Small Intestine

The small intestine is a specialized tubular structure within the abdominal cavity in continuity with the stomach proximally and the colon distally. The small bowel increases in length from about 250 cm in the full-term newborn to 600 to 800 cm in the adult.

The duodenum, the most proximal portion of the small intestine, begins at the duodenal bulb, travels in the retroperitoneal space around the head of the pancreas, and ends on its return to the peritoneal cavity at the ligament of Treitz. The remainder of the small intestine is suspended within the peritoneal cavity by a thin broad-based mesentery that is attached to the posterior abdominal wall and allows relatively free movement of the small intestine within the abdominal cavity. The proximal 40% of the mobile small intestine is the jejunum, and the remaining 60% is the ileum. The jejunum occupies the left upper portion of the abdomen, and the ileum is positioned in the right abdomen and upper part of the pelvis. No distinct anatomic demarcation exists between jejunum and ileum.

Visual examination of the luminal surface of the small intestine reveals mucosal folds, the plicae circulares. More numerous in the proximal jejunum, the plicae circulares decrease in number in the distal small bowel and are absent in the terminal ileum. Aggregates of lymphoid follicles are scattered throughout the small intestine but are found in highest concentration in the ileum, where they are designated Peyer’s patches. Peyer’s patches normally are more prominent during infancy and childhood than they are in adulthood.

The small bowel transitions to the colon at the ileocecal valve, which consists of two semilunar lips that protrude into the cecum. The ileocecal valve provides a barrier to retrograde flow of colonic contents into the small intestine. This barrier appears to be a function of the angulation between the ileum and cecum and is maintained by the superior and inferior ileoceal ligaments; a true tonic sphincter-type pressure does not appear to be present in this region.

Colon and Rectum

The colon is a tubular structure approximately 30 to 40 cm in length at birth in the full-term infant. In the adult, the colon measures approximately 150 cm, about one quarter of the length of the small intestine. The diameter of the colon is greatest in the cecum (7.5 cm) and narrowest in the sigmoid (2.5 cm). The colon is continuous with the small intestine proximally at the ileocecal valve and ends distally at the anal verge (Fig. 96-1). The external appearance of the colon differs from that of the small intestine because the longitudinal muscle fibers of the colon coalesce into three discrete bands called taeniae, located at 120-degree intervals about the colonic circumference: taenia liberis, taenia omentalis, and taenia mesocolica. The taeniae start at the base of the appendix and extend continuously to the proximal rectum. Outpouchings of the colon, the haustra, are found between the taeniae. Semilunar folds characterize the mucosa between haustra. Small sacs of peritoneum filled with adipose tissue, the appendices epiploicae, are found on the external surface of the colon.

Figure 96-1. Macroscopic characteristics of the colon. Note the taeniae, haustra between the taeniae and appendices epiploicae on the outer surface, and the semilunar folds on the luminal side.

(From Netter FH. The Netter Collection of Medical Illustration. vol 3. Teterboro, NJ: Icon Learning System; 2002.)

The most proximal portion of the colon, the cecum, lies in the right iliac fossa and projects downward as a blind pouch below the entrance of the ileum. The cecum is a sacculated structure 6 to 8 cm in length and breadth. Because of its large diameter, it is the part of the colon most apt to rupture with distal obstruction, and cecal tumors can grow to be quite large without producing symptoms of obstruction. The mobility of the cecum normally is fixed by a small mesocecum; an anomaly in fixation exists in 10% to 20% of people, especially women, predisposing them to cecal volvulus. The vermiform appendix is a blind outpouching of the ceum that begins inferior to the ileocecal valve. Appendiceal anatomy is discussed further in Chapter 116.

The ascending colon extends from the cecum distally for 12 to 20 cm along the right side of the peritoneal cavity to the hepatic flexure. The ascending colon is covered with peritoneum and thus constitutes a retroperitoneal organ.

At the hepatic flexure, the colon turns medially and anteriorly to emerge into the peritoneal cavity as the transverse colon. This is the longest portion (40 to 50 cm) and the most mobile segment of the colon and drapes itself across the anterior abdomen between the hepatic and splenic flexures. When a person assumes the upright position, the transverse colon may actually dip down into the pelvis. The transverse colon may become fixed in this festooned position by adhesions, most commonly resulting from hysterectomy, potentially leading to a technically difficult colonoscopy.

