Advances in Evaluation of Chronic Diarrhea in Infants

Abstract

Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents. Congenital diarrheas and enteropathies (CODEs) are rare causes of devastating chronic diarrhea in infants. Evaluation of CODEs is a lengthy process and infrequently leads to a clear diagnosis. However, genomic analyses and the development of model systems have increased our understanding of CODE pathogenesis. With these advances, a new diagnostic approach is needed. We propose a revised approach to determine causes of diarrhea in infants, including CODEs, based on stool analysis, histologic features, responses to dietary modifications, and genetic tests. After exclusion of common causes of diarrhea in infants, the evaluation proceeds through analyses of stool characteristics (watery, fatty, or bloody) and histologic features, such as the villus to crypt ratio in intestinal biopsies. Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt ratios and morphology. Whole-exome and genome sequencing in the early stages of evaluation can reduce the time required for a definitive diagnosis of CODEs, or lead to identification of new variants associated with these enteropathies. The functional effects of gene mutations can be analyzed in model systems such as enteroids or induced pluripotent stem cells and are facilitated by recent advances in gene editing procedures. Characterization and investigation of new CODE disorders will improve management of patients and advance our understanding of epithelial cells and other cells in the intestinal mucosa.

Keywords: Detection; Gastrointestinal Disorder; Inherited; Pediatric.

Figure 1.

Initial evaluation of neonate/infant with diarrhea. Initial evaluation of diarrhea in infants starting with key historical information, identification of red-flag findings, and key stool studies and blood tests. Infants with red-flag findings or that require critical intervention soon after birth will need evaluation for NEC and anatomical abnormalities, as well as further investigation for congenital diarrheas. Important common etiologies to investigate especially presenting beyond the neonatal period include cow’s milk protein colitis, infections, food protein enterocolitis. CBC, complete blood count; CMV, cytomegalovirus; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GISBFT, gastrointestinal fluoroscopy with small bowel follow-through, NPO, nil per os.

Figure 2.

Diagnostic algorithm for evaluation of CODEs. Abetalipo, abetalipoproteinemia; CLD, congenital lactase deficiency; CMP, cow’s milk protein; DGAT1, diacylglyceroltransferase 1; GGM, glucose galactose malabsorption; Hypobetalipo, hypobetalipoproteinemia; NEUROG3, Neurogenin3 deficiency; pBAD, primary bile acid diarrhea; BAM, bile acid malabsorption; PCSK1, proprotein convertase kinase deficiency; RD, retention disease; Suc/Iso, sucrose-isomaltase deficiency; TTC7A, tetratricopeptide repeat domain 7A; VEOIBD, very-earlyonset inflammatory bowel disease.

Figure 3.

CODE histology. (A) Autoimmune enteropathy (H&E) showing extensive villus atrophy, crypt hyperplasia, increased lamina propria inflammation (arrows), neutrophilic crypt abscess (asterisk). Scale bar = 50 μm. (B) Autoimmune enteropathy (H&E) showing crypt base apoptosis. Scale bar = 10 μm. (C) Autoimmune enteropathy (H&E) showing crypt intraepithelial lymphocytosis, absent Paneth cells and rare crypt epithelial apoptosis (arrows). Scale bar = 10 μm. (D) Abetalipoproteinemia (H&E) showing fat globules in enterocytes. Scale bar = 25 μm. (E) Normal villus stained with villin showing clear brush-border staining (arrows). Scale bar = 5 μm. (F) MVID patient with abnormal villin staining with villin signal present in intracellular microvillus inclusions (arrows) and relative lack of brush-border staining (asterisk). Scale bar = 5 μm. (G) MVID patient with abnormal intracellular CD10 staining (arrows). Scale bar = 10 μm. (H) Transmission electron micrograph showing characteristic microvillus inclusion in MVID. (I) Tufting enteropathy patient showing characteristic epithelial tufts in the small intestine (arrows). Scale bar = 25 μm. (J) Membranous MOC31 (EPCAM) staining in unaffected patient. Scale bar = 50 μm. (K) Complete loss of MOC31 (EPCAM) staining in tufting enteropathy patient. Scale bar = 50 μm. (L) Characteristic tufts also seen in the colon in tufting enteropathy (arrows). Scale bar = 25 μm.

Figure 4.

Pathophysiology of CODEs: Illustration of major categories of CODEs with example disorders. (A) Disorders of epithelial transport: GGM, glucose galactose malabsorption affecting sodium glucose cotransporter SLC5A1; CCD, congenital chloride diarrhea affecting the Cl/HCO3 – exchanger DRA (SLC26A3); CSD, congenital sodium diarrhea affecting the Na/Hþ exchanger, NHE3 and the guanylin receptor GC-C (GUCY2C); cGMP, cyclic guanosine monophosphate. (B) Disorders of epithelial enzymes and metabolism: SI, sucrase-isomaltase deficiency; LCT, lactase deficiency; DGAT1, diacylglyceroltransferase 1 deficiency, hypobetalipoproteinemia affecting apolipoprotein B (ApoB), abetalipoproteinemia affecting microsomal triglyceride transfer protein (MTTP) and chylomicron retention disease affecting SAR1B. (C) Disorders of epithelial trafficking and polarity: MVID affecting myosin 5b (MYO5B) and syntaxin 3 (STX3), Tufting enteropathy affecting EPCAM. TTC7A, tetratricopeptide repeat domain 7A. (D) Disorders of enteroendocrine cells: PCSK1, proprotein convertase kinase deficiency; NEUROG3, Neurogenin3 deficiency; RFX6, Mitchell-Riley syndrome. (E) Immune dysregulation–associated enteropathy: X-linked inhibitor of apoptosis (XIAP) affecting BIRC4, FOXP3, CTLA4, LRBA affecting T- and B-cell regulation/stimulation.