Search

Background & Aims: Body-growth, expressed as weight- and height gain, is a strong predictor of morbidity and mortality in patients with cystic fibrosis (CF). Whether current historically based recommendations on a high-energy diet are sufficient for optimal growth is questionable. We therefore assessed the longitudinal relation between body-growth and routine energy intake in paediatric CF patients., Methods: Included were patients with CF, aged 2-10 years of whom we obtained 969 measurements of weight and height along with dietary records, and 786 coefficient of fat absorption measurements (CFA). We described body-growth, energy intake, macronutrient intake and the long-term effect of energy intake and coefficient of fat absorption on body-growth during the 8-year follow-up period., Results: Enrolled were 191 children with CF who had a compromised growth when compared to healthy children. The dietary intake was ≥110% estimated average requirement (EAR) in 47% of the measurements (457/969) and did not (fully) achieve the recommended high-energy level (110-200% EAR). Further, the intake expressed as EAR decreased with increasing age. Cross-sectionally, boys and girls with higher caloric intakes had higher weight-for-age (WFA). The caloric intake explained 18 and 6% of the variation. Further, boys with higher caloric intakes had also higher height-for-age-adjusted-for-target-height (HFA/TH) or BMI. The caloric intake explained 6 or 7% of the variation. Longitudinally, caloric intake was associated with both WFA in boys and girls, and with BMI in boys. Each 100 calories increased intake would result in a 0.01 (girls)-0.02 increase in z-score WFA and 0.03 increase in z-score BMI. We found no significant association between CFA and WFA, HFA/TH or BMI. The contribution of protein, fat and carbohydrates was not associated with WFA, nor with HFA/TH or BMI., Conclusion: Even at this relatively early age, a compromised growth in children with CF was found when compared to healthy children. The energy intake was below 110% EAR in 47% of the measurements, and appeared to be insufficient to prevent suboptimal body-growth over the 8-years of follow-up., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Familial intrahepatic cholestasis (FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1 , ABCB11 and ABCB4 . Phenotypes range from benign recurrent intrahepatic cholestasis (BRIC), associated with recurrent cholestatic attacks, to progressive FIC (PFIC). Patients often suffer from severe pruritus and eventually progressive cholestasis results in liver failure. Currently, first-line treatment includes ursodeoxycholic acid in patients with ABCB4 deficiency (PFIC3) and partial biliary diversion in patients with ATP8B1 or ABCB11 deficiency (PFIC1 and PFIC2). When treatment fails, liver transplantation is needed which is associated with complications like rejection, post-transplant hepatic steatosis and recurrence of disease. Therefore, the need for more and better therapies for this group of chronic diseases remains. Here, we discuss new symptomatic treatment options like total biliary diversion, pharmacological diversion of bile acids and hepatocyte transplantation. Furthermore, we focus on emerging mutation-targeted therapeutic strategies, providing an outlook for future personalized treatment for inherited cholestatic liver diseases., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interest for this article.

Background: Height evaluation is an integral part of cystic fibrosis (CF) care. Height is compared with reference values by converting it to height-for-age (HFA) z scores. However, HFA z scores do not adjust for genetic potential (ie, target height [TH]), which could result in an incorrect estimation of the height., Materials and Methods: To evaluate the magnitude of this potential problem, we assessed the agreement between HFA and HFA-adjusted-for-TH (HFA/TH) z scores in 474 Dutch children with CF., Results: In this study sample, HFA z scores were -0.07 (95% confidence interval, -0.02 to -0.12) lower than HFA/TH z scores. When HFA and HFA/TH z scores were subdivided into 4 categories (≥0, <0 and ≥-1, <-1 and ≥-2, and ≤-2), a moderate agreement was found. HFA z scores were classified lower than HFA/TH z scores in 21% of the measurements and higher in 15% of the measurements., Conclusion: In clinical routine, height evaluation based on HFA may result in underestimation or overestimation of height growth, which may induce inappropriate nutrition interventions.

Background: Ursodeoxycholic acid (UDCA) might prevent progression of cystic fibrosis liver disease, but objective parameters for its effect are lacking., Methods: We used liver stiffness measurements to evaluate the effect of Ursodeoxycholic acid., Results: Paired measurements of liver stiffness were done in 73 patients without UDCA and in 32 patients with UDCA. In the latter group, 6 patients had cirrhosis; in 15 patients, UDCA was started based on Colombo criteria, and in 11 patients for other reasons. In patients without UDCA, liver stiffness increased: 0.19 (-0.03 to 0.59)kPa/year. Liver stiffness also increased in patients with cirrhosis: 4.6 (0.67-12.4)kPa/year. In patients who had UDCA based on Colombo criteria, a decrease of liver stiffness was observed: 0.70 (-1.6 to 0.55)kPa/year (P=0.01). In patients on UDCA for other reasons, liver stiffness increased: 0.23 (-0.20 to 0.51)kPa/year., Conclusion: UDCA reduced liver stiffness in patients with well-defined, mild liver disease., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Laparoscopic antireflux surgery (LARS) is a well-established treatment option for children with proton pomp inhibitor (PPI)-resistant gastroesophageal reflux disease (GERD). Besides preventing reflux of gastric fluid and solid content, LARS may also impair the ability of the stomach to vent intragastric air (i.e. gastric belching) and induce gas-related complications, such as bloating and/or hyperflatulence. Furthermore, it was previously hypothesized that LARS induces a behavioral type of belching, not originating from the stomach, called supragastric belching. The aim of this study was to objectively evaluate the impact of LARS on gastric (GB) and supragastric belching (SGB) in children with GERD., Methods: We performed a prospective, Dutch multicenter cohort study including 25 patients (12 males, median age 6 (range 2-18) years) with PPI-resistant GERD who were scheduled for LARS. Twenty-four-hour multichannel intraluminal impedance pH monitoring (MII-pH monitoring) was performed before and 3 months after fundoplication. Impedance pH tracings were analyzed for reflux episodes and GBs and SGBs., Key Results: LARS reduced acid exposure time from 8.5% (6.0-16.2%) to 0.8% (0.2-2.8%), p < 0.001. The number of GBs also significantly decreased after LARS (59 [43-77] VS 5 [2-12], p < 0.001). The number of air swallows remained unchanged after LARS. SGBs were infrequent before LARS with no change in the number of SGB observed after the procedure. Postoperative belching symptoms were associated with GBs, not with SGBs., Conclusion & Inferences: LARS significantly reduces the number of GBs in children with GERD, whereas the number of air swallows remains unchanged. Postoperative symptomatic belching is associated with GBs, but not with SGBs. These findings suggest that LARS does not induce the occurrence of SGBs in children, but longer follow-up is required., (© 2016 John Wiley & Sons Ltd.)

Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation., (Copyright © 2016, American Association for the Advancement of Science.)

