Esophageal polyps in pediatric patients undergoing routine diagnostic upper gastrointestinal endoscopy: a multicenter study.

Esophageal polyps are uncommon findings in pediatric patients, and reports have been limited to case reports. Esophageal polyps have been previously ascribed to esophagitis secondary to gastroesophageal reflux, medications, infections and recurrent vomiting. They have been associated with underlying conditions such as hiatal hernia, Barrett's esophagus, eosinophilic esophagitis and Crohn's disease. Presenting complaints of children with esophageal polyps have included vomiting, dysphagia, hematemesis and abdominal pain. The aim of this paper is to characterize the incidence, clinical presentation and progression, histologic subtypes and associated mucosal abnormalities in children with esophageal polyps. A retrospective multicenter study was performed at four institutions identifying diagnosis of esophageal polyps in pediatric patients (<21 years). Information was obtained from patient charts, endoscopy reports and histopathology reports. Specimens and slides were examined by experienced pediatric pathologists for all included cases. Esophageal polyps were identified in 13 patients (9 M) from 9438 esophagogastroduodenoscopies (0.14%). Mean age of subjects was 9.2 years. Vomiting was the most common indication for endoscopy. Polyp location was at the gastroesophageal junction in 7 of the 13 cases. Most polyps were inflammatory (n = 7). Esophagitis was noted in 69% of those with esophageal polyps. Repeat endoscopies in six patients at a mean interval of 8 months noted persistence of polyps in all six patients. This paper is the first to characterize esophageal polyps in pediatrics. These polyps are rare in children and often are associated with esophagitis. Presenting complaints seem to vary by age. Polyps did not consistently change with either time or acid suppression. The optimal management strategy has yet to be defined and likely depends on the underlying pathophysiologic process.

Critical analysis of bariatric procedures in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a complex genetic disorder localized to chromosome 15 and is considered the most common genetic cause of the development of life-threatening obesity. Although some morbidities associated with PWS, including respiratory disturbance/hypoventilation, diabetes, and stroke, are commonly seen in obesity, others such as osteoporosis, growth hormone deficiency, and hypogonadism, and also altered pain threshold and inability to vomit, pose unique issues. Various bariatric procedures have been used to cause gastric stasis, decrease gastric volume, and induce malabsorption, with poor results in PWS patients in comparison with normal obese individuals.

Inflammatory bowel disease in children: a pediatrician's perspective.

Crohn's disease (CD) and ulcerative colitis (UC) are common and heterogeneous chronic inflammatory bowel disorders of childhood that account for up to 25% of all patients with inflammatory bowel disease (IBD). In CD, the familial pattern of disease concordance would suggest that genetics contribute to disease etiology. Children are more likely to have proximal small bowel disease complicated by stricture formation, fistulization and the need for surgical intervention. The predisposition for small bowel disease has been associated with mutations of the nucleotide oligomerization domain 2 (NOD2)/Caspase activation and recruitment domain 15 (CARD15) gene on chromosome 16 in 1/3 of patients with CD. Homozygous patients also show an early age at disease onset and a relatively high relative risk for isolated stricturing distal ileal disease. The potential clinical role for NOD2 testing in either the diagnosis or the therapeutic management of patients with CD has yet to be determined. The precise age of onset of CD and UC can be difficult in children. Subclinical phases of disease can be identified through a decrease in weight and height velocity, and a delay in pubertal development. However, a confident distinction between CD and UC also remains a taxonomic dilemma in 25% of pediatric patients with IBD, despite recent technological advances in diagnostic techniques, including gadolinium enhanced magnetic resonance imaging (MRI) and capsule endoscopy, and serological testing. The early introduction of immunomodulators, including azathioprine and 6-mercaptopurine have proven efficacy in maintaining long-term remission without concurrent corticosteroids. The pharmacogenomic of 6-MP metabolism has been shown to be useful in predicting susceptibility to antimetabolite induced toxicity, and possibly allowing physician's to individualize drug therapy to improve clinical response. Novel treatment strategies, including infliximab are being developed in Pediatrics with the aim at improving overall treatment efficacy and potentially avoid surgery.

Optimization of the safety and efficacy of interferon beta 1b and azathioprine combination therapy in multiple sclerosis.

We conducted an open-label pilot clinical trial to evaluate the safety and efficacy of adding oral azathioprine to the treatment regimen of 15 multiple sclerosis patients breaking through monotherapy with interferon beta-1b. There were no serious adverse events. Gastrointestinal side effects and leukopenia were the most common adverse events and limited dose escalation. There was a 65% reduction in the number of gadolinium-enhanced magnetic resonance imaging (MRI) lesions on combination therapy compared to the baseline values (P =0.003). A total WBC count less than 4800/mm3 was the best predictor of MRI response.

