A cross-sectional study of nausea in functional abdominal pain: relation to mucosal mast cells and psychological functioning.

BACKGROUND: Nausea is a common symptom in youth with chronic abdominal pain. The aims of the current study were to assess: 1) the frequency of nausea in patients with functional dyspepsia (FD) and irritable bowel syndrome (IBS), respectively, as defined by Rome IV criteria; and, 2) relationships between nausea and mucosal inflammation as defined by antral and duodenal eosinophil and mast cell densities. A secondary aim was to assess relationships between nausea and other gastrointestinal symptoms, non-gastrointestinal somatic symptoms, and psychological dysfunction. METHODS: Records from patients with pain associated functional gastrointestinal disorders were retrospectively reviewed for gastrointestinal and somatic symptoms and anxiety, depression, and somatizations scores as assessed by the Behavior Assessment System for Children (BASC-2). In addition, previous gastric and mucosal biopsies were assessed for mast cell and eosinophil densities, respectively. RESULTS: 250 patients, ages 8 to 17 years, were assessed. Nausea was reported by 78% and was equally prevalent in those with FD alone, those with IBS alone, and those with both FD and IBS. Nausea was associated with increased mean (21.4 vs. 17.5) and peak (26.2 vs. 22.9) duodenal mast cell densities as compared those without nausea. Nausea was also associated with a wide variety of individual gastrointestinal symptoms, as well as headaches, fatigue, and dizziness. Lastly, nausea was associated with elevated self-report scores for anxiety (55.2 vs. 50.0), depression (50.2 vs. 46.1), and somatization (70.3 vs. 61.8). CONCLUSIONS: Nausea is common in children and adolescents with pain-associated FGIDs as defined by Rome IV and is not unique to either FD or IBS. Nausea is associated with increased mucosal mast cell density, non-gastrointestinal somatic symptoms, and psychologic dysfunction.

Mucosal Th17 Cells Are Increased in Pediatric Functional Dyspepsia Associated with Chronic Gastritis.

BACKGROUND: Chronic gastritis is a common histologic finding in children with functional dyspepsia (FD). While Th17 cells have been implicated in other forms of gastritis, they have not been evaluated in chronic gastritis. AIMS: The aim of the current study was to assess Th17 cells in children with FD with and without chronic gastritis. METHODS: Densities were determined for Th17 cells, eosinophils, and mast cells, respectively, in both the gastric antrum and the duodenum. Densities were compared between five groups: FD with chronic gastritis (N = 20), FD without chronic gastritis (N = 20), Helicobacter pylori-associated gastritis (N = 10), Crohn's gastritis (N = 10), and normal controls (N = 10). Th17 densities were also compared between patients with and without early satiety. RESULTS: FD with chronic gastritis was associated with higher Th17 cell density as compared to normal controls and comparable to both H. pylori-associated gastritis and Crohn's gastritis. Eosinophil and mast cell densities were higher in FD patients with chronic gastritis as compared to either FD without gastritis or normal controls. Th17 density was higher in patients reporting early satiety but not in those with epigastric pain. CONCLUSIONS: FD with chronic gastritis is associated with higher Th17 cell, eosinophil, and mast cell density as compared to FD without chronic gastritis or normal controls. Chronic gastritis demonstrated Th17 cell density similar to that seen in other conditions where Th17 cells are believed to play a pathogenic role. Th17 cells may represent another therapeutic target in these patients.

Presence of Increased Mast Cells in Infants and Children with Volume and Variety Limited Intake.

BACKGROUND: Reports indicate patients with feeding difficulties demonstrate signs of inflammation on biopsies, notably eosinophilia, but it is unknown whether mast cell density contributes to variety or volume limitation symptoms. The aim of our study was to evaluate eosinophil and mast cell density of EGD biopsies in pediatric patients with symptoms of decreased volume or variety of ingested foods. METHODS: We conducted a single-center, retrospective chart review of EMRs for all new feeding clinic patients between 0 and 17 years of age. Patients were categorized by symptoms at the initial visit as well as eosinophil and mast cell densities in those with EGD biopsies. Ten patients were identified as controls. RESULTS: We identified 30 patients each with volume and variety limitation. Antral mast cell density was increased in 32.1% of variety-limited patients, 37.5% of volume limited patients, and in no controls; Duodenal mast cell density was increased in 32.1% of variety-limited patients, 40.6% of volume-limited patients, and in no controls. CONCLUSIONS: In both variety- and volume-limited patients, antral and duodenal mast cell densities were increased. These associations warrant further investigation of the mechanism between mast cells and development of feeding difficulties, allowing more targeted pediatric therapies.