Background & Aims: ATP8B1 deficiency is an autosomal recessive liver disease characterized by intrahepatic cholestasis. ATP8B1 mutation p.I661T, the most frequent mutation in European patients, results in protein misfolding and impaired targeting to the plasma membrane. Similarly, mutations in cystic fibrosis transmembrane conductance regulator (CFTR), associated with cystic fibrosis, impair protein folding and trafficking. The aim of this study was to investigate whether compounds that rescue CFTR F508del trafficking are capable of improving p.I661T-ATP8B1 plasma membrane expression., Methods: The effect of CFTR corrector compounds on plasma membrane expression of p.I661T-ATP8B1 was evaluated by cell surface biotinylation and immunofluorescence. ATPase activity was evaluated of a purified analogue protein carrying a mutation at the matching position (p.L622T-ATP8A2)., Results: The clinically used compounds, 4-phenylbutyric acid (4-PBA), suberoylanilide hydroxamic acid (SAHA) and N-butyldeoxynojirimycin (NB-DNJ) improved p.I661T-ATP8B1 plasma membrane targeting. Compounds C4, C5, C13 and C17 also significantly increased plasma membrane expression of p.I661T-ATP8B1. SAHA and compound C17 upregulated ATP8B1 transcription. p.I661T-ATP8B1 was partly targeted to the canalicular membrane in polarized cells, which became more evident upon treatment with SAHA and/or C4. p.L622T-ATP8A2 showed phospholipid-induced ATPase activity, suggesting that mutations at a matching position in ATP8B1 do not block functionality. Combination therapy of SAHA and compound C4 resulted in an additional improvement of ATP8B1 cell surface abundance., Conclusions: This study shows that several CFTR correctors can improve trafficking of p.I661T-ATP8B1 to the plasma membrane in vitro. Hence, these compounds may be suitable to be part of a future therapy for ATP8B1 deficiency and other genetic disorders associated with protein misfolding., Lay Summary: Compounds that improve the cellular machinery dealing with protein homeostasis (proteostasis) and allow for proper folding of proteins with (mild) missense mutations are called proteostasis regulators (Balch, Science 2008). Such compounds are potentially of high therapeutic value for many (liver) diseases. In this manuscript, we investigated whether compounds identified in screens as CFTR folding correctors are actually proteostasis regulators and thus have a broader application in other protein folding diseases. Using these compounds, we could indeed show improved trafficking to the (apical) plasma membrane of a mutated ATP8B1 protein, carrying the p.I661T missense mutation. This is the most frequently identified mutation in this rare cholestatic disorder. Importantly, ATP8B1 shows no similarity to CFTR. These data are important in providing support for the concept that rare, genetic liver diseases can potentially be treated using a generalized strategy., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Pancreatic insufficient cystic fibrosis (CF) patients receive vitamin A supplementation according to CF-specific recommendations to prevent deficiencies. Whether current recommendations are optimal for preventing both deficiency and toxicity is a subject of debate. We assessed the longitudinal relation between serum retinol levels and appropriate variables., Methods: We studied vitamin A intake, and the long-term effects of vitamin A intake, coefficient of fat absorption (CFA) and immunoglobulin G (IgG) on serum retinol levels in 221 paediatrics CF patients during a seven-year follow up period., Results: Total vitamin A intake, derived from 862 dietary assessments, exceeded the tolerable upper intake level in 30% of the assessments, mainly up to age six. Although CF patients failed to meet the CF-specific recommendations, serum retinol deficiency was found in only 17/862 (2%) of the measurements. Longitudinally, we observed no association to serum retinol levels for total vitamin A intake, CFA, gender or age but serum retinol levels were associated with serum IgG levels. Each g/L increase in serum IgG level would result in a 2.49% (95% CI -3.60 to -1.36%) reduction in serum retinol levels., Conclusion: In this large sample of children and adolescents with CF, serum retinol deficiency was rare despite lower than the CF-specific recommendations. However, the TUL was commonly exceeded. A reduction in CF-specific vitamin A supplementation recommendations should therefore be considered. Moreover, serum retinol levels were not associated with vitamin A intake, CFA, gender or age, although a decreased serum retinol was associated with an increased serum IgG., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The deleterious effects of a disrupted copper metabolism are illustrated by hereditary diseases caused by mutations in the genes coding for the copper transporters ATP7A and ATP7B. Menkes disease, involving ATP7A, is a fatal neurodegenerative disorder of copper deficiency. Mutations in ATP7B lead to Wilson disease, which is characterized by a predominantly hepatic copper accumulation. The low incidence and the phenotypic variability of human copper toxicosis hamper identification of causal genes or modifier genes involved in the disease pathogenesis. The Labrador retriever was recently characterized as a new canine model for copper toxicosis. Purebred dogs have reduced genetic variability, which facilitates identification of genes involved in complex heritable traits that might influence phenotype in both humans and dogs. We performed a genome-wide association study in 235 Labrador retrievers and identified two chromosome regions containing ATP7A and ATP7B that were associated with variation in hepatic copper levels. DNA sequence analysis identified missense mutations in each gene. The amino acid substitution ATP7B:p.Arg1453Gln was associated with copper accumulation, whereas the amino acid substitution ATP7A:p.Thr327Ile partly protected against copper accumulation. Confocal microscopy indicated that aberrant copper metabolism upon expression of the ATP7B variant occurred because of mis-localization of the protein in the endoplasmic reticulum. Dermal fibroblasts derived from ATP7A:p.Thr327Ile dogs showed copper accumulation and delayed excretion. We identified the Labrador retriever as the first natural, non-rodent model for ATP7B-associated copper toxicosis. Attenuation of copper accumulation by the ATP7A mutation sheds an interesting light on the interplay of copper transporters in body copper homeostasis and warrants a thorough investigation of ATP7A as a modifier gene in copper-metabolism disorders. The identification of two new functional variants in ATP7A and ATP7B contributes to the biological understanding of protein function, with relevance for future development of therapy., (© 2016. Published by The Company of Biologists Ltd.)