Pediatric jejunoileitis: a severe Crohn's disease phenotype that requires intensive nutritional management.

BACKGROUND: Jejunoileitis (JI) is an unusual manifestation of Crohn's disease (CD) that has been associated with high morbidity and the frequent need for surgical intervention. Although the disease has been well-described in adults, the true prevalence and clinical phenotype in children is unknown. AIM: To compare the clinical course and nutritional impact of CD in children with and without proximal small bowel involvement. METHODS: Patients with either Crohn's jejunitis or JI with or without colonic involvement were identified through a clinical database (1996--2002). All radiologic studies were reviewed by an experienced radiologist blinded to the clinical diagnosis. Thirty-six patients with CD without histologic or radiologic signs of proximal small bowel involvement were used for comparison. All medical, surgical, and hematologic parameters were compared in both disease groups. RESULTS: Among the 134 patients with CD, 23 (17%) had radiologic signs of JI, including intestinal fold thickening (57%), luminal narrowing (31%), and skip lesions (13%). Enteric fistula (6%) and strictures (6%) were less common. Patients with JI were likely to be stunted at the time of diagnosis, require surgical intervention (P < 0.03) and nutritional therapy in the form of nasogastric tube feeds (P < 0.03). Nutritional therapy was also associated with an improvement in height in patients with proximal small bowel disease (OR:5.87). DISCUSSION: JI is a relatively common disease phenotype in children with CD that requires aggressive nutritional and surgical intervention. Future studies are required to determine if the early detection and use of immune modulators may lessen the morbidity associated with proximal small bowel disease.

Peripheral blood mononuclear cell DNA 6-thioguanine metabolite levels correlate with decreased interferon-gamma production in patients with Crohn's disease on AZA therapy.

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are well known for their lymphocytotoxic and bone marrow suppressive effects in the management of patients with leukemia. Although their immunosuppressive properties are mediated by the active AZA antimetabolite 6-thioguanine (6-TG), its mechanism of action is largely unknown. In IBD, a significant inverse correlation has been shown between erythrocyte 6-TG metabolite levels and disease activity, further supporting the proposed immunosuppressive role for 6-TG. Since leukocytes possess quantitatively different purine metabolic pathways compared to erythrocytes, this study aims to measure lymphocyte DNA 6-TG metabolites and correlate levels with the INF-gamma and IL-10 cytokine profile in patients with Crohn's disease (CD). Forty-six adult patients with CD, either naive (17) or on long-term (>4-month) AZA therapy (29), had erythrocyte and lymphocyte DNA 6-TG levels measured by reverse-phase HPLC under UV detection (6-TG, 340 nm). Lymphocyte DNA 6-TG was expressed as picomoles per milligram of DNA. Lymphocyte DNA 6-TG metabolite levels were correlated with INF-gamma and IL-10 cytokine profiles using the OptEIA kit (Pharmigen). Lymphocyte DNA 6-TG metabolite levels correlate with erythrocyte 6-TG levels (P < 0.03) but not total patient leukocyte levels. Erythrocyte 6-TG metabolite levels correlated (P < 0.01) inversely with INF-gamma but not IL-10 cytokine levels. This study suggests a preferential dampening of the TH1 response on exposure to 6-TG and a possible immunosuppressive mechanism of action for AZA. Future studies are needed to determine if cytokine profiles can be used to predict recalcitrant CD to AZA therapy.

The clinical spectrum of duodenal polyps in pediatrics.

OBJECTIVES: The aim of this retrospective study was to determine the prevalence, clinical presentation, and histologic subclassification of duodenal polyps identified on endoscopy (EGD) in pediatric patients. METHODS: We performed an 18-year retrospective study of all pediatric patients (< 21 years) with duodenal polyps diagnosed between 1983 and 2001 at The Johns Hopkins Children's Center. Our analysis includes a formal histologic evaluation of duodenal polyps either biopsied using cold-forceps or removed by snare cautery. RESULTS: Duodenal polyps were reported in 22 of 5766 EGDs (0.4%) performed in 16 (M:F; 1:1) patients with a mean (SD) age of 14.1 (5.1) years. Polyps were equal in both the Caucasian and African American population (adjusted ratio 1.2:1). The histologic subtypes included Adenomatous (42%), Brunner's gland hyperplastic (33%), hamartomatous (17%), and heterotopic gastric gland polyps (8%). The most frequent indication for EGD was surveillance in patients with polyposis syndromes; most of these patients were asymptomatic at the time of their EGD. In comparison, the most frequent indication for an EGD in patients without polyposis syndromes was abdominal pain and vomiting. CONCLUSIONS: Duodenal polyps are most frequently encountered in children with polyposis syndromes, most of whom are asymptomatic. In nonsyndromic patients, the most common histologic subtype is Brunner's gland hyperplastic polyp and presenting symptoms include abdominal pain and vomiting.

