Elsevier

Human Pathology

Volume 38, Issue 4, April 2007, Pages 570-580
Human Pathology

Original contribution
Enteroendocrine cell dysgenesis and malabsorption, a histopathologic and immunohistochemical characterization

https://doi.org/10.1016/j.humpath.2006.10.014Get rights and content

Summary

Enteroendocrine cell dysgenesis was observed in 3 patients with intestinal failure of unknown cause. Enteroendocrine cell dysgenesis is a congenitally acquired life-threatening malabsorptive condition with a unique clinical phenotype paired with a histologically identifiable disease pattern. Two cases were first presented at the Ninth International Small Bowel Transplantation Symposium, Brussels 2005, and were subsequently published (N Engl J Med 2006;355:270). We now present the histopathologic and immunohistochemical findings of the gastric antrum, small bowel, and colon in greater detail. The clinical phenotype of the patients was unusual in that the affected patients demonstrated profound malabsorption of all nutrients, except water, from birth. The small intestine in each patient demonstrated almost no abnormality, except a near absence of endocrine cells in the mucosa. The colon appeared similarly affected. Known causes of congenital malabsorption, inflammatory, and infectious causes of diarrhea were excluded. The defect is secondary to point mutations in NEUROG3, which result in an arrest of endocrine cell development in the small intestine and colon. This work describes the pathologic characterization of enteroendocrine cell dysgenesis using routine techniques. The pattern of injury is distinct from other histopathologically assessed congenital malabsorptive conditions such as microvillus inclusion disease, tufting enteropathy, and abetalipoproteinemia. It is also easily distinguished from inflammatory conditions such as food allergy, gluten-sensitive enteropathy, autoimmune enteropathy, IPEX (immune dysfunction, polyendocrinopathy, enteropathy, and X-linked inheritance), and inflammatory bowel disease. The histopathology of disease is similar to what has been found transiently in a single patient with autoimmune polyglandular syndrome type I.

Introduction

Intestinal failure is a life-threatening condition that results from a reduction of nutrient-absorptive capacity below what is necessary to sustain normal growth in children [1]. There are a number of causes of intestinal failure that are treated by parenteral nutrition or small bowel transplantation. The pathologist plays an important role in defining the cause of malabsorptive diseases, most of which do not result in intestinal failure, parenteral nutrition, or transplantation. Malabsorptive diseases of childhood have a broad differential diagnosis and may be classified as congenital disorders resulting from a single gene defect affecting transport proteins or digestive enzymes; or inflammatory disorders including allergy, infection, or idiopathic; or they may be structural such as in short gut [2], [3], [4]. The pathologist may encounter congenital diseases such as microvillus inclusion disease, tufting enteropathy, and abetalipoproteinemia in the infant population. These entities have nearly pathognomonic patterns in mucosal biopsies and usually have strong clinical support as a cause of congenital malabsorption. In the pediatric population, inflammatory diseases such as food allergy, gluten-sensitive enteropathy, infectious diseases, and inflammatory bowel disease (IBD) also have recognizable patterns of injury. The correct diagnosis is vital because appropriate treatment of many inflammatory conditions prevents malabsorption and avoids parenteral nutrition or small intestinal transplantation. In other forms of congenital malabsorption, such as congenital lactase deficiency, glucose-galactose transport deficiency, or congenital sucrase isomaltase deficiency, the role of the pathologist is limited except to confirm microscopically normal structure. Lastly, there are gross structural abnormalities that lead to short bowel syndrome such as gastroschisis or trauma that are not further discussed.