The descending colon, about 30 cm in length, travels posteriorly and then inferiorly in the retroperitoneal compartment to the pelvic brim. There, it emerges into the peritoneal cavity as the sigmoid colon. This is an S-shaped redundant segment of variable length, tortuosity, and mobility, which challenges the endoscopist and radiologist, and is susceptible to volvulus. Because the sigmoid is the narrowest part of the colon, tumors and strictures of this region typically cause obstructive symptoms early in the course of disease.

The rectum, 10 to 12 cm in length in the adult, begins at the peritoneal reflexion and follows the curve of the sacrum, ending at the anal canal.

Anal Canal

The anal canal is approximately 5 cm in length in the adult and has discrete upper and lower demarcations. The anorectal ring is located proximally and is composed of the upper portion of the internal sphincter, the longitudinal muscle of the rectum, the deep portion of the external sphincter, and the puborectalis portion of the levator ani muscle; distally, the anal verge represents the transition of anoderm to true skin. The mucosa of the distal 3 cm of the rectum and the anal canal contains 6 to 12 redundant longitudinal folds called the columns of Morgagni, which terminate in the anal papillae. These columns are joined together by mucosal folds called the anal valves, which are situated at the dentate line. The muscularis mucosae disappears in the anorectal canal, and the inner circular coat of muscularis propria thickens to form the internal anal sphincter. The external anal sphincter surrounds the anal canal, and its fibers blend with those of the levator ani muscle to attach posteriorly to the coccyx and anteriorly to the perineal body. The anatomy and function of these muscles are described in more detail in Chapter 125.

Vasculature

The superior mesenteric artery delivers oxygenated blood to the distal duodenum, the jejunum and ileum, the ascending colon, and the proximal two thirds of the transverse colon. The remainder of the colon is supplied by branches of the inferior mesenteric artery. The arterial supply of the anal area is from the superior, middle, and inferior hemorrhoidal arteries, which are branches of the inferior mesenteric, hypogastric, and internal pudendal arteries respectively. Venous drainage of the anus is by both the systemic and portal systems. The internal hemorrhoidal plexus drains into the superior rectal veins and then into the inferior mesenteric vein, which, with the superior mesenteric vein, joins the splenic vein to form the portal vein. The distal anus drains by the external hemorrhoidal plexus through the middle rectal and pudendal veins into the internal iliac vein. (See Chapter 114 for additional discussion of the intestinal blood supply.)

Lymphatic Drainage

The lymphatic drainage of both the small intestine and colon follows their respective blood supplies to lymph nodes in the celiac, superior preaortic, and inferior preaortic regions. Lymphatic drainage proceeds to the cisterna chyli and then via the thoracic duct into the left subclavian vein. Proximal to the dentate line, lymphatic drainage is to the inferior mesenteric and periaortic nodes, whereas distal to the dentate line, lymphatic drainage is to the inguinal lymph nodes. Therefore, inguinal lymphadenopathy can be seen with inflammatory and malignant disease of the lower anal canal.

Extrinsic Innervation

The autonomic nervous system—sympathetic, parasympathetic, and enteric—innervates the gastrointestinal tract. The sympathetic and parasympathetic nerves constitute the extrinsic nerve supply and connect with the intrinsic nerve supply, which is composed of ganglion cells and nerve fibers within the intestinal wall. Innervation of the small intestine and colon is discussed in detail in Chapters 97 and 98, respectively.

General Considerations

The small and large intestine share certain histologic characteristics. The wall of the small intestine and colon is composed of four layers: mucosa (or mucous membrane), submucosa, muscularis (or muscularis propria), and adventitia (or serosa) (Fig. 96-2).

Figure 96-2. Photomicrograph of the small intestine showing its general microscopic architecture. m, mucosa; mm, muscularis mucosae; mp, muscularis propria; s, serosa; sm, submucosa. (Hematoxylin and eosin, ×25.)

Mucosa

The mucosa is the innermost layer formed by glandular epithelium, lamina propria, and muscularis mucosae (Fig. 96-3A and B). The glandular epithelium forms cylindrical structures called crypts. The lamina propria, which supports the epithelium, is a layer of reticular connective tissue with elastin, reticulin, and collagen fibers, lymphocytes, plasma cells, and eosinophilic granulocytes, as well as lymphatics and capillaries. The muscularis mucosae consists of a thin layer of smooth muscle at the boundary of the mucosa and submucosa.

Figure 96-3. Histologic and electron microscopic photographs of the small intestine. A, Components of the mucosa: ge, glandular epithelium; lp, lamina propria. Note the absorptive cells that appear as high columnar cells with eosinophilic cytoplasm (arrow). (Hematoxylin and eosin, ×250.) B, Goblet cells (arrow) and brush border are stained red. mm, muscularis mucosae. (Periodic acid–Schiff stain, ×150.) C, Microvilli (mv) are seen as delicate finger-like projections on electron microscopic examination, ×9000.