Inflammatory bowel disease in the pediatric and adolescent patient.

Advances in genetic testing have confirmed the presence of susceptibility loci on chromosomes 12 and 16 for UC and CD. These loci show a strong association with particular disease phenotypes that may explain the clinical heterogeneity of IBD. Whether multiple genotypes will be found to explain these phenotypes remains to be determined. Pharmacogenetic differences in 6-mercaptopurine metabolism can be used clinically to predict patient susceptibility to drug-induced toxicity. Novel treatment strategies are being developed at The Johns Hopkins Medical Center Hospital based on these inherent genetic differences. The aim is to improve treatment efficacy and clinical response times and prevent untoward drug-induced toxicity.

Gastric polyps in pediatrics: an 18-year hospital-based analysis.

OBJECTIVE: Gastric polyps are recognized as either an incidental finding on routine gastroscopy or a frequent occurrence in patients with polyposis syndromes. The aim of this study is to determine the prevalence, clinical presentation, and histological subclassification of gastric polyps identified on esophagogastroduodenoscopy in pediatric patients. METHODS: We performed an 18-yr retrospective study of all pediatric (<21 yr) patients with gastric polyps diagnosed between 1983 and 2000 at The Johns Hopkins Children's Center. The histology slides were all evaluated at the time of the study according to the accepted histological classification of gastric polyps. RESULTS: Gastric polyps were reported in 40 procedures (0.7%) [corrected] performed in 35 (male:female 1.3:1) patients with a mean (SEM) age at diagnosis of 14.4 (0.9) yr. Polyps were more frequent in white than in black patients (adjusted ratio 1.4:1). The histological subtypes included hyperplastic-inflammatory (42%), fundic gland (40%), hamartomatous (10%), adenomatous (5%), and heterotopic polyps (3%). Fundic gland polyps were frequently encountered in patients with familial adenomatous polyposis (81%). These patients tended to be asymptomatic at the time of their surveillance esophagogastroduodenoscopy, and frequently harbored histological changes of either dysplasia (31%) or indeterminate of dysplasia (19%). CONCLUSIONS: Hyperplastic polyps are the most frequently identified gastric polyps in our pediatric population. Fundic gland polyps are common in patients with familial adenomatous polyposis wherein they tend to harbor histological changes of dysplasia. Future longitudinal studies are needed to evaluate the temporal progression of dysplasia to gastric cancer in patients with fundic gland polyps, and to establish esophagogastroduodenoscopy surveillance guidelines.

Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease.

BACKGROUND AND AIM: The immunosuppressive properties of 6-mercaptopurine and its parent compound azathioprine are mediated by their intracellular metabolism into active 6-thioguanine (6-TG) metabolites. Measurement of erythrocyte 6-TG metabolite levels has been proposed as a useful clinical tool for assessing treatment efficacy in patients with inflammatory bowel disease (IBD). AIM: The purpose of the study was to establish a therapeutic index of treatment efficacy based on measurement of erythrocyte 6-TG metabolite levels, and apply it clinically to guide therapy. METHODS: Heparinised blood was obtained from 82 adult patients with IBD on long term (more than three months) antimetabolite therapy (63 Crohn's disease; 19 ulcerative colitis). Erythrocyte 6-TG metabolite levels were measured using reverse phase high performance chromatography, and correlated with treatment efficacy. In 22 patients with refractory Crohn's disease despite long term azathioprine therapy, their dosage was increased by 25 mg/day at eight week intervals as needed. Serial erythrocyte 6-TG metabolite levels were measured at each clinic visit and correlated with treatment efficacy. RESULTS: Clinical remission, as defined by a low disease index score in patients weaned off or on a low alternate day dose (<20 mg on alternate days) of corticosteroid, was achieved in 68% of patients on long term antimetabolite therapy. Treatment efficacy correlated with erythrocyte 6-TG levels greater than 250 pmol/8x10(8) red blood cells in patients with colonic and fistulising Crohn's disease (p<0.01) but not in patients with ileocolonic disease. Eighteen of 22 patients with incompletely responsive Crohn's disease achieved disease remission by optimising their dose of azathioprine therapy. Median (range) erythrocyte 6-TG metabolite levels increased from 194 (67-688) to 303 (67-737) pmol/8x10(8) red blood cells (p<0.05). Clinical response associated well with a reduction in corticosteroid requirements. Mean (SEM) white blood cell count decreased from 8.6 (0.9) to 6.9 (0.6) x10(3)/microl with adjustment in azathioprine dosage. No patient incurred azathioprine induced leucopenia. CONCLUSION: Measurement of erythrocyte 6-TG metabolite levels is helpful in determining the adequacy of azathioprine dosage and can be used to optimise the dose of antimetabolite therapy to achieve an improved clinical response without inducing leucopenia. Patients who are clinically refractory to azathioprine therapy despite achieving high erythrocyte 6-TG levels (>250) should be considered for adjunct or alternative forms of immunosuppressive therapy or surgery.