Background: Progressive familial intrahepatic cholestasis (PFIC) with low gamma-glutamyl transpeptidase (GGT) and Alagille syndrome are associated with persistent cholestasis and severe pruritus. Various types of biliary diversion have been used to reduce this pruritus and prevent liver dysfunction. We report our experience concerning the efficacy and safety of total biliary diversion (TBD) as an additional treatment option., Methods: TBD was performed in four PFIC patients and one patient with Alagille syndrome, and was accomplished by anastomosing a jejunal segment to the choledochal duct terminating as an end stoma, or by disconnecting the choledochal duct after previous cholecystojejunocutaneostomy., Results: TBD resulted in a marked improvement of symptoms and biochemical parameters in all PFIC patients. Despite relief of pruritus, cholestasis persisted in the Alagille patient. During 5-15years of follow-up, no clinical signs of fat malabsorption such as diarrhea or weight loss were encountered. However, to maintain adequate levels of fat-soluble vitamins, especially of vitamin K, substantial supplementation was necessary., Conclusions: Total biliary diversion can be a useful surgical treatment option for patients with low-GGT PFIC and possibly also Alagille syndrome, when partial biliary diversion is insufficient. It can be performed without inducing clinical signs of fat malabsorption although individualized supplementation of fat-soluble vitamins with careful monitoring is warranted., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Pancreatic enzyme replacement therapy (PERT) is the proven therapy to substantially reduce fat malabsorption in patients with cystic fibrosis (CF). Few details of the daily practice regarding PERT and the resulting coefficient of fat absorption (CFA) are known. We therefore recorded the PERT and CFA in a large cohort of pancreatic insufficient pediatric patients with CF., Methods: We retrospectively studied 1719 completed 3-day dietary food records, including the pancreatic enzyme intake registrations, and 1373 CFA assessments of 224 patients with CF, ages 0-17 years. The clinical characteristics, PERT, expressed as an intake of lipase unit (LU) per gram of fat per day and LU per kilogram per day, and the CFA were described for the group as a whole and separately for those on enteral tube feeding. Cross-sectional relationship between the CFA and the LU per gram of fat per day and LU per kilogram per day were determined for each year of age. We also addressed the effect of the interventions done in patients with CFA outcomes <85%., Results: The LU per gram of fat per day was relatively stable throughout the age groups, whereas the LU per kilogram per day fell markedly with age. The median CFA in the age group 17 varied between 86% and 91%, however, with a CFA below 85% in 325 of 1373 (24%) of the measurements. No relationship was found between PERT and CFA. The patients with persistent CFA less than 85% had significant lower z scores weight for age and weight for height (P = 0.01) than those with CFA at least 85%., Conclusions: In this study population, no correlation between an enzyme dosage and the degree of fat malabsorption was found; however, a CFA below 85% was found in 24% of the measurements.

Background: Identification of patients at risk for developing cirrhotic cystic fibrosis liver disease (CCFLD) is essential for targeting potentially preventive treatment. We studied the evolution of serum liver enzymes and thrombocyte counts as predictors of CCFLD development., Methods: For this study, we defined the diagnosis of CCFLD as the combination of splenomegaly (on either physical examination or ultrasound scan) and macronodularity of the liver on ultrasound scan. We reviewed the medical records of 277 pediatric patients with CF for the diagnosis of CCFLD. In each patient with CCFLD, we reviewed serum liver enzymes and thrombocyte counts in the 2-year period preceding the diagnosis of CCFLD. We compared these results with a non-CCFLD control group (patients with CF older than 15 years with no reported signs or symptoms of CCFLD)., Results: In the 2 years preceding the diagnosis, the γ-glutamyltranspeptidase (GGT) levels of patients with CCFLD were significantly higher compared to non-CCFLD controls (42 ± 5 vs 17 ± 2 U/L, respectively; P < 0.001). Corresponding aspartate aminotransferase and alanine aminotransferase levels did not significantly differ between patients with CCFLD and controls. The thrombocyte counts in patients with CCFLD were significantly lower than those in controls (252 ± 108 vs 320 ± 94 × 10 /L, respectively; P < 0.05). The predictive value for CCFLD of a single GGT measurement was low; however, for patients with CF with a mean GGT > 35 U/L, based on repeated measurements, the odds ratio for developing CCFLD was 39 (95% confidence interval 9-175, specificity was 95%, sensitivity was 64%, positive predictive value was 50%). For the thrombocytes, however, no reliable cutoff value could be identified., Conclusions: In pediatric patients with CF, a persistently high-normal GGT is strongly associated with the diagnosis of CCFLD within 2 years. The prognostic value of a single GGT measurement is limited, but repeated GGT measurements may allow the identification of groups of patients at increased risk for CCFLD.

Aim: To investigate whether performing immunohistochemical CD3 staining, in order to improve the detection of intra-epithelial lymphocytosis, has an additional value in the histological diagnosis of celiac disease., Methods: Biopsies obtained from 159 children were stained by hematoxylin and eosin (HE) and evaluated using the Marsh classification. CD3 staining was subsequently evaluated separately and independently., Results: Differences in evaluation between the routine HE sections and CD3 staining were present in 20 (12.6%) cases. In 10 (6.3%) patients the diagnosis of celiac disease (Marsh II and III) changed on examination of CD3 staining: in 9 cases, celiac disease had initially been missed on the HE sections, while 1 patient had been over-diagnosed on the routine sections. In all patients, the final diagnosis based on CD3 staining, was concordant with serological results, which was not found previously. In the other 10 (12.3%) patients, the detection of sole intra-epithelial lymphocytosis (Marsh I) improved. Nine patients were found to have Marsh I on CD3 sections, which had been missed on routine sections. Interestingly, the only patient with negative serology had Giardiasis. Finally, in 1 patient with negative serology, in whom Marsh I was suspected on HE sections, this diagnosis was withdrawn after evaluation of the CD3 sections., Conclusion: Staining for CD3 has an additional value in the histological detection of celiac disease lesions, and CD3 staining should be performed when there is a discrepancy between serology and the diagnosis made on HE sections.

Background: It has been suggested that higher serum retinol levels could have protective effects on pulmonary function (PF) in patients with cystic fibrosis (CF). However, serum retinol levels will be transiently decreased during pulmonary exacerbation. Therefore, the extent of chronic pulmonary inflammation should be included when describing the association between PF and serum retinol. We assessed the longitudinal relation between serum retinol, immunoglobulin G (IgG) and PF in paediatric CF patients., Methods: We studied the serum retinol, IgG and forced expiratory volumes in one second (FEV(1)% pred.) of 228 CF patients during a seven-year follow up period. The cross-sectional and longitudinal relations between these variables were assessed., Results: Serum retinol, with medians levels between 1.2 and 1.4 μmol/l, were relatively stable, while median serum IgG gradually increased during the age years. The FEV(1)% pred. was longitudinally inversely associated with serum IgG and age, but not with serum retinol. Each g/l increase in serum IgG level was associated with an accelerated yearly decline in FEV(1)% pred. of 0.5% (95% CI -0.8 to -0.1, p=0.008), and each year increase in age was associated with a 1.7% (95% CI -2.1 to -1.3, p=0.000) decline in FEV(1)% pred. This effect was not observed with respect to serum retinol levels (95% CI -1.9 to 2.2, p=0.570)., Conclusions: In this large sample of children and adolescents with CF, we found no evidence that higher serum retinol levels had protective effects on PF., (Copyright © 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Pancreatic insufficiency cystic fibrosis (CF) patients receive vitamin E supplementation according to CF-specific recommendations in order to prevent deficiencies. It has been suggested that higher serum α-tocopherol levels could have protective effects on pulmonary function (PF) in patients with CF. Whether current recommendations are indeed optimal for preventing deficiency and whether vitamin E has therapeutic benefits are subjects of debate. Therefore, we studied vitamin E intake as well as the long-term effects of vitamin E intake, the coefficient of fat absorption (CFA) and IgG on α-tocopherol levels. We also examined the long-term effects of serum α-tocopherol and serum IgG on forced expiratory volume in 1 s expressed as percentage of predicted (FEV₁% pred.) in paediatric CF patients during a 7-year follow-up period. We found that CF patients failed to meet the CF-specific vitamin E recommendations, but serum α-tocopherol below the 2·5th percentile was found in only twenty-three of the 1022 measurements (2 %). Furthermore, no clear effect of vitamin E intake or the CFA on serum α-tocopherol was found (both P≥ 0·103). FEV₁% pred. was longitudinally inversely associated with age (P< 0·001) and serum IgG (P= 0·003), but it was not related to serum α-tocopherol levels. We concluded that in the present large sample of children and adolescents with CF, vitamin E intake was lower than recommended, but serum α-tocopherol deficiency was rare. We found no evidence that higher serum α-tocopherol levels had protective effects on PF. Adjustment of the recommendations to the real-life intake of these patients may be considered.

