Ruth De Bruyne

Vitamin K, an update for the paediatrician.

IntroductionThis review summarizes current knowledge on vitamin K for the paediatrician. Vitamin K is a fat-soluble vitamin, present in plants as phylloquinone and produced by bacteria as menaquinone. It is acting as a co-factor for γ-glutamyl carboxylase. This enzyme is responsible for post-translational modification of some glutamate side chains to γ-carboxyglutamate. The majority of γ-carboxylated proteins function in blood coagulation; others play a role in calcium homeostasis.DataNewborn babies are at particular risk of vitamin K deficiency, as placental transfer is limited and human milk is a poor source. Vitamin K prophylaxis at birth effectively prevents vitamin K deficiency bleeding (VKDB), formerly known as “haemorrhagic disease of the newborn”. Recent epidemiological studies provide data on the effectiveness of different administration routes and dosing schemes. Infants of mothers taking drugs that inhibit vitamin K are at risk of early VKDB and should receive 1xa0mg intramuscular (IM) as soon as possible after birth. Classic VKDB is prevented by intramuscular as well as by oral administration of 1xa0mg vitamin K. In exclusively breast-fed infants, single IM administration at birth is also effectively preventing (rare) late VKDB but single oral administration is not. If given orally, prophylaxis should be continued by either weekly administration of 1xa0mg till 12xa0weeks or repeating 2xa0mg at weeksxa01 and 4. Daily administration of 25xa0μg offers insufficient protection. The only infants not fully protected in this way are those with yet unrecognised liver disease.ConclusionsFurther work is needed before firm recommendations can be made regarding dose in preterm infants and in patients with fat malabsorption/cholestasis or regarding the role of vitamin K in the prevention of osteoporosis.INTRODUCTIONnThis review summarizes current knowledge on vitamin K for the paediatrician. Vitamin K is a fat-soluble vitamin, present in plants as phylloquinone and produced by bacteria as menaquinone. It is acting as a co-factor for gamma-glutamyl carboxylase. This enzyme is responsible for post-translational modification of some glutamate side chains to gamma-carboxyglutamate. The majority of gamma-carboxylated proteins function in blood coagulation; others play a role in calcium homeostasis.nnnDATAnNewborn babies are at particular risk of vitamin K deficiency, as placental transfer is limited and human milk is a poor source. Vitamin K prophylaxis at birth effectively prevents vitamin K deficiency bleeding (VKDB), formerly known as haemorrhagic disease of the newborn. Recent epidemiological studies provide data on the effectiveness of different administration routes and dosing schemes. Infants of mothers taking drugs that inhibit vitamin K are at risk of early VKDB and should receive 1 mg intramuscular (i.m.) as soon as possible after birth. Classic VKDB is prevented by intramuscular as well as by oral administration of 1 mg vitamin K. In exclusively breast-fed infants, single i.m. administration at birth is also effectively preventing (rare) late VKDB but single oral administration is not. If given orally, prophylaxis should be continued by either weekly administration of 1 mg till 12 weeks or repeating 2 mg at weeks 1 and 4. Daily administration of 25 microg offers insufficient protection. The only infants not fully protected in this way are those with yet unrecognised liver disease.nnnCONCLUSIONSnFurther work is needed before firm recommendations can be made regarding dose in preterm infants and in patients with fat malabsorption/cholestasis or regarding the role of vitamin K in the prevention of osteoporosis.

