Gareth Jevon

Can Tissue Transglutaminase Antibody Titers Replace Small-Bowel Biopsy to Diagnose Celiac Disease in Select Pediatric Populations?

Objectives. The use of screening tests for celiac disease has increased the number of patients referred for evaluation. We proposed that the subgroup of patients with very high tissue transglutaminase antibody (TTG) titers is positive for celiac disease and a small-bowel biopsy is not necessary to make the diagnosis. A gluten-free diet should be attempted and, if the patient’s symptoms do not improve, then a biopsy should be performed to confirm the diagnosis. Methods. A chart review of data for 103 patients who underwent both TTG testing and a small-bowel biopsy was performed. We examined the impact of using TTG values of >100 U and <20 U as cutoff values and suggested performing biopsies for patients with TTG values of 20 to 100 U, as is current practice. Results. Fifty-eight of 103 patients demonstrated positive biopsy results. Forty-nine of 103 patients had TTG levels of >100 U, with 48 of 49 exhibiting positive biopsy results. Only 7 of 16 patients with TTG values of 20 to 100 U exhibited positive biopsy results. Three patients with TTG levels of <20 U had positive biopsies; 2 were IgA negative and 1 had a duodenal ulcer. With the cutoff values of >100 U and <20 U with known IgA status, the sensitivity was 0.980 (48 of 49 cases) and the specificity was 0.972 (35 of 36 cases). An incremental cost analysis found that this proposal could potentially decrease the costs of investigation and diagnosis by almost 30%. Conclusions. When the cutoff values were changed to >100 and <20 U and IgA levels were verified, the sensitivity and specificity were very high. Patients with mid-range TTG values (20–100 U) or values of <20 U with negative IgA status should continue to undergo biopsies for diagnosis of celiac disease.

Murine MPS I: insights into the pathogenesis of Hurler syndrome

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from deficiency of the lysosomal enzyme α‐L‐iduronidase. A murine model which shows complete deficiency in α‐L‐iduronidase activity has been developed and shows phenotypic features similar to severe MPS I in humans. Here we report on the long‐term clinical, biochemical, and pathological course of MPS I in mice with emphasis on the skeletal and central nervous system (CNS) manifestations. Affected mice show a progressive clinical course with the development of coarse features, altered growth characteristics and a shortened life span. Progressive lysosomal accumulation is seen in all tissues. Skeletal manifestations represent the earliest clinical finding in MPS I mice with histologic analysis of growth plate and cortical bone revealing evidence that significant early pathology is present. Analysis of the CNS has revealed the novel finding of progressive neuronal loss within the cerebellum. In addition, brain tissue from MPS I mice shows increased levels of GM2 and GM3 gangliosides. This murine model clearly shows phenotypic and pathologic features which mimic those seen in severe human MPS I and should be an invaluable tool for the study of the pathogenesis of generalized storage disorders.

Biliary atresia and cytomegalovirus infection: a DNA study.

ABSTRACT The cause of extrahepatic biliary atresia (EHBA) is undetermined in most instances, but an infectious agent is widely suspected. Cytomegalovirus (CMV) infection has been associated with intrahepatic bile duct destruction and paucity, raising the question of its role in EHBA. We identified 12 children in the past 5 years with biliary atresia and examined the bile duct biopsy. These showed acute/chronic inflammation and epithelial degeneration. CMV inclusions were not identified. We used in situ hybridization and the polymerase chain reaction (PCR) for CMV-DNA on formalin-fixed, paraffin-embedded tissue. All samples showed the presence of amplifiable DNA using β-globin primers. No biopsy tissue showed CMV DNA using specific probes and primers. The absence of demonstrable CMV DNA by in situ hybridization and PCR in EHBA biopsies implies that it is unlikely that this virus has any major role in the pathogenesis of this condition.

Histopathologic approach to metabolic liver disease: Part 1.

INTRODUCTION Traditional approaches to the diagnosis of genetic metabolic diseases are often based on descriptions of metabolic pathways, for example, urea cycle disorders, or by moiety classes, such as carbohydrates, amino acids, lipids, or structural proteins. The address might be by clinical presentation, a method of value to the pediatrician and of assistance to the pathologist. Some disorders are expressed acutely and severely in the fetus and neonate, others in a more chronic manner in older infants and children. Ultrastructural morphologists, using an organelle-based approach, discuss peroxisomopathies, mitochondrial and lysosomal disorders. These viewpoints broaden the approach to differential diagnoses, but the analysis of diagnostic possibilities often begins with the histologic picture seen by the pathologist examining a liver biopsy. Inherited disorders of metabolism may have no morphologic impact on the liver, or the manifestation may be minimal, as, for example, in most urea cycle disorders where trivial steatosis, congestion, or very occasional hepatocellular necrosis occurs. Under these circumstances, the pathologist has no opportunity to offer a diagnosis, except an exclusionary one. Many metabolic diseases affecting the liver do create typical histopathologic patterns that assist the pathologist in the diagnostic workup (Table 1). Others show a limited number of patterns, while some evolve from one pattern to another. The interpretation, therefore, requires knowledge of the histologic mosaic and is improved by understanding the pathogenesis, pace, and course of metabolic diseases. The presentation here highlights lightand electron-microscope manifestations in the liver at the time of biopsy, with emphasis on the value of morphology in guiding the investigation of metabolic diseases.

