Enteropathies Associated with Chronic Diarrhea and Malabsorption in Childhood

Introduction and General Remarks

The aims of this chapter are to review the pathological features of the major intestinal disorders of infancy and early childhood, with an emphasis on congenital disorders resulting in chronic diarrhea and malabsorption, and to illustrate their appearance on small-intestinal biopsies and specimens ( Box 10.1 ). Other major categories of disorders that can cause chronic diarrhea, such as infections, immunodeficiencies (primary and secondary), gluten-sensitive enteropathy (GSE) and other food allergies, and motility and pancreatic disorders are discussed in other chapters of this book. Chronic diarrhea occurring in the neonatal period presents particularly difficult diagnostic and therapeutic challenges. Intractable diarrhea of infancy is a term that was coined by Avery and colleagues to refer to these cases, most of which remained undiagnosed and were associated with high mortality at that time. Since these initial reports, more precise identification of disorders that cause intractable diarrhea of infancy has led to the use of prolonged parenteral nutrition, immunosuppression, and bowel and hematopoietic stem cell transplantation to improve survival of these children, prompting the need for timely and accurate diagnosis. Investigation of some of these disorders has also led to significant advances in our understanding of gastrointestinal (GI) and immunological functions. For instance, investigation of microvillus inclusion disease has helped identify genes responsible for intracellular vesicular transport. The discovery that mutations in the gene that codes for FOXP3 cause immunodysregulation, polyendocrinopathy and enteropathy (IPEX) syndrome and its animal homologue, the Scurfy mouse, has led to recognition of the critical role this gene plays in control of the immune response and in autoimmunity and immune tolerance.

Biopsy Sampling and Indications in Children

In current pediatric GI practice, intestinal biopsies are most frequently obtained from the duodenum via forceps during endoscopic examination, during which biopsies are also obtained from the esophagus and stomach (esophagogastroduodenoscopy [EGD]). In addition to obtaining biopsies for routine histology, samples may also be snap-frozen (for disaccharidase analysis) or submitted for electron microscopy (for confirmation of microvillus inclusion disease). Biopsies from both proximal and distal duodenum are recommended, including biopsies of endoscopically normal mucosa, as many disorders affecting the duodenum have a focal distribution. In children, for example, the lesions in GSE may be patchy, and villous atrophy may coexist with normal mucosa. Furthermore, villous atrophy may be limited to or most severe in the duodenal bulb at the time of diagnosis. ^, As pediatric EGD has evolved into a routine outpatient procedure, the indications for its use have correspondingly changed. At The Children’s Hospital of Philadelphia, the first-time EGD rate increased 12-fold in a 20-year interval between 1985 and 2005, with isolated abdominal pain replacing GI bleeding as the most frequent indication. Much of this increase appears to have been driven by the dramatic increase in food allergy–related disorders such as eosinophilic esophagitis, by the increased prevalence of celiac disease and its clinically atypical forms (for which intestinal biopsy is the “gold standard” for establishing a diagnosis), and by the routine use of EGD in addition to colonoscopy in the evaluation of children with suspected inflammatory bowel disease (IBD). According to one study, the most frequent indications for EGD and colonoscopy in children younger than 1 year of age were diarrhea, failure to thrive, reflux, and rectal bleeding. Histological abnormalities were detected in two-thirds of cases, whereas only 2% of mucosal biopsies were insufficient. Sampling even endoscopically normal-appearing mucosa is recommended, as it may help assess the “background” features of the mucosa, and histological examination may reveal clinically relevant findings unsuspected by the endoscopist (e.g., granulomas). ^, A pediatric study found that a routine duodenal biopsy performed for indications such as gastroesophageal reflux, vomiting, abdominal pain, anemia, and during the evaluation of Crohn’s disease yielded pathological findings in about 17% of cases.

Intestinal biopsy findings in some entities, such as congenital transport disorders, are associated with a normal biopsy, whereas others, such as autoimmune enteropathy (AIE) or celiac disease, have variable degrees of villous atrophy with or without inflammation. A few disorders, such as abetalipoproteinemia or microvillus inclusion disease, present characteristic findings on intestinal biopsy ( Table 10.1 ).