Post-transplant food allergy in children is associated with liver and not with renal transplantation: A monocentric comparative study

Food allergy is increasingly reported after paediatric liver transplantation. The underlying physiopathological mechanism remains incompletely understood. Therefore, we aimed to determine the incidence, clinical presentation, possible risk factors, and prognosis of post-transplant food allergy in children currently followed after liver and renal transplantation. The study population consists of 49 liver and 21 renal transplant patients transplanted between the age of 22xa0months and 15xa0years. Data were collected retrospectively from medical records and via a doctor’s questionnaire taken from the parents in a monocentric setting. Post-transplant food allergy has developed in 13 liver transplant patients and in none of the renal transplant recipients. Within the liver transplant group, median age at liver transplantation is significantly lower in the food-allergic (10xa0months) versus non-food-allergic group (3.3xa0years; pu2009=u20090.002). The use of tacrolimus as primary maintenance immunosuppression is associated with food allergy (pu2009=u20090.032) and mean donor age is significantly lower in the food-allergic group (pu2009=u20090.009). Compared to the renal transplant group, median age at transplantation is significantly lower in the liver patients (pu2009<u20090.001). No significant differences are found in primary immunosuppressive regimens between renal and liver transplant patients. Conclusion: Post-transplant food allergy is an important clinical problem in children after liver transplantation which does not affect renal transplant patients despite similar immunosuppressive regimens. Within the group of liver transplant recipients, tacrolimus use, young age at time of transplant and younger donor age were associated with the development of food allergy.

A systematic review on bowel management and the success rate of the various treatment modalities in spina bifida patients.

Study design:Systematic review.Objectives:To determine the different treatment modalities aimed at achieving fecal continence in spina bifida (SB) patients and their effectiveness.Setting:International literature.Method:Electronic databases were searched (‘Pubmed’, ‘Web of science’, ‘CINAHL’ and ‘Cochrane’) identifying studies published since the mid-eighties and screened for relevance according to the Centre for Reviews and Dissemination procedure guidelines. A total of 37 studies were selected for inclusion.Results:Studies on toilet sitting, biofeedback, anal plug, retrograde colon enemas (RCE) and antegrade colon enemas were found. Fecal continence was achieved in 67% of SB patients using conservative methods (n=509). In patients using RCE (n=190) an 80% continence rate was reached. Patients following surgical treatment (n=469) reached an 81% continence rate, however, 23% needed redo surgery because of complications. Better fecal continence was associated with an improved quality of life, which was negatively influenced by the amount of time spent on bowel management.Conclusion:Evidence favors an individually tailored stepwise approach with surgery as a final step in case of failure of conservative measures. Continued specialized support throughout life remains important to maintain continence. Cross-over and comparative trials are needed in order to optimize treatment.

Longitudinal Transient Elastography Measurements Used in Follow-up for Patients with Cystic Fibrosis

Cystic fibrosis-related liver disease (CFLD) is diagnosed using a combination of criteria. Transient elastography (TE), an ultrasonographic method to evaluate liver stiffness, can differentiate patients with and without liver disease. This retrospective study (2007-2013) aimed to detect developing CFLD using consequent TE measurements. All cystic fibrosis patients with TE measurements between 2007 and 2013 (nxa0=xa0150, median age 17 (9-24) y) were included, of which 118 had a median of three (range, 2-4) measurements with an interval of 1 (1-2) y. Twenty (14%) had CFLD at the first TE measurement; five (3%) developed CFLD during follow-up. The median TE value in CFLD was 14xa0kPa (8.7-32.2) compared with 5.3 (4.9-5.7) in cystic fibrosis patients without liver disease (CFnoLD; pxa0=xa00.0001). In CFnoLD, TE was correlated with age (pxa0=xa00.031). A TE result >6.8xa0kPa had a sensitivity of 91.5% and a specificity of 91.7% in predicting CFLD, according to the receiver operating characteristics analysis. It also has a positive predictive value of 88.6% and a negative predictive value of 86.9%, increasing to 91.7% and 98%, respectively, in patients at risk (<14xa0y) for developing CFLD. Patients with developing CFLD had progressively increasing consecutive TE measurements.

