*Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition
†Department of Pathology
‡Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Address correspondence and reprint requests to Michael J. Rosen, MD, MSCI, Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, 2215 Garland Ave, 1025 Medical Research Building IV, Nashville, TN 37232 (e-mail: email@example.com).
Received 15 August, 2011
Accepted 18 November, 2011
M.J.R. is supported by the CDHNF/NASPGHAN/George Ferry Young Investigator Award and a Vanderbilt Physician Scientist Development Award.
The authors report no conflicts of interest.
We report a rare case of autoimmune metaplastic atrophic gastritis (AMAG) and associated enterochromaffin-like (ECL) cell hyperplasia in a 15-year-old girl. The patient presented with 8 months of epigastric abdominal pain unresponsive to proton pump inhibitor (PPI). Her mother had a history of immunoglobulin (Ig) A nephropathy and vitamin B12 deficiency. Physical examination was unremarkable. Complete blood count, metabolic panel, lipase, C-reactive protein, and celiac serology were normal. Esophagogastroduodenoscopy revealed numerous 2- to 4-mm nodules in the body of the stomach (Fig. 1).
On pathology, the stomach demonstrated multifocal chronic atrophic gastritis, focal intestinal metaplasia, and ECL cell hyperplasia (Fig. 2A and B). CDX-2 staining confirmed the foci of small intestinal epithelium (Fig. 2H). Synaptophysin is a glycoprotein present in neuronal presynaptic vesicles and is a useful marker of neuroendocrine cells. Synaptophysin staining highlighted an increase in ECL cells within the glands (linear hyperplasia) and florets of ECL cells in the lamina propria (nodular hyperplasia), which were most prominent in the areas of glandular atrophy (Fig. 2C–E). Because ECL cell hyperplasia is caused by hypergastrinemia, gastrin staining was performed, which showed proliferation of antral G cells (Fig. 2F). Helicobacter pylori staining, serology, and biopsy urease testing were negative.
Because ECL cell hyperplasia can be associated with neuroendocrine tumors (NETs), a second esophagogastroduodenoscopy with endoscopic mucosal resection of several clusters of nodules was performed to assess for invasion into the submucosa. No invasion or malignancy was identified, and histopathologic findings were similar to those seen on the earlier biopsies (Fig. 2B and E).
ECL cell hyperplasia results from hypergastrinemia associated with atrophic gastritis (either H pylori–associated or autoimmune), chronic PPI use, or Zollinger-Ellison syndrome from a gastrin-secreting tumor with or without multiple endocrine neoplasia 1 (1). Further laboratory evaluation undertaken to determine the cause in this patient is detailed in Table 1. A pancreatic protocol computed tomography scan was negative for any mass. Given her negative secretin stimulation test, neutral gastric pH confirming achlorhydria, negative evaluation for H pylori, gastric pathology, and family history of pernicious anemia, the patient was diagnosed with AMAG with associated ECL cell hyperplasia.
Atrophic gastritis typically presents in the 6th to 7th decade and, when found in children, is almost exclusively associated with H pylori infection. Here we present a rare case of AMAG in an adolescent female with no evidence of H pylori infection. Additionally, to our knowledge, this is the first description of ECL cell hyperplasia associated with AMAG in a pediatric patient.
AMAG is caused by progressive autoimmune destruction of the oxyntic glands leading to achlorhydria and hypergastrinemia. Due to gradual loss of intrinsic factor production, patients are at high risk for vitamin B12 deficiency. Although this patient does not yet have a low serum vitamin B12 level, it is interesting that her mother is vitamin B12–deficient. Although the patient's mother has never undergone gastroscopy, her history of vitamin B12 deficiency and autoimmune disease suggests a familial origin.
In the early stages of AMAG, the gastric body may have nodules or pseudopolyps, which are actually retained islands of normal gastric mucosa amidst focal areas of atrophy (Figs. 1 and 2B) (2). Although nodular gastropathy associated with H pylori infection can have a similar appearance, it is typically antral predominant. Nonetheless, the similar endoscopic appearance underscores the importance of multiple biopsies in the body and antrum in patients with gastric nodularity.
AMAG can be associated with circulating antibodies against intrinsic factor and parietal cells; however, absence of autoantibodies in this patient does not exclude a diagnosis of AMAG. In fact, only 70% of patients with pernicious anemia produce anti-intrinsic factor antibodies and even fewer, 55%, produce anti-parietal cell antibodies. Furthermore, younger patients are more likely to be autoantibody negative (3).
Atrophic gastritis in children almost exclusively occurs in the setting of H pylori infection. The largest series of children with AMAG was in association with autoimmune thyroid disorders (4). In the present study of 129 children with autoimmune thyroid disorders, 30% had anti-parietal cell antibodies. Hypergastrinemia was demonstrated in 45% and 12% of anti-parietal cell antibody–positive and –negative children, respectively. Gastroscopy was performed in 18 antibody-positive patients, and 10 were found to have H pylori–negative atrophic gastritis, all of whom had hypergastrinemia.
ECL cell hyperplasia occurs in 60% of adults with AMAG (1). Chronically, increased circulating gastrin in response to achlorhydria directly stimulates ECL cell proliferation. This feedback response can lead to progression from linear to micronodular ECL cell hyperplasia, and, in some instances, gastric NETs. PPIs have been implicated as a cause of ECL cell hyperplasia in adults and children. In one study, 60% of children treated with PPI for gastroesophageal reflux disease for a median 2.3 years showed minor degrees of ECL cell hyperplasia (5). Of note, most had only an increase in the number of ECL cells, and none progressed to a micronodular pattern of hyperplasia. Although it is important to recognize that long-term PPI treatment can cause histologic changes, these data suggest that this patient's micronodular ECL cell hyperplasia cannot be attributed to PPI use alone.
AMAG has been associated with gastric adenocarcinoma and NETs. The incidence of gastric adenocarcinoma in adults with AMAG varies from similar to the general population to a 3-fold increase (6). There are only 2 reported cases of gastric adenocarcinoma associated with AMAG in adolescents (7,8). Gastric NETs occur in 4% to 7% of patients with AMAG (6). Gastric NETs associated with AMAG are typically small, well-differentiated, benign tumors (6). We are not aware of any reports of gastric NETs associated with AMAG in children.
The long-term outcome of AMAG in children is unknown. American Society for Gastrointestinal Endoscopy guidelines recommend a single endoscopy in adults with pernicious anemia to evaluate for NET and gastric cancer, but state there are insufficient data to support routine surveillance endoscopy in patients with AMAG (6).
To our knowledge, this is first description of AMAG with associated ECL cell hyperplasia in an adolescent patient. Pediatric gastroenterologists and pathologists must be aware that AMAG can begin at a young age, and evaluate them for associated lesions such as ECL cell hyperplasia or NET and gastric cancer.
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