Unlabelled: ATP8B1 deficiency is a severe autosomal recessive liver disease resulting from mutations in the ATP8B1 gene characterized by a continuous phenotypical spectrum from intermittent (benign recurrent intrahepatic cholestasis; BRIC) to progressive familial intrahepatic cholestasis (PFIC). Current therapeutic options are insufficient, and elucidating the molecular consequences of mutations could lead to personalized mutation-specific therapies. We investigated the effect on pre-messenger RNA splicing of 14 ATP8B1 mutations at exon-intron boundaries using an in vitro minigene system. Eleven mutations, mostly associated with a PFIC phenotype, resulted in aberrant splicing and a complete absence of correctly spliced product. In contrast, three mutations led to partially correct splicing and were associated with a BRIC phenotype. These findings indicate an inverse correlation between the level of correctly spliced product and disease severity. Expression of modified U1 small nuclear RNAs (snRNA) complementary to the splice donor sites strongly improved or completely rescued splicing for several ATP8B1 mutations located at donor, as well as acceptor, splice sites. In one case, we also evaluated exon-specific U1 snRNAs that, by targeting nonconserved intronic sequences, might reduce possible off-target events. Although very effective in correcting exon skipping, they also induced retention of the short downstream intron., Conclusion: We systematically characterized the molecular consequences of 14 ATP8B1 mutations at exon-intron boundaries associated with ATP8B1 deficiency and found that the majority resulted in total exon skipping. The amount of correctly spliced product inversely correlated with disease severity. Compensatory modified U1 snRNAs, complementary to mutated donor splice sites, were able to improve exon definition very efficiently and could be a novel therapeutic strategy in ATP8B1 deficiency as well as other genetic diseases., (© 2014 by the American Association for the Study of Liver Diseases.)

Background and Aims: Data on risk of hepatocellular carcinoma (HCC) in patients with Wilson disease are scarce. We determine HCC risk in a well-defined cohort of Wilson patients., Methods: All patients with a confirmed diagnosis of Wilson disease (Leipzig score ≥ 4) in three Dutch university referral hospitals were included in this retrospective cohort study. End of follow-up was defined as date of diagnosis of HCC, liver transplantation, death, or last available hospital visit. Also, a meta-analysis was performed to determine incidence and mortality rate of HCC in Wilson disease based on all published cohorts., Results: In total, 130 patients with Wilson disease were followed during a median follow-up of 15 years (range 0.1-51.2). At baseline, cirrhosis was present in 74 patients (57% of total: 64% compensated, and 36% decompensated). At end of follow-up, liver disease severity was improved, stable or deteriorated in 20%, 46%, and 24% of all cases (10% unknown), respectively. Two patients developed HCC (one despite excellent decoppering after 50 years follow-up, the other with newly diagnosed Wilson disease). Estimated annual HCC risk for all patients was 0.09% (95% confidence interval [CI]: 0.01-0.28). Subgroup analysis in cirrhotic patients revealed an annual HCC risk of 0.14% (95% CI: 0.02-0.46). The meta-analysis showed an annual HCC risk of 0.04% (95% CI: 0.01-0.10) and HCC mortality rate of 2.6/10 000 person-years (95% CI: 0.7-7.0)., Conclusions: Even in case of cirrhosis, HCC risk is low in Wilson disease. Our data do not support regular HCC surveillance in Wilson disease., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Ketoacidosis is a potentially lethal condition caused by the imbalance between hepatic production and extrahepatic utilization of ketone bodies. We performed exome sequencing in a patient with recurrent, severe ketoacidosis and identified a homozygous frameshift mutation in the gene encoding monocarboxylate transporter 1 (SLC16A1, also called MCT1). Genetic analysis in 96 patients suspected of having ketolytic defects yielded seven additional inactivating mutations in MCT1, both homozygous and heterozygous. Mutational status was found to be correlated with ketoacidosis severity, MCT1 protein levels, and transport capacity. Thus, MCT1 deficiency is a novel cause of profound ketoacidosis; the present work suggests that MCT1-mediated ketone-body transport is needed to maintain acid-base balance.

