Margaret Marcon

Activated mucosal mast cells differentiate eosinophilic (allergic) esophagitis from gastroesophageal reflux disease.

Objectives: To evaluate the utility of activated mucosal mast cells (MC) in the differential diagnosis of eosinophilic esophagitis (EE) and gastroesophageal reflux disease (GERD). Methods: Intraepithelial eosinophils and MC were quantified in esophageal biopsies from 25 children with EE, 22 children with GERD and 22 controls. MCs were identified by immunohistochemistry for MC tryptase, whereas MC activation status was evaluated by immunohistochemistry for immunoglobulin E (IgE) and by electron microscopy. Results: Esophageal biopsies from patients with EE showed higher intraepithelial eosinophil counts (55 ± 27.5 vs 6.9 ± 9.7, P < 0.0001) and MC counts (26.3 ± 12.7 vs 7.8 ± 8.9, P < 0.0001) than those from patients with GERD. Almost all EE biopsies (24 of 25 patients; 96%) contained IgE-bearing cells compared with 9 of 22 (41%) GERD biopsies (P < 0.001). GERD biopsies with intraepithelial eosinophil counts >7/high-power field (suggesting an allergic component) contained IgE-bearing cells in 6 of 7 (86%) cases compared to 3 of 15 (20%) cases with eosinophil counts <7/h.p.f (P < 0.01). No intraepithelial eosinophils, MC or IgE-positive cells were present in controls. Electron microscopy confirmed the presence of intraepithelial MC and changes in cytoplasmic granules indicative of MC and eosinophil activation. Conclusions: Intraepithelial MC counts and IgE-bearing cells may help to differentiate EE and GERD and to define a subset of GERD patients in which an allergic component is present. The findings support a role for a MC-mediated hypersensitivity reaction in the pathogenesis of EE.

Pharmacokinetics of orally administered omeprazole in children

Abstract OBJECTIVES: The aim of this study was to examine the pharmacokinetics of orally administered omeprazole in children. METHODS: Plasma concentrations of omeprazole were measured at steady state over a 6-h period after administration of the drug. Patients were a subset of those in a multicenter study to determine the dose, safety, efficacy, and tolerability of omeprazole in the treatment of erosive reflux esophagitis in children. Children were 1–16 yr of age, with erosive esophagitis and pathological acid reflux on 24 h-intraesophageal pH study. The “healing dose” of omeprazole was that at which subsequent intraesophageal pH study normalized. Children remained on this dose for 3 months, and during this period the pharmacokinetics were measured. RESULTS: A total of 57 children were enrolled in the overall healing phase of the study. Pharmacokinetic study was optional for subjects and was performed in 25 of the 57 enrolled. The doses of omeprazole required were substantially higher doses per kilogram of body weight than in adults. Values of the pharmacokinetic parameters of omeprazole were generally within the ranges previously reported in adults. However, the plasma levels, area under the plasma concentration versus time curve (AUC), plasma half-life (t 1 2 ), and maximal plasma concentration (Cmax), were lower in the younger age group, when the AUC and Cmax were normalized to a dose of 1 mg/kg. Furthermore, within the group as a whole, these values showed a gradation from lowest in the children 1–6 yr of age to higher in the older age groups. CONCLUSIONS: The pharmacokinetics of omeprazole in children showed a trend toward higher metabolic capacity with decreasing age, being highest at 1–6 yr of age. This may explain the need for higher doses of omeprazole on a per kilogram basis, not only in children overall compared with adults but, in many cases, particularly in younger children.

Pharmacokinetics of orally administered omeprazole in children. International Pediatric Omeprazole Pharmacokinetic Group.