The gastrointestinal system has been referred to as the largest endocrine organ of the body, and the endocrine cells of the gastrointestinal tract have numerous roles in proper digestion [5], [6], [7]. They function by secreting peptide hormones and other compounds that act systemically and locally to regulate secretion, motility, metabolism, and feeding behavior. Although there has been some confusion in the past regarding their place in the so-called diffuse neuroendocrine system, enteroendocrine cells are firmly established as endodermally derived specialized epithelial cells and are not of neural crest origin [8], [9]. Some gut enteroendocrine cells can be seen with routine histology, but immunohistochemistry (IHC) for chromogranin A (CG) as a general marker for the large dense core vesicle is both sensitive and specific. The embryogenesis of these cells has received a great deal of attention, and the development of gut epithelium, including the endocrine cells, is well described in murine models [9], [10]. Disorders of the endocrine cells include neoplasia, hyperplasia, metaplasia, and loss [11]. Acquired deficiencies of pancreatic endocrine cells are well established, such as β-cell loss in type 1 diabetes [12], [13], [14]. However, a state of congenital deficiency of intestinal endocrine cells is a recently described phenomenon [15]. The pathologic term given for the first case was enteroendocrine cell dysgenesis as a cause of what was subsequently deemed enteric anendocrinosis, clinically. The near absence of small intestinal and colonic endocrine cells is ascribed to point mutations in NEUROG3. Neurogenin 3 (NEUROG3) is a transcription factor that controls the developmental pathway of gut and pancreatic epithelial stem cells destined to become endocrine cells [8], [9], [16], [17], [18]. The point mutations alter the amino acids in the conserved region of the DNA binding domain of NEUROG3. Mice lacking NEUROG3 expression fail to develop enteric and pancreatic endocrine cells, and have some preserved gastric endocrine cell development [16], [17].

The patient clinical characteristics described in this study have been previously reported [15]. Briefly, all 3 patients were male and had a congenital diarrheal syndrome with unique clinical characteristics such as diarrhea with feeds (whether carbohydrate, amino acid, or lipid), cessation of diarrhea without feeds, and normal absorption of water when given alone. Mucosal disaccharidase levels were within the reference range. The subtle defect (although present) was not detected in the initial pathologic examinations of small bowel mucosa, but eventually, a near absence of endocrine cells was detected. No assessment of serum levels of enteric hormones was carried out. All 3 patients were parenteral nutritionally dependent. All were HIV negative. The autoantibody status of 1 patient was negative for antinuclear antibody (ANA), smooth muscle antibody (SMA), double stranded DNA (dsDNA), islet cells, and an IBD panel; antienterocyte and goblet cell antibody studies were not performed on any of the 3 patients. B- and T-cell subsets were normal. No infectious causes of diarrhea were found. Two patients had small bowel follow-through studies showing normal gut length. Two patients were determined to have a normal apolipoprotein profile. One patient underwent small bowel transplantation and was progressed to enteral feeds and eventually discharged home. He never had clinical signs of pancreatic exocrine or endocrine dysfunction. The disease persisted in the 2 others who remain below the fifth percentile for weight, and they developed type 1 diabetes at the age of 8 years.

In this study, the claim that discrete endocrine cell loss is a cause of malabsorption is reasserted. We show that routine hematoxylin and eosin (H&E) staining, plus CG IHC, and internal laboratory controls are sufficient to objectively diagnose enteroendocrine cell dysgenesis in a way that should be reproducible in any surgical pathology practice. The histopathologic distinction of enteroendocrine cell dysgenesis from other pediatric malabsorptive disorders is also presented. The 2 most likely competing diagnoses, autoimmune enteropathy and autoimmune polyglandular syndrome type 1, are distinguished on pathologic and clinical grounds. We further describe the quantitative differences between endocrine cells of the small intestine and colon of patients with enteroendocrine cell dysgenesis and morphologically normal mucosa.

Section snippets

Methods

Endoscopic mucosal biopsies and surgically resected material from patient 1 were sent for surgical pathology assessment. The specimens were fixed in 10% buffered formaldehyde or sent for electron microscopy. The enterectomy and partial colectomy specimen from patient 1 was received fresh from the operating room. The remaining specimen was fixed in 10% buffered formaldehyde. Sections were processed for routine paraffin embedding. Mucosal biopsies from patients 2 and 3 (taken during the first

Results

Three male patients with unexplained enteropathy presenting as congenital intractable diarrhea were examined clinically and pathologically. All patients experienced generalized malabsorptive diarrhea to all forms of simple nutrients, including carbohydrates, amino acids, and fats. Patient 1 was the product of a consanguineous union, but other family medical history for patient 1 was remarkable. The family history was not available for patients 2 and 3 secondary to adoption, but both children

Discussion

This report presents the histopathologic assessment of a congenital deficiency of enteroendocrine cells and malabsorption. The defect is one of the enteroendocrine cell dysgenesis, resulting in a marked diminution of endocrine cells in the small intestine and colon in infants with intractable diarrhea. The 3 cases demonstrate small intestinal enteroendocrine cell number 3 SDs below the controls. In patients 1 and 2, where gastric antral and colonic mucosa were available for study, the antral

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