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1.  Mutational Analysis of ATP8B1 in Patients with Chronic Pancreatitis 
PLoS ONE  2013;8(11):e80553.
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.
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.
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.
We did not find an association between heterozygous ATP8B1 variants and chronic pancreatitis in our cohort of patients with hereditary and idiopathic chronic pancreatitis.
PMCID: PMC3834041  PMID: 24260417
2.  Children with celiac disease and high tTGA are genetically and phenotypically different 
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.
PMCID: PMC3819547  PMID: 24222955
Celiac disease; Serology; Anti-tissue transglutaminase antibodies; Human leukocyte antigen; Phenotype
3.  Tissue transglutaminase levels above 100 U/mL and celiac disease: A prospective study 
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.
PMCID: PMC3436057  PMID: 22969205
Celiac disease; Diagnosis, Serology; Anti-tissue-transglutaminase antibodies; Anti-endomysium antibodies
4.  The Effects and Efficacy of Antireflux Surgery in Children with Gastroesophageal Reflux Disease: A Systematic Review 
Journal of Gastrointestinal Surgery  2011;15(10):1872-1878.
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.
Three electronic databases (Medline, Embase, and the Cochrane Library) were searched for prospective studies reporting on ARS in children with GERD.
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.
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.
PMCID: PMC3179590  PMID: 21800225
Gastroesophageal reflux; Antireflux surgery; Fundoplication; Children
5.  Differences in presentation and progression between severe FIC1 and BSEP deficiencies 
Journal of hepatology  2010;53(1):170-178.
Background & Aims
Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these 2 disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations.
A retrospective multi-center study was conducted, using questionnaires and chart review. Available clinical and biochemical data from 145 PFIC patients with mutations in either ATP8B1 (61 “FIC1 patients”) or ABCB11 (84 “BSEP patients”) were evaluated.
At presentation, serum aminotransferase and bile salt levels were higher in BSEP patients; serum alkaline phosphatase values were higher, and serum albumin values were lower, in FIC1 patients. Elevated white blood cell counts, and giant or multinucleate cells at liver biopsy, were more common in BSEP patients. BSEP patients more often had gallstones and portal hypertension. Diarrhea, pancreatic disease, rickets, pneumonia, abnormal sweat tests, hearing impairment, and poor growth were more common in FIC1 patients. Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation.
Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.
PMCID: PMC3042805  PMID: 20447715
cholestasis; genetics; transport protein; pediatrics; P-type ATPase; ATP binding cassette protein; ATP8B1; FIC1; ABCB11; BSEP
6.  Intestinal Obstruction Syndromes in Cystic Fibrosis: Meconium Ileus, Distal Intestinal Obstruction Syndrome, and Constipation 
Current Gastroenterology Reports  2011;13(3):265-270.
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.
PMCID: PMC3085752  PMID: 21384135
Abdominal radiography; Anthropometric variables; Body mass index; Coefficient of fat absorption; Constipation; Cystic fibrosis transmembrane regulator; Cystic fibrosis; Distal intestinal obstruction syndrome; Fat malabsorption; Height; Nutritional status; Meconium ileus; Meconium ileus equivalent; Modifier genes; Pulmonary function; Steatorrhea; Spirometry; Survival; Weight
7.  Multiple common variants for celiac disease influencing immune gene expression 
Nature genetics  2010;42(4):295-302.
We performed a second-generation genome wide association study of 4,533 celiac disease cases and 10,750 controls. We genotyped 113 selected SNPs with PGWAS<10−4, and 18 SNPs from 14 known loci, in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome wide significance (Pcombined<5×10−8), most contain immune function genes (BACH2, CCR4, CD80, CIITA/SOCS1/CLEC16A, ICOSLG, ZMIZ1) with ETS1, RUNX3, THEMIS and TNFRSF14 playing key roles in thymic T cell selection. A further 13 regions had suggestive association evidence. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P<0.0028, FDR 5%) with cis gene expression.
PMCID: PMC2847618  PMID: 20190752
8.  Starreveld scoring method in diagnosing childhood constipation 
Pediatric Radiology  2010;40(11):1789-1793.
Four scoring methods exist to assess severity of fecal loading on plain abdominal radiographs in constipated patients (Barr-, Starreveld-, Blethyn- and Leech). So far, the Starreveld score was used only in adult patients.
To determine accuracy and intra- and inter-observer agreement of the Starreveld scoring method in the diagnosis of functional constipation among pediatric patients. In addition, we compared the Starreveld with the Barr scoring method.
Materials and methods
Thirty-four constipated and 34 non-constipated children were included. Abdominal radiographs, obtained before treatment, were rated (Starreveld- and Barr) by 4 observers. A second observation after 4 weeks was done by 3 observers. Cut-off level for the Starreveld score, accuracy as measured by the area under the receiver operator characteristics curve, and inter- and intra-observer agreement were calculated.
Cut-off value for the Starreveld score was 10. AUC for Starreveld score was 0.54 and for Barr score 0.38, indicating poor discriminating power. Inter-observer agreement was 0.49-0.52 4 (Starreveld) and 0.44 (Barr), which is considered moderate. Intra-observer agreement was 0.52-0.71 (Starreveld) and 0.62- 0.76 (Barr).
The Starreveld scoring method to assess fecal loading on a plain abdominal radiograph is of limited value in the diagnosis of childhood constipation.
PMCID: PMC2950268  PMID: 20593172
Constipation; Scoring; Abdominal radiograph; Child
9.  Green teeth 
PMCID: PMC2083435  PMID: 17337684

Results 1-9 (9)