OBJECTIVES:The aim of this study was to examine the pharmacokinetics of orally administered omeprazole in children.METHODS:Plasma concentrations of omeprazole were measured at steady state over a 6-h period after administration of the drug. Patients were a subset of those in a multicenter study to determine the dose, safety, efficacy, and tolerability of omeprazole in the treatment of erosive reflux esophagitis in children. Children were 1–16 yr of age, with erosive esophagitis and pathological acid reflux on 24 h-intraesophageal pH study. The “healing dose” of omeprazole was that at which subsequent intraesophageal pH study normalized. Children remained on this dose for 3 months, and during this period the pharmacokinetics were measured.RESULTS:A total of 57 children were enrolled in the overall healing phase of the study. Pharmacokinetic study was optional for subjects and was performed in 25 of the 57 enrolled. The doses of omeprazole required were substantially higher doses per kilogram of body weight than in adults. Values of the pharmacokinetic parameters of omeprazole were generally within the ranges previously reported in adults. However, the plasma levels, area under the plasma concentration versus time curve (AUC), plasma half-life (t12), and maximal plasma concentration (Cmax), were lower in the younger age group, when the AUC and Cmax were normalized to a dose of 1 mg/kg. Furthermore, within the group as a whole, these values showed a gradation from lowest in the children 1–6 yr of age to higher in the older age groups.CONCLUSIONS:The pharmacokinetics of omeprazole in children showed a trend toward higher metabolic capacity with decreasing age, being highest at 1–6 yr of age. This may explain the need for higher doses of omeprazole on a per kilogram basis, not only in children overall compared with adults but, in many cases, particularly in younger children.

Colonic expression of MUC2, MUC5AC, and TFF1 in inflammatory bowel disease in children

Background: The quantity and quality of mucins are affected in inflammatory bowel disease (IBD) both because of a reduction in the number of goblet cells and a decrease in the number of sugar residues per oligosaccharide side chain. Alteration in the types of mucins and aberrant location may contribute to the underlying pathology by affecting the mucus barrier function or may instead be a response to inflammation. The authors used the periodic acid-Schiff/Alcian blue stain to distinguish neutral and acidic mucins, and used specific antibodies to the mature goblet cell mucin MUC2, MUC2 core antigen, foveolar cell mucin MUC5AC, and gastric trefoil factor (TFF1), to characterize their presence and distribution in colonic tissue sections from patients with IBD. Results: Both core and mature MUC2 were expressed in all colonic goblet cells from patients with ulcerative colitis (UC) and Crohn disease and from healthy controls. MUC5AC and TFF1, which are not normally expressed by colonic tissue, also were expressed in scattered goblet cells, coexpressing with MUC2. In areas of goblet cell depletion, MUC2 was present in cytoplasmic granules of flattened, cuboidal, nongoblet-cell–like surface cells. The staining was more intense and homogenous with the MUC2 core antibody, suggesting expression of relatively immature mucin. Some of these cells also coexpressed MUC5AC but to a lesser extent. These findings are not unique to IBD but were also found in other types of intestinal inflammation. Conclusion: The study confirms earlier observations that MUC2 is the major colonic mucin in IBD. It appears in two forms: mature MUC2 in goblet cells and immature MUC2 especially in secretory granules of cells that are not phenotypically goblet cells. MUC5AC and TFF1 expression in goblet cells is common in IBD and other inflammatory conditions of the colon. These changes may represent a nonspecific repair function of the colon cells to compensate for damage to barrier function.

Celiac Disease and Pediatric Type 1 Diabetes: Diagnostic and Treatment Dilemmas

Despite the advent of sensitive and specific serologic testing, routine screening for celiac disease (CD) in diabetic populations may not be universal practice, and many clinicians struggle to find the optimal approach to managing CD in pediatric Type 1 diabetes (T1D) patients. While some clinicians advocate screening for CD in all patients with T1D, others are unsure whether this is warranted. The diagnosis of patients who present with symptomatic CD, including malabsorption and obvious pathology upon biopsy, remains straightforward, with improvements noted on a gluten-free diet. Many patients identified by screening, however, tend to be asymptomatic. Evidence is inconclusive as to whether the benefits of screening and potentially treating asymptomatic individuals outweigh the harms of managing a population already burdened with a serious illness. This review focuses on current knowledge of CD in children and youth with T1D, highlighting important elements of the diseases pathophysiology, epidemiology, clinical presentation, and diagnostic challenges.