Microvillus inclusion disease (MVID) is a disorder of intestinal epithelial differentiation characterized by life-threatening intractable diarrhea. MVID can be diagnosed based on loss of microvilli, microvillus inclusions, and accumulation of subapical vesicles. Most patients with MVID have mutations in myosin Vb that cause defects in recycling of apical vesicles. Whole-exome sequencing of DNA from patients with variant MVID showed homozygous truncating mutations in syntaxin 3 (STX3). STX3 is an apical receptor involved in membrane fusion of apical vesicles in enterocytes. Patient-derived organoid cultures and overexpression of truncated STX3 in Caco-2 cells recapitulated most characteristics of variant MVID. We conclude that loss of STX3 function causes variant MVID., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The recommendation for caloric intake in CF patients is to obtain intakes between 110 and 200% of the estimated average requirement (EAR) for age groups and gender, of which 35-40 energy% should be from fat. It is questionable whether the advice is met., Methods: 1726 Completed 3-day dietary food records of 234 CF patients (111 girls) and 2860 completed two non-consecutive 24-h dietary assessments of healthy controls (1411 girls) were studied. The dietary intake in CF patients was compared with that of healthy controls by using independent sample t tests., Results: Caloric intake in children with CF varied highly with age (88-127% EAR), which is below or in the lower range of the recommended 110-200% EAR. However the absolute caloric intake in CF children was significantly higher compared to controls at all ages. In addition, apart from boys aged 1-3 years, all CF children had a fat intake of 35 energy% or more. This fat intake was significantly higher than in controls, as was the consumption of saturated fat, the latter being well above 10% of the total energy intake., Conclusion: Although CF patients generally do not meet the EAR recommendations, they had a significantly higher caloric intake than controls. Moreover fat intake in CF patients does generally meet recommendations, but this resulted in a considerable consumption of saturated fat; a reduction of the latter seems appropriate., (Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aim: To measure the weight and height of children with cystic fibrosis (CF) from 2 to 10 years of age and to investigate the relationship between these parameters and forced expiratory volume in 1 sec (FEV1) beginning at 6 years of age., Methods: Weight and height were expressed as z-scores for weight-for-age (WFA), height-for-age (HFA), height-adjusted-for-target-height (HFA/TH) and weight-for-height (WFH). The children were categorised as having a z-score ≥0, between 0 and -1, or <-1 based on z-scores at 2 years of age. The cross-sectional and longitudinal relationships between FEV1 and WFA, HFA, HFA/TH and WFH were determined and the predictive value of these parameters for FEV1., Results: We enrolled 156 CF children. Their mean weight and height were below the average for the healthy population. Both WFA and WFH increased with age (primarily before the age of 6), while the reduction in HFA and HFA/TH persisted. Importantly, the yearly decline in FEV1 was significantly slowed [by 1.8 and 1.9% for each unit increase in WFA and WFH (p < 0.015)] in children who gained weight., Conclusion: CF patients aged 2 to 10 years have long-term impaired growth. Nevertheless, weight gain slowed the decline in FEV1 in these patients., (©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objective: To study long-term (10-15 years) efficacy of antireflux surgery (ARS) in a prospectively followed cohort of pediatric patients with gastroesophageal reflux disease, using 24-hour pH monitoring and reflux-specific questionnaires., Background: Studies on short-term outcome of ARS in pediatric patients with gastroesophageal reflux disease have shown good to excellent results; however, long-term follow-up studies are scarce, retrospective, and have not used objective measurements., Methods: Between 1993 and 1998, a cohort of 57 pediatric patients (ages 1 month to 18 years; 46% with neurological impairment) underwent laparoscopic anterior partial fundoplication (Thal). Preoperatively and postoperatively (at 3-4 months and at 1-5 and 10-15 years), reflux-specific questionnaires were filled out, and 24-hour pH monitoring was performed., Results: At 3 to 4 months, at 1 to 5 years, and at 10 to 15 years after ARS, 81%, 80%, and 73% of patients, respectively, were completely free of reflux symptoms. Disease-free survival analysis, however, demonstrated that only 57% of patients were symptom free at 10 to 15 years after ARS. Total acid exposure time significantly decreased from 13.4% before ARS to 0.7% (P < 0.001) at 3 to 4 months after ARS; however, at 3 to 4 months after ARS, pH monitoring was still pathological in 18% of patients. At 10 to 15 years after ARS, the number of patients with pathological reflux had even significantly increased to 43% (P = 0.008). No significant differences were found comparing neurologically impaired and normally developed patients., Conclusions: As gastroesophageal reflux persists or recurs in 43% of children 10 to 15 years after laparoscopic Thal fundoplication, it is crucial to implement routine long-term follow-up after ARS in pediatric patients with gastroesophageal reflux disease.

Background: Mutations in genes encoding cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (SPINK1) and chymotrypsinogen C (CTRC) are associated with chronic pancreatitis. However, in many patients with a familial chronic pancreatitis pattern suggesting a genetic cause, no mutations in either of these genes can be found, indicating that other, still unknown, associated genes exist. In this respect ATP8B1 is an interesting candidate due to its strong expression in the pancreas, its supposed general function in membrane organization and the higher incidence of pancreatitis in patients with ATP8B1 deficiency., Methods: We analyzed all 27 ATP8B1 coding exons and adjacent non-coding sequences of 507 chronic pancreatitis patients by direct sequencing. Exons that harbored possible relevant variations were subsequently sequenced in 1,027 healthy controls., Results: In the exonic regions, 5 novel non-synonymous alterations were detected as well as 14 previously described alterations of which some were associated with ATP8B1 deficiency. However, allele frequencies for any of these variations did not significantly differ between patients and controls. Furthermore, several non-synonymous variants were exclusively detected in control subjects and multiple variants in the non-coding sequence were identified with similar frequencies in both groups., Conclusions: We did not find an association between heterozygous ATP8B1 variants and chronic pancreatitis in our cohort of patients with hereditary and idiopathic chronic pancreatitis.

Aim: To investigate whether celiac disease (CD) patients with tissue-transglutaminase antibody (tTGA) ≥ 100 U/mL are different from patients with lower tTGA levels., Methods: Biopsy-proven (Marsh III) pediatric CD patients (n = 116) were prospectively included between March 2009 and October 2012. The biopsies were evaluated by a single pathologist who was blinded to all of the patients' clinical data. The patients were distributed into 2 groups according to their tTGA level, which was measured using enzyme-linked immunoassay: tTGA ≥ 100 U/mL and tTGA < 100 U/mL. The patients'characteristics, symptoms, human leukocyte antigen (HLA) genotype and degree of histological involvement were compared between the 2 groups., Results: A total of 34 (29.3%) children had tTGA values < 100 U/mL and 82 (70.7%) tTGA levels of ≥ 100 U/mL. Patients with high tTGA levels had lower average body weight-for-height standard deviation scores (SDS) than did patients with tTGA < 100 U/mL (-0.20 ± 1.19 SDS vs 0.23 ± 1.03 SDS, P = 0.025). In the low tTGA group, gastrointestinal symptoms were more common (97.1% vs 75.6%, P = 0.006). More specifically, abdominal pain (76.5% vs 51.2%; P = 0.012) and nausea (17.6% vs 3.7%, P = 0.018) were more frequent among patients with low tTGA. In contrast, patients with solely extraintestinal manifestations were only present in the high tTGA group (18.3%, P = 0.005). These patients more commonly presented with aphthous stomatitis (15.9% vs 0.0%, P = 0.010) and anemia (32.9% vs 11.8%, P = 0.019). In addition, when evaluating the number of CD-associated HLA-DQ heterodimers (HLA-DQ2.5, HLA-DQ2.2 and HLA-DQ8), patients with low tTGA levels more commonly had only 1 disease-associated heterodimer (61.8% vs 31.7%, P = 0.005), while patients with high tTGA more commonly had multiple heterodimers. Finally, patients with tTGA ≥ 100 U/mL more often had a Marsh IIIc lesion (73.2% vs 20.6%, P < 0.001) while in patients with low tTGA patchy lesions were more common (42.4% vs 6.8%, P < 0.001)., Conclusion: Patients with tTGA ≥ 100 U/mL show several signs of more advanced disease. They also carry a larger number of CD associated HLA-DQ heterodimers.