Esophageal Crohn disease in children: a clinical spectrum.

BackgroundThe incidence of esophageal Crohn disease (ECD) in adults ranges from 0.2% to 11.2% and in children is up to 43%. The aim of the study was to determine the clinical and endoscopic spectrum of ECD and its prevalence in our patient population. MethodsChart review of children with Crohn disease (CD). Esophageal Crohn disease was defined by accepted endoscopic and/or histologic findings. Results210 children with CD were identified; 27 of those children had ECD. Nine children presented with specific upper GI symptoms; dysphagia, heartburn, nausea, vomiting, and odynophagia. Esophagoscopy in children with upper gastrointestinal symptoms revealed deep ulcers (n = 2), aphthous ulcers (n = l), erosions (n = l), edematous nodules, (n = l) and normal mucosa (n = 4). In asymptomatic children aphthous ulcers (n = 5), erosions (n = 3), deep ulcers (n = 3), and normal looking mucosa (n = 7) were seen. Twenty children also had gastric lesions, 3 children had duodenal lesions, and 3 children had both duodenal and gastric involvement. All 27 children had evidence of ileo-colonic or colonic disease. Acid suppressive medications were given only to children with upper GI symptoms and endoscopic esophageal lesions. The mean duration of follow-up from diagnosis of CD was 3.02 years (range 2 months—11.7 years). At last follow-up review, 7 children were receiving acid suppression and no children were receiving steroids. There were no complications related to ECD. ConclusionThe prevalence of endoscopic ECD is 7.6% but as many as 17.6% of our patient population had histologic evidence of ECD. The clinical and endoscopic spectrum of ECD are highly variable and poorly correlate with each other.

Differential responses of VIPergic and nitrergic neurons in paediatric patients with Crohn's disease

Inflammatory bowel disease is a recurrent intestinal inflammatory disorder that in adults has been associated with changes in enteric nervous system neuropeptide expression. The aim of the present study was to determine whether similar changes were observed in paediatric Crohns disease. The distribution of vasoactive intestinal peptide (VIP) and neuronal nitric oxide synthase (nNOS) was determined in colonic tissues from children with ileo-colonic (n=4) and colonic (n=3) Crohns disease. The submucosal plexus of inflamed regions showed significant increase in density of VIP immunoreactive neurons (margin, 48% vs. inflamed tissue, 82% of HuC/D positive neurons). The density of submucosal plexus nNOS immunoreactive neurons was too low to be reliably quantified. Using the pan-neuronal marker HuC/D, no significant difference in numbers of HuC/D positive submucosal neurons was evident except where neurons were normalized to length of tissue (margins, 3.6+/-0.7 vs. inflamed tissue, 4.0+/-0.6 neurons/ganglia, p=0.33; margins, 2.7+/-0.4 vs. inflamed tissue, 5.7+/-1.2, neurons/mm, p=0.03). In the myenteric plexus, there was a significant increase in the percent of NOS neurons (38% vs. 82% of HuC/D positive neurons) while there was no significant difference in percent of VIP neurons (4% vs. 8%). No difference in number of HuC/D positive myenteric neurons among margin and inflamed tissues was observed (margin, 12.2+/-3.0 vs. inflamed tissue, 12.5+/-5.1 neurons/ganglia, p=0.50; margins 9.1+/-2.1 vs. inflamed tissue, 13.7+/-2.3 neurons/mm, p=0.11). These data demonstrate that inflammation is associated with a differential expression of VIP and nNOS neuronal subpopulations within the two major enteric plexi, likely due to phenotypic switch. Such changes might contribute to the pathogenesis of IBD and ongoing symptoms even in quiescent disease.