Slow-release 5-aminosalicylic acid therapy in children with small intestinal Crohn's disease.

Pharmacologic agents effective in the treatment of Crohns disease confined to the small intestine are limited. The therapeutic efficacy of oral mesalazine in small bowel inflammation, although theoretically promising, remains unproven. In an open-labeled initial trial, timed-release 5-aminosalicylic acid (5-ASA), administered al a daily dosage of 30.6 ± 9.0 mg/kg (mean ± SEM) to children with active Crohns disease involving the small intestine, was associated with improvement on the Harvey index in six of 12 patients treated for 8.1 ± 3.9 weeks. In a subsequent prospective, double-blind study 14 children, ages 9.3 to 16.1 years, with active Crohns disease limited radiologically in the small intestine were randomized to receive either timed-release 5-ASA [50 mg/kg/day (maximum 3 g/day)] or placebo for 8 weeks. Following a 4-week washout period, patients crossed over to receive the other study drug for a further 8 weeks. Six children completed the entire 20-week trial. The van Hees index improved among patients receiving 5-ASA for 8 weeks (Δ = - 18 ± 6.4) but deteriorated among patients given placebo (Δ = + 14 ± 4.1) (p < 0.05). Mean Crohns Disease Activity Index (CDAI) decreased marginally after 8 weeks of 5-ASA treatment (Δ = - 48 ± 38.2) but not with placebo (Δ = - 3.0 ± 7.9) (p = 0.31). Of the eight noncompleters, more patients dropped out of the study because of lack of therapeutic response to placebo (n = 5) than to 5-ASA (n = 2). No serious adverse clinical effects were observed during either trial, but one adolescent girl reported mild hair loss that was promptly reversed after the drug was discontinued. These results indicate that timed-release 5-ASA may be beneficial in the medical therapy of children with active small bowel Crohns disease.

Changes in gastric emptying in early postnatal life

OBJECTIVE To study the pattern of gastric emptying in very premature infants and to determine whether there are changes with postnatal age and the ability to tolerate feedings. METHODS Sequential ultrasound measurements of the gastric antral cross-sectional area were obtained in 32 infants (mean gestational age, 26 +/- 1 weeks) before and after feeding for 2 hours. Studies were carried out after initiation of feedings, when full feedings were received, and at 32 weeks. Infants classified as feeding intolerant (n = 9) were also studied when feedings were restarted. Gastric emptying was assessed by the time taken for antral cross-sectional area to reach maximal value and to decrease to half the maximal increment (half-antral clearance). RESULTS Delayed antral distention was observed at the time of the initial study in both feeding-tolerant (8 of 23) and feeding-intolerant (8 of 9) infants; however, there were significant differences in times for maximal antral distention (p < 0.002) and half-antral clearance (p < 0.006) between the feeding-tolerant and feeding-intolerant infants. By the time of full feedings, the feeding-intolerant infants showed immediate gastric emptying but still had a longer half-antral clearance time (p < 0.01). By 32 weeks, all infants had immediate antral distention and a more mature curvilinear pattern of gastric emptying. CONCLUSIONS Knowledge of these different patterns of gastric emptying in very premature infants may lead to the development of more rational feeding strategies.

A single center 26-year experience with treatment of esophageal achalasia: is there an optimal method?