Background & Aims: Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease., Methods: We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began)., Results: Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018)., Conclusions: Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine., (Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Biliary atresia (BA) is a progressive inflammatory destructive process of the bile ducts occurring in about one of every 20,000 live births. If left untreated, biliary atresia can lead to liver failure. The only effective treatments for BA at the moment are the Kasai operation and liver transplantation. Kasai portoenterostomy increases the survival of children with BA and postpones subsequent liver transplantation. Because long-term survival is rare, there is not much known about the long-term efficacy of the Kasai operation., Methods: The aim of this review was to study the outcome of patients with BA who survived more than 20 years on their native liver. We performed a systematic search on PubMed using MeSH terms for articles describing the long-term outcomes of patients with biliary atresia. We searched for patients who have lived at least 20 years with their native liver and we registered the number of complications. The endpoints identified in these articles were: death, cholangitis, portal hypertension and gastrointestinal bleeding., Results: From 53 articles we included 14 articles for analysis. In total 184 patients were above the age of 20 years. Of these 162 patients, 88% (162/184) were still alive with their native liver and 60.5% (98/162) were suffering from liver-related complications., Conclusions: It is possible for patients with biliary atresia to survive more than 20 years on their native liver after undergoing the Kasai operation during early infancy. However, 60.5% of the long-term survivors alive on their native liver end up suffering from progressive liver-related complications.

Background: To systematically assess the literature published after 1997 describing the effectiveness of nutritional interventions in Cystic Fibrosis patients., Methods: An online search in PUBMED, EMBASE and COCHRANE databases was conducted. Original studies with 4 patients or more, describing a nutritional intervention and giving at least weight as an outcome parameter were included., Results: The inclusion criteria were met by 17 articles, focusing on respectively behavioural interventions (n=6), oral supplementation (n=4) or enteral tube feeding (n=7). This latter intervention was universally successful to induce weight gain. One behavioural study and 2 oral supplementation studies also reported significant weight gain., Conclusion: Enteral tube feeding is effective to improve nutritional status, while the described effects of behavioural intervention and oral supplementation are not consistent at present., (Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Aim: To investigate whether a tissue-transglutaminase antibody (tTGA) level ≥ 100 U/mL is sufficient for the diagnosis of celiac disease (CD)., Methods: Children suspected of having CD were prospectively included in our study between March 2009 and September 2011. All patients with immune globulin A deficiency and all patients on a gluten-free diet were excluded from the study. Anti-endomysium antibodies (EMA) were detected by means of immunofluorescence using sections of distal monkey esophagus (EUROIMMUN, Luebeck, Germany). Serum anti-tTGA were measured by means of enzyme-linked immunosorbent assay using human recombinant tissue transglutaminase (ELiA Celikey IgA kit Phadia AB, Uppsala, Sweden). The histological slides were graded by a single experienced pathologist using the Marsh classification as modified by Oberhuber. Marsh II and III lesions were considered to be diagnostic for the disease. The positive predictive values (PPVs), negative predictive values (NPVs), sensitivity and specificity of EMA and tTGA along with their 95% CI (for the cut off values > 10 and ≥ 100 U/mL) were calculated using histology as the gold standard for CD., Results: A total of 183 children were included in the study. A total of 70 (38.3%) were male, while 113 (61.7%) were female. The age range was between 1.0 and 17.6 years, and the mean age was 6.2 years. One hundred twenty (65.6%) patients had a small intestinal biopsy diagnostic for the disease; 3 patients had a Marsh II lesion, and 117 patients had a Marsh III lesion. Of the patients without CD, only 4 patients had a Marsh I lesion. Of the 183 patients, 136 patients were positive for EMA, of whom 20 did not have CD, yielding a PPV for EMA of 85% (95% CI: 78%-90%) and a corresponding specificity of 68% (95% CI: 55%-79%). The NPV and specificity for EMA were 91% (95% CI: 79%-97%) and 97% (95% CI: 91%-99%), respectively. Increased levels of tTGA were found in 130 patients, although only 116 patients truly had histological evidence of the disease. The PPV for tTGA was 89% (95% CI: 82%-94%), and the corresponding specificity was 78% (95% CI: 65%-87%). The NPV and sensitivity were 92% (95% CI: 81%-98%) and 97% (95% CI: 91%-99%), respectively. A tTGA level ≥ 100 U/mL was found in 87 (47.5%) patients, all of whom were also positive for EMA. In all these 87 patients, epithelial lesions confirming CD were found, giving a PPV of 100% (95%CI: 95%-100%). The corresponding specificity for this cut-off value was also 100% (95% CI: 93%-100%). Within this group, a total of 83 patients had symptoms, at least gastrointestinal and/or growth retardation. Three patients were asymptomatic but were screened because they belonged to a group at risk for CD (diabetes mellitus type 1 or positive family history). The fourth patient who lacked CD-symptoms was detected by coincidence during an endoscopy performed for gastro-intestinal bleeding., Conclusion: This study confirms based on prospective data that a small intestinal biopsy is not necessary for the diagnosis of CD in symptomatic patients with tTGA ≥ 100 U/mL.

The genetic defect in a number of rare disorders of metal metabolism remains elusive. The limited number of patients with these disorders impedes the identification of the causative gene through positional cloning, which requires numerous families with multiple affected individuals. However, with next-generation sequencing all coding DNA (exomes) or whole genomes of patients can be sequenced to identify genes that are consistently mutated in patients. With this strategy only a limited number of patients and/or pedigrees is needed, bringing the elucidation of the genetic cause of even very rare diseases within reach. The main challenge associated with whole exome sequencing is the identification of the disease-causing mutation(s) among abundant genetic candidate variants. We describe several strategies to manage this data wealth, including comparison with control databases, increasing the number of patients and controls, and reducing the genomic region under investigation through homozygosity mapping. In this review we introduce a number of rare disorders of copper metabolism, with a suspected but yet unknown monogenetic cause, as an attractive target for this strategy. We anticipate that use of these novel techniques will identify the basic defect in the disorders described in this review, as well as in other genetic disorders of metal metabolism, in the next few years.

Celiac disease (CD) is one of the most common immune-mediated diseases with a worldwide prevalence of around 1%, although a couple of decades ago the disease was thought to be very rare. CD is characterized by an inadequate inflammatory response to gluten in genetically susceptible individuals. In this inflammatory response both the adaptive and innate immunity are involved. The clinical picture of CD is variable ranging from severe malabsorption syndrome to silent cases. Disease specific antibodies can aid in selecting patients for a small intestinal biopsy, which is thought to be the gold standard investigation to diagnose CD. However, in selected patients, serology can be sufficient to confirm the diagnosis and a biopsy is not needed. Hitherto, the only treatment for CD is adherence to a lifelong strict gluten-free diet. The purpose of this review was to summarize current literature on the epidemiology and pathophysiology of CD and to discuss diagnostic and therapeutic approaches.