Spectrum of Gastritis in Celiac Disease in Childhood

ABSTRACT Celiac disease (CD) may cause changes throughout the gastrointestinal tract. The pathology is best described in the distal duodenum and jejunum. It is also associated with lymphocytic gastritis (LG) and varioliform gastritis in adults and children, but the histologic spectrum in the gastric biopsy and the clinical implications are undefined. In this report we relate our experience with the clinical, endoscopic, and histologic changes in gastric biopsies in CD in childhood. Slides (hematoxylin and eosin stained) were reviewed from 33 celiac children, 5 having had more than 1 gastric biopsy during a 7-year period. Gastric intraepithelial lymphocyte (IEL) counts were compared with those of 10 histologically normal controls (normal range, 1–7 IEL/100 antral or body epithelial cells) and 10 nonceliac chronic gastritis (CG) biopsies without H. pylori (normal range, 1–19 IEL/100 antral cells), noting changes in the epithelium and lamina propria (LP). LG was present in 29/33 initial biopsy sets. Fifteen of 29 showed LG/CG. The IEL number was greater in LG/CG than in LG only (27.2 ± 9.3, n = 14 vs. 18.6 ± 13.4, n = 15 in the antrum; 23.5 ± 2.8, n = 4 vs. 13.0 ± 8.4 in the body). In CD the difference between these mean values and those of normal and nonceliac CG controls was statistically significant. In CG/LG the inflammatory infiltrate was predominantly diffuse/superficial in the LP; mucin depletion was noted in 11/15. The IELs were in the LG/CG range in two CG controls. The IELs were normal at follow-up in five cases. There were no statistically significant differences between the groups with respect to clinical parameters or gastric endoscopic findings. No child had varioliform gastritis. We conclude that in CD children, the stomach is endoscopically unremarkable but may show LG, or LG/CG with or without mucin depletion, or occasionally appear normal. Gastric histology returned to normal with gluten withdrawal. Normal gastric histology is not typical, but does not exclude CD.

Localized dystrophic periocular calcification : A complication of intralesional corticosteroid therapy for infantile periocular hemangiomas

Abstract: Two female infants with eyelid hemangiomas developed prickly, rock‐hard, subcutaneous crystals following intralesional corticosteroid injections. In each case, the crystals were isocentered on the injection locus and partly eroded the skin, causing local discomfort and inflammation. This complication occurred after two treatment sessions and presented 8 to 9 months after the second injection. An MRI scan showed subcutaneous calcification in the location of the injected orbital hemangioma in one patient. Histopathologic examination confirmed calcification in areas of degenerate hemangioma. There was no recurrence of either hemangioma or calcium deposition following surgical excision. Localized dystrophic calcification may be a late complication of intralesional corticosteroid therapy of periocular hemangiomas.

Effect of long-term omeprazole treatment on antral G and D cells in children

Background Long-term omeprazole therapy is associated with hypergastrinemia. In the antrum, gastrin secretion from G cells is inhibited in a paracrine manner by somatostatin secreted from D cells. Omeprazole may alter the ratio of G to D cells; however, there are limited data concerning such an effect in humans and none in children. The authors studied the effect of long-term omeprazole therapy on antral G- and D-cell numbers in children. Methods Six children received omeprazole for 4 to 7 years for erosive reflux esophagitis. Endoscopic antral biopsy specimens obtained at baseline and at 1, 4, and 7 years of omeprazole administration were immunostained to assess G and D cell numbers per antral gland. The G- and D-cell numbers were also assessed in an age-matched control group consisting of 24 healthy children from six different age groups. Results The mean G-cell number per unit area showed a significant increase at 4 years (85 ± 5.7 years) and at 7 years (89 ± 6.8 years) on omeprazole compared with baseline (56 ± 4.8 years) (P < 0.01). D-cell numbers did not change. The ratio of G to D cells increased progressively, and the change from baseline was significant at 7 years taking omeprazole (P < 0.02). In the control group, G- and D-cell numbers did not differ significantly within the six age groups. Conclusions Long-term omeprazole therapy is associated with a significant increase in G-cell numbers and in the ratio of G to D cells in children. These changes reflect the effect of omeprazole because there was no change in these parameters in the age-matched control group.

Mucopolysaccharidosis type VII (Sly syndrome) presenting as neonatal cholestasis with hepatosplenomegaly.

Mucopolysaccharidosis type VII (Sly syndrome), a rare lysosomal storage disorder caused by deficiency of the enzyme -glucuronidase, was first reported in 1973 in a two year old boy with hepatosplenomegaly, skeletal abnormalities and moderate mental retardation (1). MPS type VII is unusual amongst the MPS syndromes in that it can manifest clinically in the newborn period often in association with hydrops fetalis, however transient functional liver abnormalities have also been described. We report a neonate with MPS type VII who presented with significant cholestatic jaundice and hepatosplenomegaly and provide a review of the literature.