Enhanced bioavailability of azathioprine compared to 6-mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy.

BACKGROUND: Azathioprine and 6-mercaptopurine have proven efficacy in the treatment of Crohn's disease. Immunosuppression is mediated by their intracellular metabolism into active 6-thioguanine metabolites, and clinical responsiveness to therapy in patients with inflammatory bowel disease has been correlated with the measure of erythrocyte 6-thioguanine levels. AIMS AND METHODS: To perform a dosing equivalency analysis and comparison of clinical efficacy in 82 patients with inflammatory bowel disease on long-term (> 2 months) therapy with either branded azathioprine (Imuran) (n=26), generic azathioprine (n=38), or 6-mercaptopurine (n=18), based on the measurement of erythrocyte 6-thioguanine metabolite levels. RESULTS: Disease remission was achieved in 51% (42 out of 82) of patients treated with either azathioprine or 6-mercaptopurine therapy, and correlated well with high erythrocyte 6-thioguanine levels (> 250 pmoles/8 x 108 RBCs). Patients treated with either branded azathioprine or 6-mercaptopurine achieved significantly higher erythrocyte 6-thioguanine levels than patients treated with generic azathioprine, thereby suggesting that branded azathioprine has improved oral bioavailability compared to generic azathioprine. These data are consistent with the putative immunosuppressive role of 6-thioguanine metabolites in the treatment of inflammatory bowel disease, and provides a basis for developing a therapeutic index of clinical efficacy based on the measurement of erythrocyte 6-thioguanine metabolite levels. CONCLUSIONS: Our results suggest that differences in bioavailability may have clinical relevance when considering the need to optimize erythrocyte 6-thioguanine metabolite levels in patients deemed unresponsive to treatment on conventional drug dosages.

Dientamoeba fragilis masquerading as allergic colitis.

BACKGROUND: Dientamoeba fragilis is a rare cause of chronic infectious diarrhea and colitis in children. METHODS: Review of the clinical manifestations, diagnostic methods, and clinical course of D. fragilis infection in our hospital. RESULTS: Eleven pediatric patients are discussed, seven of whom had a history of recent travel. Clinical manifestations of infectious diarrhea included anorexia, intermittent vomiting, abdominal pain, and diarrhea, ranging from 1 to 100 weeks in duration. Peripheral eosinophilia was present in seven patients. One patient with well-documented bovine protein allergy had intermittent episodes of diarrhea and abdominal pain, despite an appropriate elimination diet. Eosinophilic colitis documented by colonoscopy, was due to D. fragilis. Metronidazole was effective in treating five patients, and iodoquinol was effective in treating four others. CONCLUSIONS: D. fragilis should be included in the differential diagnosis of chronic diarrhea and eosinophilic colitis. The identification of this pathogen requires clinical awareness of epidemiologic risk factors and presenting complaints, as well as the laboratory staining procedures essential to its proper identification.

A case of non A, non B, non C hepatitis that relapsed into fulminant hepatic failure.

We describe a 12 year-old patient that relapsed into fulminant non A, non B, non C (NANBNC) hepatitis 10 weeks post-clinical recovery. A complete clinical and pathological evaluation, including an ultra-structural examination of a liver biopsy was consistent with the diagnosis of NANBNC hepatitis. The patient relapsed into hepatic failure and required transplantation. NANBNC hepatitis may have a relapsing form that can lead to hepatic failure requiring transplantation. Consultants in hepatology should have a high degree of clinical awareness and maintain prolonged patient follow-up.

Dysplastic nitrergic neurons in the rectum of a patient with rectal ectasia.