Evaluation of Exercise Performance, Cardiac Function, and Quality of Life in Children After Liver Transplantation

Background In children, after having liver transplantation (LT), it is important to assess the quality of life (QOL). Physical fitness is an important determinant of QOL, and because cardiac function can influence exercise performance, it is the purpose of the present study to assess these factors. Methods Children in stable follow-up for more than 6 months post-LT were invited to participate in a case control study. Patients underwent cardiopulmonary exercise testing and echocardiography to assess systolic and diastolic function, and left ventricular wall dimensions. Health-related QOL was evaluated using child- and adolescent-reported PedsQL questionnaire. Results Twenty-eight of 31 included patients performed a maximal exercise test (15 boys, 11.6 ± 2.9 years, weight, 40.9 ± 13.1 kg; length, 148.6 ± 17.3 cm; body mass index, 17.6 ± 2.3). Liver transplantation patients had lower maximal oxygen consumption (VO2max/kg) (37.5 ± 9.3 mL/kg per minute vs 44.1 ± 8.8 mL/kg per minute), shorter exercise duration (9.3 ± 2.8 minutes vs 13.3 ± 3 minutes) and lower load (71 ± 14 vs 85 ± 20%). They reached the ventilatory anaerobic threshold earlier (81.4 ± 9.5 vs 88.3 ± 11.9%). Echocardiography demonstrated increased interventricular septal wall thickness (interventricular septum in diastole Z value, +0.45 ± 0.49, P < 0.001) and more diastolic dysfunction (lower E, Z value, −0.7 ± 1.02, P = 0.002, higher E/E Z value, 0.64 ± 1.05. P = 0.005) but no relations with cardiopulmonary exercise testing. Health-related QOL showed lower overall, emotional, psychosocial, and school functioning scores. Children on antihypertensive medication had impaired physical functioning compared with other LT patients. Conclusions Lower physical fitness level, more deconditioning and lower health-related QOL in children after LT emphasize the importance of exercise stimulation and fitness programs. Patients on antihypertensive medication seem to be the most vulnerable group suffering from decreased physical fitness.

Clinical zinc deficiency as early presentation of Wilson disease.

ABSTRACT Wilson disease is a rare autosomal recessive disorder of the copper metabolism caused by homozygous or compound heterozygous mutations in the ATP-ase Cu(2+) transporting polypeptide (ATP7B) gene. The copper accumulation in different organs leads to the suspicion of Wilson disease. We describe a child with clinical zinc deficiency as presenting symptom of Wilson disease, which was confirmed by 2 mutations within the ATP7B gene and an increased copper excretion.

Microsomal protein per gram of liver (MPPGL) in paediatric biliary atresia patients

The microsomal protein per gram of liver (MPPGL) is an important scaling factor in the in vitro–in vivo extrapolation of metabolic data obtained in liver microsomes. This study aimed to determine the MPPGL in four biliary atresia patients (0.6–1.6u2009years old) undergoing liver transplantation, as it is known that the MPPGL is affected by age and possibly by liver disease. Due to the presence of bilirubin in the homogenates and microsomes, the NADPH‐cytochrome reductase activity was used to determine the recovery factor, rather than methods using the dithionite difference spectrum. A mean value of 18.73 (± 2.82) mg/g (geometric meanu2009±u2009SD, nu2009=u20094) was observed, which is lower than the expected MPPGL based on the age of the patients (26.60u2009±u20090.40u2009mg/g). This suggests a decreased amount of microsomal protein in the livers of biliary atresia patients. Moreover, no differences in MPPGL between different zones of the liver could be detected. Copyright

C-ANCA/Proteinase 3-Positive Colitis in Children: A Distinctive Form of Inflammatory Bowel Disease or Vasculitis With Colitis as Initial Presentation?

Aim: Anti-neutrophil cytoplasmic antibodies (ANCAs) detected by indirect immunofluorescence have been found in patients with inflammatory bowel disease (IBD). Nevertheless, specific antibodies against proteinase-3 (PR3) are rare in this context. Methods: Sera from 30 consecutive pediatric patients with IBD were evaluated for ANCA-indirect immunofluorescence and its specific antibodies to investigate whether PR3-ANCA positivity (PR3-ANCA+) identifies a distinct IBD subtype. Results: The 5 PR3-ANCA+ patients (17%) showed significantly more concomitant biliary disease and severe anal blood loss (Pu200a<u200a0.05). None had vasculitis features at diagnosis nor during follow-up. Conclusions: This pilot study demonstrates significant clinical differences between the PR3-ANCA–positive and –negative IBD subset.

