS: No statistically significative difference found in the referring to BMI, age or renal function. Small increase in fecal fat in celiac children. Citrulline, arginine and glutamine are significantly lower in cases (17.7 µmol/l, 38.7 µmol/l, 479.6 µmol/l respectively) than in controls (28.9 µmol/l, 56.2 µmol/l, 563.7 µmol/l). Citrulline levels are significantly lower in the severe degrees of atrophy than in mild ones (13.8 µmol/l vs. 19.7 µmol/l, p < 0.05), not happening so with rest of amminoacids. SUMMARY: Postabsortive mean of plasma citrulline is a good marker of reduction in enterocyte mass in celiac patients with villous atrophy; secondary reduction in plasma arginine too. Just a small histological alteration in intestinal biopsy is enough to differentiate citrulline in cases and controls and besides it can be seen that high levels of atrophy present with lower plasma citrulline.