Purpose: To investigate the course of life of young adults diagnosed with biliary atresia (BA) in infancy by comparing patients who did and did not underwent transplantation with an age-matched Dutch reference group., Methods: All patients from the Dutch BA registry, aged >18 years, were invited to complete the course of life questionnaire., Results: Forty patients participated (response = 74%). Twenty-five had not undergone transplantation; 15 had undergone orthotopic liver transplantation. One significant between-group difference was found, namely in substance use and gambling. BA patients who underwent transplantation reported less use than the reference group (p = .01, moderate effect size). Additional moderate effect sizes were found for differences in psychosexual and social development and antisocial behavior. Patients who underwent transplantation had lower scores than one or both other groups., Conclusions: Development of BA survivors who did not undergo transplantation seems not delayed, whereas that of transplanted patients does seem somewhat delayed. However, patients who underwent transplantation display less risk behavior. Larger samples are necessary to confirm these findings., (Copyright © 2012 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: It is suggested that patients with constipation should be screened for celiac disease. Similarly, it is recommended to investigate these patients for hypothyroidism and hypercalcemia. However, no evidence for these recommendations is available so far. We therefore set out to determine the prevalence of celiac disease, hypothyroidism, and hypercalcemia in children with constipation., Methods: Prospective cohort study of 370 consecutive patients who met the Rome III criteria for constipation. These patients were referred by a general practitioner to a pediatrician because of failure of laxative treatment., Results: Seven of these patients had biopsy-proven celiac disease. This is significantly higher (p < 0.001) than the 1:198 prevalence of celiac disease in the Netherlands. Two patients had auto-immune thyroiditis. No patient had hypercalcemia., Conclusions: We conclude that celiac disease is significantly overrepresented in patients with constipation who are referred by a general practitioner to a pediatrician because of failure of laxative treatment. All such patients should, therefore, be screened for celiac disease.

To investigate the usefulness of deamidated-gliadin-peptides-antibodies in the diagnosis of celiac disease, serology was tested in 212 children suspected with celiac disease who had undergone a small-intestinal-biopsy. For deamidated-gliadin-peptides-antibodies, two kits were tested. Positive and negative predictive values for IgA deamidated-gliadin-peptides-antibodies using the Bindazyme-kit were 89% and 74%, while the Quanta-Lite-kit had values of 89% and 85%, respectively. For the IgG subtype using the Bindazyme-kit, these values were 85% and 89%, while they were 85% and 91% for the Quanta-Lite-kit. The positive predictive values for endomysium and tissue-transglutaminase antibodies were disappointing (77% and 87%), although the negative predictive values were better (97% and 96%). When the analysis was restricted to the 41 children aged <2 years, no misclassifications occurred with IgG deamidated-gliadin-peptides-antibodies giving 100% accuracy in both kits. The positive predictive value reached 100% for tissue-transglutaminase antibodies and both kits for IgA deamidated-gliadin-peptides-antibodies, while the negative predictive value was 94% in these assays. Positive and negative predictive values for endomysium antibodies were 96% and 93%, respectively. In conclusion, although deamidated-gliadin-peptides-antibodies do not outperform anti-endomysium antibodies in the total study population, the IgG subtype seems to be the best test in children aged <2 years, reaching 100% accuracy., (© 2011 The Authors. APMIS © 2011 APMIS.)

Background & Aims: Surgical treatment with Kasai portoenterostomy has improved the prognosis for patients with biliary atresia, although most patients ultimately require liver transplantation. Well-described patients with long-term, transplant-free survival are scarce; we assessed liver status and health perception among Dutch patients who survived 20 years after therapy and investigated whether the rate of transplant-free survival increases with time., Methods: By using the Dutch national database for biliary atresia, we identified 104 patients, born between 1977 and 1988. We collected data on clinical characteristics, liver biochemistry, and ultrasonography from all transplant-free patients who were alive at age 20 years (n = 28; 27% of the patients). General health perception data (RAND-36) were collected at the last examination., Results: The 20-year transplant-free survival rate increased from 20% (10 of 49) in the 1977 to 1982 cohort to 32% (18 of 55) in the 1983 to 1988 cohort (P = .03). Twenty-one percent of the long-term survivors (6 of 28) had normal liver biochemistry test results and no clinical or ultrasonographic signs of cirrhosis. The general health perception of female, but not male, patients, was lower, compared with controls (RAND-36 score, 54 ± 14 vs 74 ± 18; P = .005)., Conclusions: More than 25% of patients with biliary atresia survive at least 20 years without liver transplantation in The Netherlands. Women with biliary atresia have a reduced perception of their health, compared with control patients. Twenty percent of long-term survivors are symptom-free, without clinical or ultrasonographic signs of cirrhosis or portal hypertension., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Antireflux surgery (ARS) for gastroesophageal reflux disease (GERD) is one of the most frequently performed major operations in children. Many studies have described the results of ARS in children, however, with a wide difference in outcome. This study aims to systematically review the efficacy of pediatric ARS and its effects on gastroesophageal function, as measured by gastroesophageal function tests. This is the first systematic review comprising only prospective, longitudinal studies, minimizing the risk of bias., Methods: Three electronic databases (Medline, Embase, and the Cochrane Library) were searched for prospective studies reporting on ARS in children with GERD., Results: In total, 17 eligible studies were identified, reporting on a total of 1,280 children. The median success rate after ARS was 86% (57-100%). The success rate in neurologically impaired children was worse in one study, but similar in another study compared to normally developed children. Different surgical techniques (total versus partial fundoplication, or laparoscopic versus open approach) showed similar reflux recurrence rates. However, less postoperative dysphagia was observed after partial fundoplication and laparoscopic ARS was associated with less pain medication and a shorter hospital stay. Complications of ARS varied from minimal postoperative complications to severe dysphagia and gas bloating. The reflux index (RI), obtained by 24-h pH monitoring (n = 8) decreased after ARS. Manometry, as done in three studies, showed no increase in lower esophageal sphincter pressure after ARS. Gastric emptying (n = 3) was reported either unchanged or accelerated after ARS. No studies reported on barium swallow x-ray, endoscopy, or multichannel intraluminal impedance monitoring before and after ARS., Conclusion: ARS in children shows a good overall success rate (median 86%) in terms of complete relief of symptoms. Efficacy of ARS in neurologically impaired children may be similar to normally developed children. The outcome of ARS does not seem to be influenced by different surgical techniques, although postoperative dysphagia may occur less after partial fundoplication. However, these conclusions are bound by the lack of high-quality prospective studies on pediatric ARS. Similar studies on the effects of pediatric ARS on gastroesophageal function are also very limited. We recommend consistent use of standardized assessment tests to clarify the effects of ARS on gastroesophageal function and to identify possible risk factors for failure of ARS in children.