Colonic mucosal eosinophilia in children without inflammatory bowel disease.

Children undergoing colonoscopy and mucosal biopsies may show increased colonic mucosal eosinophils, which may or may not be associated with inflammatory bowel disease. There is not much clinical data on American children who have isolated increased colonic mucosal eosinophils. We sought to study the clinical correlates of children without inflammatory bowel disease who show increased mucosal eosinophils to understand their clinical presentation, etiological associations, and outcome. A retrospective analysis of children seen at a tertiary-level Children's hospital was performed by reviewing their medical charts and extracting pertinent data. There were 110 children in the study who had increased colonic mucosal eosinophils. Most children presented with abdominal pain, but several of them also had constipation, blood in stools, and diarrhea. Food allergies, irritable bowel syndrome, asthma, and lactase deficiency were the top four conditions present in these patients. Pathology of the colonic distribution revealed involvement of more than two colonic regions in 86% of the subjects, and only two subjects showing epithelial or crypt involvement by eosinophils. All subjects had a good outcome. Children with colonic mucosal eosinophilia (CME) who do not have an inflammatory bowel disease most frequently present with abdominal pain and primarily an increase of lamina propria eosinophils in two or more colonic regions. Based on the etiological associations we noted in the study, a work-up of children with CME may encompass detailed history for functional gastrointestinal disorders and lactose intolerance, testing for food and environmental allergies, stool examination for parasites, and peripheral blood counts. Almost all children had resolution of symptoms in the studied period suggesting that CME in children has a good clinical outcome.

Mucosal eosinophils, mast cells, and intraepithelial lymphocytes in youth with rumination syndrome.

BACKGROUND: Rumination syndrome has been associated with increased duodenal eosinophils and intraepithelial lymphocytes in adults. The aims of the current study were to assess densities of antroduodenal eosinophils and mast cells and duodenal intraepithelial lymphocytes in youth with rumination syndrome and to compare cell densities in those with and without abdominal pain or early satiety. METHODS: Twenty-eight youth fulfilling Rome IV criteria for rumination syndrome who had undergone endoscopy were identified and compared to 10 controls. Antral and duodenal biopsies were assessed to determine densities of eosinophils, mast cells, and intraepithelial lymphocytes. Cell densities were also compared between rumination patients with and without abdominal pain and those with and without early satiety. KEY RESULTS: Antral mast cell (peak 18.5±6.5 vs. 12.5±2.7) and eosinophil (peak 9.6±5.2 vs. 4.9±2.1) densities were significantly greater in patients with rumination syndrome as compared to controls. Duodenal intraepithelial lymphocyte densities were also increased in rumination syndrome (18.9 ± 5.1 vs. 11.7 ± 1.5; p<.001). Associations were independent of the presence of abdominal pain or early satiety. CONCLUSIONS AND INFERENCES: In conclusion, we found an increase in eosinophil and mast cell densities in the gastric antrum and an increase in intraepithelial lymphocytes in the duodenum in youth with rumination syndrome which was independent of the presence of abdominal pain or early satiety. These findings suggest a potential role for inflammation in the pathophysiology of rumination syndrome. Future studies should address whether treatment directed at these cells are beneficial in treating rumination syndrome.

Symptoms and subtypes in pediatric functional dyspepsia: relation to mucosal inflammation and psychological functioning.