Tacrolimus predose concentration is associated with hypertension in pediatric liver transplant recipients

Background: The aim of the study was to analyze the incidence of hypertension in pediatric liver transplantation (LT) recipients using ambulatory blood pressure measurements (ABPM) and to identify factors associated with hypertension. We also investigated whether hypertension or tacrolimus predose concentration (TAC C0) was associated with increased left ventricular (LV) wall thickness. Patients and Methods: On a retrospective longitudinal base, we included 39 pediatric LT recipients. Median time since transplantation was 65 months (range: 11–183). Two consecutive ABPM were analyzed with a median time interval of 13 months. Data from echocardiographic evaluation parallel to the baseline ABPM were analyzed. All patients except 1 were prescribed tacrolimus. The median TAC C0 was 4 ng/mL (range 0.9–11.2). Univariate and multivariate logistic regression models were fitted to identify factors associated with systolic and diastolic hypertension and LV wall thickness. Results: Twenty-two of 39 children were hypertensive at baseline and 19 of 32 were hypertensive at follow-up. At baseline 10 (26%) children had masked systolic hypertension. TAC C0 was associated with systolic (Pu200a=u200a0.007, Exp(B) 2.02, 95% CI 1.2–3.3) and diastolic (Pu200a=u200a0.044, Exp(B) 1.48, 95% CI 1.0–2.2) hypertension. LV wall thickness was increased in children after LT compared with healthy population, but it was not associated with hypertension or TAC C0. Conclusions: Given the high prevalence of masked hypertension, ABPM should be performed in all pediatric LT recipients. Systolic and diastolic hypertension is associated with TAC C0; therefore, children with a higher target TAC C0 require a more intensive blood pressure surveillance.

Severe hepatopathy and neurological deterioration after start of valproate treatment in a 6-year-old child with mitochondrial tryptophanyl-tRNA synthetase deficiency

BackgroundThe first subjects with deficiency of mitochondrial tryptophanyl-tRNA synthetase (WARS2) were reportedxa0in 2017. Their clinical characteristics can be subdivided into three phenotypes (neonatal phenotype, severe infantile onset phenotype, Parkinson-like phenotype).ResultsHere, we report on a subject who presented with early developmental delay, motor weakness and intellectual disability and who was considered during several years as having a non-progressive encephalopathy. At the age of six years, she had an epileptic seizure which was treated with sodium valproate. In the months after treatment was started, she developed acute liver failure and severe progressive encephalopathy. Although valproate was discontinued, she died six months later. Spectrophotometric analysis of the oxidative phosphorylation complexes in liver revealed a deficient activity of complex III and low normal activities of the complexes I and IV. Activity staining in the BN-PAGE gel confirmed the low activities of complex I, III and IV and, in addition, showed the presence of a subcomplex of complex V. Histochemically, a mosaic pattern was seen in hepatocytes after cytochrome c oxidase staining. Using Whole Exome Sequencing two known pathogenic variants were detected in WARS2 (c.797delC, p.Pro266ArgfsTer10/ c.938 Axa0>xa0T, p.Lys313Met).ConclusionThis is the first report of severe hepatopathy in a subject with WARS2 deficiency. The hepatopathy occurred soon after start of sodium valproate treatment. In the literature, valproate-induced hepatotoxicity was reported in the subjects with pathogenic mutations in POLG and TWNK. This case report illustrates that the course of the disease in the subjects with a mitochondrial defect can be non-progressive during several years. The subject reported here was first diagnosed as having cerebral palsy. Only after a mitochondriotoxic medication was started, the disease became progressive, and the diagnosis of a mitochondrial defect was made.