Intestinal Development in Children

Villi appear in the duodenum during the 8th week postfertilization, and crypts of Lieberkuhn are noted during the 9th week, spreading caudally and arriving in the distal ileum by the 14th week. The definitive histological features of the duodenum are established by the 14th week postfertilization, and its histology closely resembles that of the newborn by 20 weeks. The transition from pyloric to duodenal mucosa is gradual in some cases; duodenal-like villi may be found in the distal pylorus, and pyloric-like epithelium may be found in the duodenum. Enteroendocrine and goblet cells appear to differentiate before 14 weeks under the influence of the Notch pathway and transcription factors such as Hes 1 and Atoh1 (Math1). The villus height–crypt depth ratio in the duodenum of a newborn is similar to that of an adult. Newborns usually lack plasma cells in the first week of life, gradually acquiring them during the first month of life, with IgM-containing plasma cells predominating. By 3 months of life, IgA plasma cells predominate. Normal numbers of plasma cells and ratios of IgA/IgM/IgG are attained by the first year of life.

Congenital Disorders of Intestinal Digestion, Absorption, and Transport

This group of disorders is among the most common cause of congenital diarrhea. These are conditions in which a defect in one mechanism of digestion or transport leads to chronic diarrhea ( Table 10.2 ). The clinical picture of congenital disaccharidase deficiency and carbohydrate malabsorption, for example, is an osmotic diarrhea due to the unabsorbed solute in the ileum. The more rapid transit through the GI tract in the child results in a more severe diarrhea than in the adult. The diagnosis is obtained by the determination of disaccharidase activities in homogenates of small-bowel biopsies or by breath testing. Intestinal biopsies in these disorders are generally normal or only very slightly abnormal, without ultrastructural anomalies, except for the lipid trafficking disorders, which will be discussed in the next section. Thus a normal-appearing small-bowel mucosa from a patient with prolonged diarrhea, especially a young infant, should alert the clinician to consideration of these entities.

Lipid Trafficking Disorders

Most clinical disorders of fat malabsorption result either from pancreatic disease (such as cystic fibrosis) or ileal involvement (as in Crohn’s disease) with loss of the enterohepatic circulation of bile acids. Intestinal biopsies play a limited role in the diagnosis of these disorders. However, primary abnormalities involving abnormalities of fat transport within the enterocyte, though much less frequent, can result in a characteristic vacuolization of the enterocyte in intestinal biopsies.

Abetalipoproteinemia

Abetalipoproteinemia is an autosomal recessive disorder characterized by the absence of apo B-containing lipoproteins. The molecular basis for the defect is a mutation of the gene coding for microsomal triglyceride transfer protein (MTP) located on chromosome 4q22 (see Table 10.2 ). MTP is responsible for assembly of lipoprotein particles and for the proper folding of ApoB, preventing its premature degradation. Fatty acids within intestinal cells thus cannot be exported as chylomicrons. Patients have diarrhea and fat malabsorption, usually appearing within the first few months of life, with acanthocytosis and deficiencies in fat-soluble vitamins that result in retinitis pigmentosa and neurological symptoms. There is clinical heterogeneity, however, with signs and symptoms presenting in older adult patients in a significant proportion of cases. Serum levels of cholesterol and triglycerides are typically low and do not increase after a fatty meal. Small-bowel biopsies typically reveal preserved villous morphology ( Fig. 10.1A ). Characteristic multivacuolated fat-filled enterocytes are noted in intestinal biopsies of fasting patients, which on electron microscopy are irregular in size and generally non–membrane-bound (see Fig. 10.1B ). No lipid is noted in the extracellular space. Hepatic biopsies in these cases typically reveal steatosis, with numerous non–membrane-bound lipid droplets noted in the hepatic cytoplasm. Fibrosis evolving to cirrhosis has been reported in occasional patients.

Hypobetalipoproteinemia

Hypobetalipoproteinemia is an autosomal dominant disorder caused by a mutation in the APO B gene located on chromosome 2, leading to truncated apo B protein. Homozygous patients have a clinical and histological phenotype essentially indistinguishable from abetalipoproteinemia, whereas heterozygous patients have only a mild phenotype.

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