We present a histochemical study of resected colon from a 13-year-old boy diagnosed with rectal ectasia. Laminar preparations and sectioned tissue of rectum were assayed histochemically for nitric oxide (NO) synthase activity by reducing nitro blue tetrazolium salt in the presence of the cofactor NADPH. Tissue preparations displayed intensely labelled neurons and fibers throughout the gut wall. Laminar preparations of Meissner's plexus showed a hyperplasia of ganglia and NO-related neurons throughout the length of the resected rectum compared with normal bowel. Sectioned tissue of the Auerbach's plexus demonstrated a normal number of ganglia and NO-related neurons. As well, the ectatic bowel showed a proliferation of nerve fibers in keeping with the degree of circular smooth muscle hypertrophy. This proliferation may represent a reactive phenomenon secondary to the functional obstruction. The NO histochemical technique may form the basis of further investigations in defining the cause of this functional obstruction.

Acute intrahepatic portal vein thrombosis complicating cholangitis in biliary atresia.

UNLABELLED: A 2-year-old boy with Kasai portoenterostomy had systemic features suggestive of cholangitis and acute portal vein obstruction. The rapid rise in portal pressure caused a transient, severe decompensation of hepatic function. A superior mesenteric arterial angiogram confirmed the presence of diffuse intrahepatic portal vein thrombosis. CONCLUSION: This case provides clinical and radiological evidence supporting an association between ascending cholangitis and acute intrahepatic portal vein thrombosis.

6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity.

BACKGROUND: 6-Mercaptopurine (6-MP) has confirmed short and longterm efficacy in the treatment of IBD. However, the relation between its metabolism, efficacy, and side effects is not well understood. AIMS: To assay 6-MP metabolites and to correlate levels with drug compliance, disease activity, and adverse effects of treatment. PATIENTS: Heparinised blood was obtained prior to daily administration of 6-MP in 25 adolescent Crohn's disease patients (14 ileocolitis, 11 colitis) receiving 1.2 (range 0.4-1.6) mg/kg/day for a mean of 17 (range 4-65) months. METHODS: Erythrocyte free bases 6-thioguanine (6-TG) and 6-methyl-mercaptopurine (6-MMP) were measured (pmol/8 x 10(8) red blood cells) using reverse phase high performance liquid chromatography. RESULTS: Disease activity (modified Harvey-Bradshaw index) improved significantly with 6-MP (p = 0.001). Clinical remission was achieved in 72% of patients, who stopped taking prednisone, or were successfully weaned to a low alternate day dose (< 0.4 mg/kg/OD). Remission correlated well with erythrocyte 6-TG (p < 0.05), but not 6-MMP levels. Neutropenia was associated with 6-MP use (p < 0.005), but did not correlate with erythrocyte 6-MP metabolite levels. One patient refractory to 6-MP had 6-TG, but no measureable 6-MMP production, suggesting deficient thiopurine methyl-transferase activity or poor compliance. 6-MP induced complications (hepatitis, pancreatitis, and marrow suppression) were generally associated with increased 6-MMP levels. CONCLUSIONS: These results suggest that high performance liquid chromatography measurement of erythrocyte 6-MP metabolites may provide a quantitative assessment of patient responsiveness and compliance to treatment. The data support an immunosuppressive role for 6-TG, and potential cytotoxicity of raised 6-MMP levels.

Quantitation of 6-thioguanine in peripheral blood leukocyte DNA in Crohn's disease patients on maintenance 6-mercaptopurine therapy.

The effects of 6-mercaptopurine (6MP) in inflammatory bowel disease are believed to be primarily mediated by its metabolite 6-thioguanine (6TG). Our aim was to develop an assay for measuring leukocyte DNA 6TG levels in patients with Crohn's disease, and to correlate them with levels of 6TG in erythrocytes. Heparinized blood was obtained from 15 adolescent Crohn's disease patients receiving 6MP at an average dose of 1.3 mg.kg-1 day-1 (range 0.8-1.6 mg.kg-1 day-1) for a mean of 23.7 months (range 3-71 months). Leukocyte DNA and erythrocyte 6TG levels were measured by an HPLC assay. Leukocyte 6TG levels ranged from 100 to 2305 pmol/mg DNA, while erythrocyte 6TG levels ranged from 64 to 1038 pmol/8 x 10(8) red blood cells, demonstrating significant interpatient variability. Leukocyte DNA 6TG levels correlated directly with erythrocyte 6TG levels, as measured by the Spearman rank correlation coefficient (p < 0.05). The HPLC measurement of erythrocyte and leukocyte DNA 6TG levels can be useful clinically in monitoring compliance, as well as perhaps to tailor drug metabolite levels to achieve the desired clinical effect.