OBJECTIVES: The aim of the present study was to explore relations between antral or duodenal inflammatory cells and aspects of psychological functioning with clinical symptom presentation in children with functional dyspepsia (FD), as well as to determine whether histologic inflammation and/or psychopathology are differentially associated with FD subtypes as defined by the Rome II and Rome III criteria. PATIENTS AND METHODS: One hundred pediatric patients with dyspepsia completed a standardized history and physical examination at initial evaluation. Patients and parents also completed a measure of psychological functioning. Subsequently, 63 of these patients underwent upper endoscopy with biopsy (4 patients excluded from analysis because of mucosal disease). Inflammatory cells in the mucosa of stomach and duodenum were enumerated. Associations between specific symptoms and FD subtypes with inflammatory cell densities and anxiety, depression, and somatization scores were examined. RESULTS: Rome III subtypes were more robustly related to differences in mast cell densities and scores on psychologic subscales than was true for Rome II subtypes. At the individual symptom level, having pain wake the patient from sleep was associated with higher duodenal mast cell density. Bloating was associated with lower levels of general antral inflammation, as well as higher self-reported levels of anxiety and somatization. Early satiety and bothersome postprandial fullness also were associated with higher levels of self-reported anxiety and depression. CONCLUSIONS: The present study provides preliminary evidence for a relation between clinical presentation, specific types of inflammatory cell infiltrates, and aspects of psychological functioning in children with FD. Rome III subtyping, adopted for adult dyspepsia, may be relevant to the pediatric population.

Colonic mucosal inflammatory cells in children and adolescents with lactase deficiency.

INTRODUCTION AND OBJECTIVES: Many of the symptoms of patients with lactose intolerance are due to fermentation of undigested lactose in the colonic lumen, which may also lead to inflammatory cell changes in the colonic mucosa. The objective of our project was to understand the histopathological changes involving infiltration of eosinophils and mast cells in the colonic mucosa of children with lactase deficiency (LD). METHODS: In this retrospective study we studied colonic mucosa of children and adolescents with LD to determine if any pathological changes or inflammatory cell changes were present. Pathology reports and Hematoxylin and eosin stained slides were reviewed. Tryptase immunohistochemistry was performed for mast cell assessment. RESULT: There were 30 subjects in the study who had a LD and 15 presented with diarrhea and 15 without diarrhea. The colonic mucosa of 35.5 % of the subjects revealed increased mucosal eosinophils. There was no increase of mast cells or lymphocytic colitis in any of the subjects. Excepting for the increased eosinophils in a subset of the subjects, all had a normal appearance of the colonic mucosa. CONCLUSION: Colonic mucosa of children and adolescents with LD has a normal histological appearance in majority of the patients. However, 35 % of the patients could demonstrate elevated eosinophils. In primary LD without any comorbidity there is no increase of mast cells and lymphocytic cells in the colonic mucosa.

The relationship between mucosal inflammatory cells, specific symptoms, and psychological functioning in youth with irritable bowel syndrome.

Both mucosal inflammation and psychologic dysfunction have been implicated in irritable bowel syndrome (IBS). While some relationships between inflammation (mast cells and eosinophils) and depression have been reported in adults with IBS, relationships between inflammation and psychologic function have not been studied in children and adolescents. The aims of the current study were to: (1) assess densities of colonic mast cells, eosinophils, and TH17 cells in youth with IBS; and, (2) explore relationships between these cells and specific IBS symptoms and psychologic functioning. Utilizing previously obtained biopsies from the descending and rectosigmoid colons, densities were determined for mast cells, eosinophils, and TH17 cells, respectively, in 37 youth with IBS and 10 controls. In IBS patients, densities were assessed in relation to specific IBS symptoms and in relation to self-report anxiety and depression scores. In both the descending and rectosigmoid colons, densities of mast cells, eosinophils, and TH17 cells were higher in IBS patients as compared to controls. In IBS patients, rectosigmoid mast cell density was higher in those reporting pain relief with defecation. Also, in IBS patients, rectosigmoid eosinophilia was associated with higher anxiety scores and eosinophil density correlated with depression scores. In the descending colon, eosinophil and mast cell densities both correlated with depression scores. In conclusion, mucosal inflammation (mast cells and eosinophils) is associated with pain relief with defecation and with anxiety and depression in youth with IBS.

A Brief Report of Immunohistochemical Markers to Identify Aggressive Hepatoblastoma.