Objective: Celiac disease (CD) is characterized by histologic alterations in small bowel biopsies. Circulating specific CD antibodies at the time of diagnosis and their disappearance after a gluten-free diet support the diagnosis of CD. We aimed to determine the behavior of the CD antibodies immunoglobulin A anti-tissue transglutaminase (anti-TG2) and immunoglobulin A endomysium (EMA) in children with CD after starting a gluten-free diet., Methods: This was a retrospective multicenter study in the Netherlands between 2001 and 2009. Inclusion criteria were all newly diagnosed patients with CD younger than 19 years who had at least 1 anti-TG2 and/or EMA measurement before and after starting a gluten-free diet. Eight different anti-TG2 kits were used with substrates of guinea pig TG2 in 1 (Sigma) and 7 human-recombinant TG2: Varelisa and EliA Celikey Phadia-GmbH; Orgentec Diagnostica-GmbH; Diarect AG; Roboscreen GmbH; Aeskulisa Diagnostics; Binding Site Ltd. EMA was analyzed with indirect immunofluorescence tests. Statistical analyses were performed by using mixed-model repeated measurements and survival analysis., Results: There were 129 children with CD included (mean age: 5.6 years; SD ± 4.2). The mean concentration of anti-TG2 decreased significantly within 3 months after starting a gluten-free diet (P < .0001). The cumulative percentage of children who became negative for EMA after ½, 1, 1½, and 2 years was 31%, 60%, 74%, and 87%, respectively. For anti-TG2, a comparable trend was shown: 35%, 55%, 64%, and 78%, respectively., Conclusions: Doctors taking care of children with CD should be aware that the mean concentration of anti-TG2 will show a 74% decrease (95% confidence interval: 69%-79%) after 3 months of gluten-free diet, and ∼80% of the children will be sero-negative for EMA and anti-TG2 after 2 years of the diet.

Background: Few studies have reported on Barrett's esophagus (BE) in children. Moreover, information on the age at diagnosis and the duration between reflux-symptoms and diagnosis is lacking., Methods: A review of the literature was performed in PubMed, EMBASE and the Cochrane database., Results: Fourteen articles were included, of which 4 cohort studies and 10 studies investigating patients already diagnosed with BE. The cohort studies showed 37 patients diagnosed with BE (0.3-4.8%), mean age 12.4 years. Time between onset of reflux-symptoms and BE was 2.8 years. All 14 studies together showed 176 patients with BE (mean age 9.5 years). Time between onset of reflux-symptoms and BE was 5.3 years. During endoscopic follow-up of 45 patients, 26 still had BE, 17 no longer had evidence of BE, and two had developed esophageal-adenocarcinoma., Conclusion: This review shows that BE and esophageal-adenocarcinoma occur in children. However, criteria used to define BE by the included studies were not comparable to the current criteria and data on GERD symptoms may have been inaccurate. Therefore, we recommend performing a long-term prospective study on the relationship between (duration of) GERD and the development of BE in children in order to define screening guidelines., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Meconium ileus at birth, distal intestinal obstruction syndrome (DIOS), and constipation are an interrelated group of intestinal obstruction syndromes with a variable severity of obstruction that occurs in cystic fibrosis patients. Long-term follow-up studies show that today meconium ileus is not a risk factor for impaired nutritional status, pulmonary function, or survival. DIOS and constipation are frequently seen in cystic fibrosis patients, especially later in life; genetic, dietary, and other associations have been explored. Diagnosis of DIOS is based on suggestive symptoms, with a right lower quadrant mass confirmed on abdominal radiography, whereas symptoms of constipation are milder and of longer standing. In DIOS, early aggressive laxative treatment with oral laxatives (polyethylene glycol) or intestinal lavage with balanced osmotic electrolyte solution and rehydration is required, which now makes the need for surgical interventions rare. Constipation can generally be well controlled with polyethylene glycol maintenance treatment., (© The Author(s) 2011. This article is published with open access at Springerlink.com)

Objectives: Small intestinal histology is the criterion standard for the diagnosis of celiac disease (CD). However, results of serological tests such as anti-endomysium antibodies and anti-tissue transglutaminase antibodies (tTGA) are becoming increasingly reliable. This raises the question of whether a small intestinal biopsy is always necessary. The aim of the present study was, therefore, to investigate whether a small intestinal biopsy can be avoided in a selected group of patients., Patients and Methods: Serology and histological slides obtained from 283 pediatric patients suspected of having CD were examined retrospectively. The response to a gluten-free diet (GFD) in patients with a tTGA level ≥ 100 U/mL was investigated., Results: A tTGA level ≥ 100 U/mL was found in 128 of the 283 patients. Upon microscopic examination of the small intestinal epithelium, villous atrophy was found in 124 of these patients, confirming the presence of CD. Three patients had crypt hyperplasia or an increased number of intraepithelial lymphocytes. In 1 patient no histological abnormalities were found. This patient did not respond to a GFD., Conclusions: Pediatric patients with a tTGA level ≥ 100 U/mL in whom symptoms improve upon consuming a GFD may not need a small intestinal biopsy to confirm CD.

Objectives: Vitamin K deficiency (VKD) may cause life-threatening haemorrhages, especially in breast-fed infants with unrecognised cholestasis. Interestingly, hypoallergenic formulas appear overrepresented in reported cases of VKD bleeding (VKDB) in formula-fed infants. We therefore assessed whether the risk of VKD in formula-fed infants with cholestasis is associated with hypoallergenic formulas., Patients and Methods: Infants born in the Netherlands between January 1991 and December 2006 with cholestatic jaundice due to biliary atresia (BA) or to α-1-antitrypsin deficiency (A1ATD) were identified in the Netherlands Study Group for Biliary Atresia Registry and the A1ATD registry, respectively. The relative risk (RR) of VKDB in patients with BA or A1ATD was calculated for different formula types. The influence of prior or ongoing breast-feeding on the RR of VKDB was also assessed., Results: A total of 179 infants with either BA (139) or A1ATD (40) were included. One hundred eighteen infants were formula fed; 8 presented with VKD. Six of these 8 infants (75%) received hypoallergenic formula (whey-based hydrolysate in 4). One infant on whey-based hydrolysed formula presented with VKDB. Risk factor analysis revealed that infants receiving hydrolysed, especially whey-based, formula, had a strongly increased risk of VKD (RR 25.0 [6.4-97.2], P < 0.001)) compared with infants receiving regular formula. Prior or ongoing breast-feeding was not significantly associated with VKD., Conclusions: Infants with cholestasis receiving (whey-based) hydrolysed formula are at increased risk of developing VKD, compared with infants receiving regular formula. Because VKD may lead to serious haemorrhages, infants receiving whey-based hydrolysed formulas may need additional vitamin K supplementation.