PURPOSE Treatment modalities for achalasia are evolving and remain controversial. Herein, we report the relative efficacy and outcomes after dilatation or myotomy in children with achalasia. METHODS A retrospective analysis of all children treated for achalasia at a tertiary center from 1981 to 2007 was performed (n = 40). Demographics, presenting symptoms, perioperative parameters, and outcomes were analyzed using t tests and chi(2) statistics. RESULTS Thirty patients were initially treated by esophageal dilatation (ED), whereas 10 were treated by laparoscopic or open Heller myotomy (HM). Both groups were similar with respect to age (10.6 vs 12.4 years; P = .19). There were 18 males and 12 females in the ED group, compared to 5 males and 5 females in the HM group (P = .72). Mean duration of symptoms before diagnosis, including dysphagia, vomiting, food sticking, chest pain, and weight loss, was 15.9 months for ED and 10.7 months for HM (P = .41). Mean time from diagnosis to initial intervention was 76 days in ED vs 86 days in HM (P = .78). Subsequent interventions by myotomy or both dilatation and myotomy were required in 9 (30%) of 30 patients in the ED group and 2 (20%) of 10 patients in the HM group (P = .70). A clear transition from open to laparoscopic approach occurred between 1995 and 2001. Mean operating times were comparable (186.3 vs 156.0 minutes; P = .48). Of 14 laparoscopic myotomies, 11 (79%) had fundoplication, and 2 (18%) of the 11 were converted to open procedure. Intraoperative mucosal perforation rates were similar between open and laparoscopic groups (17% vs 18%). At follow-up, 32% of ED patients vs 43% HM had complete symptom relief (mean follow-up duration, 75.2 months; SD, 196.5). CONCLUSION Both dilatation and myotomy are effective immediate treatment of achalasia. A clear transition to and preference for laparoscopic approach has occurred in the treatment of achalasia in children.

Management of fibrosing pancreatitis in children presenting with obstructive jaundice

Background—Children with fibrosing pancreatitis are conventionally treated surgically to relieve common bile duct (CBD) obstruction caused by pancreatic compression. Residual pancreatic function has not been formally tested in these patients. Aims—To evaluate the usefulness of non-surgical temporary drainage in children with fibrosing pancreatitis and to assess pancreatic function after resolution of their CBD obstruction. Patients—Four children (1.5–13 years; three girls). Methods and results—Abdominal sonography and computed tomography revealed diffuse enlargement of the pancreas, predominantly the head. The CBD was dilated due to compression by the head of the pancreas. Pancreatic biopsy specimens obtained in three patients showed notable acinar cell atrophy and extensive fibrosis. Cystic fibrosis was excluded. No other cause of pancreatitis was identified. Pancreatic tissue from one patient contained viral DNA sequences for parvovirus B19 detected by polymerase chain reaction; serum IgM to parvovirus was positive. Three patients had temporary drainage of the CBD and one patient underwent a choledochojejunostomy. Serial imaging studies revealed resolution of the CBD obstruction with reduction in pancreatic size. Exocrine pancreatic function deteriorated. Three patients developed pancreatic insufficiency within two to four months of presentation. The fourth patient has notably diminished pancreatic function, but remains pancreatic sufficient. None has diabetes mellitus. Conclusions—Temporary drainage of the CBD obstruction is recommended in fibrosing pancreatitis in children along with close monitoring of the clinical course, before considering surgery.

Use of N-Acetyl Cysteine for the Treatment of Parenteral Nutrition-induced Liver Disease in Children Receiving Home Parenteral Nutrition

The use of long-term parenteral nutrition (PN) in children with significant gut failure has been associated with progressive cholestatic liver disease (1–4). Progression to liver cirrhosis and end-stage liver disease are well-known consequences of long-term dependence on PN. The etiology of liver disease related to PN administration seems to be multifactorial (1–3). There is evidence linking the macronutrient and micronutrient content of PN solutions to the onset and severity of PN-induced liver cholestasis (4). Recent studies in animal models, in particular, have demonstrated an association between the onset of cholestatic liver disease and intravenous (IV) methionine (MET) intake (4–6). Most commercial PN solutions have relatively higher amounts of MET and little or no cysteine (CYS) because of the instability of CYS in solution (7). Inasmuch as CYS is an important precursor of glutathione (GSH), it was hypothesized that provision of parenteral CYS could potentially counteract the oxidative stress that occurs in liver cholestasis (8). Recently, our group showed that Nacetyl cysteine (NAC) can be used as a source of CYS in PN solutions in piglets (9). We supplemented 2 infants and 1 child with PN-induced liver disease who were receiving PN at home with IV NAC as an adjunctive therapy to minimize further liver damage induced by PN.