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Although survival of patients has improved significantly over the last 2 decades, a significant number of patients do not respond to standard chemotherapy. We conducted a pilot study to understand if there was immunophenotypic difference between tumors that respond well to chemotherapy versus that do not. We selected 10 cases of HB from children presenting at our hospital. All patients had initial tissue diagnosis, underwent chemotherapy followed by surgical resection. The cases were divided into 2 groups: aggressive group with 5 cases (all of which had a poor response to chemotherapy); and a good clinical outcome group with 5 cases (all of which responded well to chemotherapy). We excluded the small cell variant of HB from the study because its poor clinical outcome is well known. To be placed in the aggressive group we used the following criteria: <70% necrosis following chemotherapy or recurrence/distant metastasis following chemotherapy. From tissue obtained before chemotherapy, 1 representative block of formalin-fixed, paraffin-embedded tissue was selected for immunohistochemistry. Following review of published literature, antibodies were selected to detect Survivin, PLK-1, Cytokeratin19 (CK19), N-Myc, Yap, Notch2, Hes1, Hes5, and C-Myc. Our results show that Survivin, CK19, and Yap have a diffuse (>75%) positive staining of tumor cells in the aggressive tumors compared with good outcome tumors. However, staining for Yap was weak. Interestingly, there was loss of nuclear expression of C-Myc in majority of tumor cells in aggressive tumors, whereas nuclear staining was retained in most tumor cells of good responders. The N-Myc and PLK-1 immunostains did not reveal any significant differences in the 2 groups of HB. The immunostains for Notch2, Hes1, and Hes5 showed weak to moderately strong staining in tumor cells, but there was no obvious difference in the 2 groups. Our pilot study suggests that in nonsmall cell HB, diffusely increased expression of Survivin and CK19, and loss of nuclear expression of C-Myc marks the tumors as having an aggressive course.

An observational study of headaches in children and adolescents with functional abdominal pain: Relationship to mucosal inflammation and gastrointestinal and somatic symptoms.

Headaches and abdominal pain are among the most common pediatric pain conditions. Mast cells have been implicated in the pathophysiology of migraines, as well as functional dyspepsia (FD) and irritable bowel syndrome (IBS). The primary aims of the current study were to assess headache prevalence in patients with FD and to assess the association between headaches and mucosal mast cells and eosinophils. An additional aim was to explore associations of headache with other symptoms.We conducted a cross-sectional retrospective chart review of 235 consecutive patients with chronic abdominal pain. All patients had completed a standardized questionnaire as part of their routine clinical evaluation. Both gastrointestinal and non-gastrointestinal somatic symptoms were included in the analysis. All patients diagnosed with FD had undergone upper endoscopy with biopsies obtained from the gastric antrum and duodenum and these specimens were utilized to assess eosinophil and mast cell densities, respectively.Overall, 86% of patients fulfilled Rome IV criteria for FD. Headache was reported by 73.8% of FD patients versus 45.2% of non-FD patients (P = .001). Duodenal mast cell densities were significantly increased in those reporting headaches. Headache was not associated with any specific gastrointestinal symptoms but was associated with a wide array of non-gastrointestinal symptoms including fatigue, dizziness, muscle pain, joint pain, and chest pain.Headaches are common in children and adolescents with abdominal pain and, utilizing Rome IV criteria, are specifically associated with FD. In patients with FD, headaches are associated with increased duodenal mast cell density and a variety of somatic symptoms, all of which are possibly the result of mast cell activation.

Histopathological changes in the gastroduodenal mucosa of children with functional dyspepsia.

INTRODUCTION AND OBJECTIVE: Functional dyspepsia (FD) is a functional gastrointestinal disorder that affects a significant number of children presenting with chronic abdominal pain. A high proportion of these children undergo endoscopy to obtain mucosal biopsies which, by standard criteria, generally do not identify a clear explanation for symptoms. We undertook this study of children diagnosed with FD to elucidate the histopathological changes of gastroduodenal mucosa and to describe mast cell and eosinophil densities. METHODS: In this retrospective study, we evaluated 114 FD subjects and 10 control subjects from whom gastric antral and duodenal biopsies were available as formalin-fixed paraffin embedded tissue. We reviewed the H&E stained slides and performed immunohistochemistry for tryptase, to determine eosinophil and mast cell densities, respectively. RESULTS: We found that the duodenal mucosa showed no evidence of inflammation in 86% of subjects, a median peak eosinophil count of 24 and a median peak mast cell count of 22. The histopathological features of the gastric antral mucosa comprised no evidence of inflammation in 52% of subjects, mild chronic inflammation in 41% of subjects, a median peak eosinophil count of 11.5 and a median peak mast cell count of 18. CONCLUSIONS: A significant proportion of children with FD do not show chronic or active inflammation, but have increased mast cell density and eosinophil density in the stomach and duodenum mucosa. Our study adds functional dyspepsia to the list of various abnormalities that have increased gastroduodenal mucosal elevations of eosinophils and/or mast cells.

Antral inflammatory cells, gastric emptying, and electrogastrography in pediatric functional dyspepsia.

The aims of the current study were to determine the activation states of antral eosinophils and mast cells and to evaluate the interactions of antral inflammatory cells with gastric emptying and electrogastrography (EGG) in 30 pediatric patients with functional dyspepsia. Eosinophil degranulation was moderate in 42% and extensive in 54% of patients. Mast cell degranulation was > 50% in 81% of patients. Elevated mast cell density was associated with slower one hour gastric emptying and increased preprandial dysrhythmia. Mast cell density correlated with the preprandial percentage tachygastria. CD3+ cell density correlated with the preprandial percentage tachygastria also, but only in patients with increased eosinophil density. In conclusion, antral eosinophils and mast cells are significantly activated in pediatric functional dyspepsia. Mast cell density is associated with delayed gastric emptying and preprandial dysrhythmia, suggesting that there may be an interaction between antral inflammation and gastric electromechanical dysfunction in the pathophysiology of pediatric functional dyspepsia.

Umbilical cord lesions in early intrauterine fetal demise.

CONTEXT: The cause for intrauterine fetal demise (IUFD) occurring in early gestation in a high percentage of spontaneous abortions is unknown. OBJECTIVE: To determine the association, if any, of umbilical cord abnormalities with early IUFD. DESIGN: All cases of IUFD occurring within 16 weeks of gestation that presented to our hospitals between August 1998 and July 2001 were prospectively studied. Once the fetal demise was diagnosed, pregnancy was terminated by medical induction, such that the products of conception were largely delivered intact. Cases with an intact umbilical cord connecting the fetus and placenta were considered in the study, whereas disrupted cord and curettage material was excluded from the study. RESULTS: A total of 153 early IUFD cases were seen during the period of study. The medical induction yielded intact products of conception in 122 cases, whereas 31 cases had to be completed by curettage, as the expulsion of the conceptus was incomplete. Thirteen of the 122 IUFD cases showed abnormalities of the umbilical cord. The cord lesions most frequently encountered were constriction and coiling abnormalities. Other lesions seen included hemorrhage, thrombosis, edema, and amniotic band. CONCLUSIONS: A significantly high number (10.7%) of IUFD in early gestation are associated with umbilical cord abnormalities. Routine assessment of umbilical cords in early pregnancy might help to detect pregnancies at risk.

Congenital lipoblastoma of the scalp.

Lipoblastoma is a unique tumor of infancy and early childhood that can occur congenitally. It commonly occurs in trunk and extremities, but also rarely in head and neck. We have not encountered any report of congenital lipoblastoma of scalp in published literature. Here we describe the case of an infant who presented with a rapidly growing large scalp mass that measured 15 x 15 x 10 cm. At birth, the mass was located on the bregma but progressed to extend into the left upper eyelid and eyebrow. The mass was resected in two stages: the first stage consisted of resecting the scalp mass and the second stage consisted of excising the eyelid extension of the lesion. The histology of both resection specimens was similar and showed lobular adipose tissue separated by fibrous septae, which was consistent with a lipoblastoma. The child is free of recurrence at follow-up 3 years after the resection.