(C, Courtesy of S. Teichberg, PhD.)

The glandular epithelium is composed of various cell types: stem cells, undifferentiated crypt cells, absorptive cells (also called columnar cells), secretory cells (goblet cells, Paneth cells, enteroendocrine cells), and M cells.

Signaling pathways such as Wnt, bone marrow protein (Bmp), PTEN/PI3K, Notch, hedgehog, platelet-derived growth factor, and SOX9 play important roles in the development of the intestinal epithelium.^1–4

Wnt signaling plays a role in promoting cell proliferation; maintains stem cells in an undifferentiated state; defines compartmentalization into Paneth cells, proliferative, and differentiation zones along the crypt-villus axis; and directs early secretory lineage development as well as terminal differentiation of Paneth cells through the transcription factor SOX9.¹

Bmps belong to the transforming growth factor-β family. Bmp signaling is important in intestinal development and homeostasis. It antagonizes crypt formation and stem cell self-renewal and has a role in directing maturation of all three secretory cell types (goblet, enteroendocrine, and Paneth). Bmp signaling in the mesenchyme plays a significant role in crypt morphogenesis; loss of Bmp leads to multiplication and elongation of crypts.²

PTEN/PI3K pathway plays a role in cell survival, proliferation, and growth.¹

Notch proteins mediate cell fate decisions and pattern by regulating the helix-loop-helix factor that controls terminal differentiation. Notch directs development of absorptive cells and depletion of secretory lineage cells, and increases proliferation.¹

The hedgehog (Hh) signaling pathway is important in crypt and villus morphogenesis and maintenance of stem cells.³ Both Sonic (Shh) and Indian (Ihh) play a role. Ihh is critical for the maintenance of intestinal stem cells, whereas Shh inhibits the growth of the villi. The contractile subepithelial pericryptal myofibroblasts represent a major target for Hh signaling. Hh signals sent to the epithelium-associated subepithelial myofibroblasts localize the precrypt structure and maintain the organization of the crypt-villus axis. Hh signaling also inhibits the proliferation or differentiation of smooth muscle and the proliferation compartment of the intestinal epithelium.³

Platelet-derived growth factor A stimulates mesenchymal condensation, proliferation, and evagination of overlying epithelium to form villi.³

Studies in animals also have contributed to the understanding of the molecular mechanism of the different pathways.^1,2

Stem cells are pluripotential cells located at the base of the intestinal crypts. Stem cells give rise to all types of mature intestinal epithelial cells and at the same time replenish themselves through self-renewal. Undifferentiated cells have fewer intracellular organelles and microvilli than do absorptive cells. The absorptive cells (see Fig. 96-3A) are high columnar cells with oval basal nuclei, eosinophilic cytoplasm, and a periodic acid–Schiff (PAS)–positive free surface, the brush border (see Fig. 96-3B). On electron microscopic examination, the brush border is seen to be composed of microvilli (see Fig. 96-3C), which are more numerous in the small intestinal than in the colonic epithelium. Small bowel enterocyte microvilli are estimated to increase the luminal surface area of the cell 14- to 40-fold. Goblet cells are oval or round, with flattened basal nuclei (Fig. 96-4A); their cytoplasm is basophilic, metachromatic (see Fig. 96-4B), and PAS positive (see Fig. 96-4C). Paneth cells are flask shaped and have an eosinophilic granular cytoplasm and a broad base positioned against the basement membrane (Fig. 96-5). Paneth cells contain zinc, antimicrobial peptides, and growth factors and secrete lysoenzymes. Enteric antimicrobial peptides produced by Paneth cells protect against intestinal infection and maintain enteric homeostasis.⁵ A cathelin-related antimicrobial peptide (CRAMP) identified in neonatal epithelium during the first weeks after birth, confers protection from Listeria monocytogenes.⁵

Figure 96-4. Photomicrographs of the large and small intestine demonstrating goblet cells. A, Clear, empty-looking cytoplasm (arrow) and basal nuclei are seen with use of hematoxylin and eosin, ×250. B, Metachromatic staining of the cytoplasm results with use of the alcian blue stain, ×150. C, The cells demonstrate red staining with use of periodic acid–Schiff stain, ×150.

Figure 96-5. Photomicrograph of the small intestinal mucosa demonstrating the crypts of Lieberkühn (lc) and Paneth cells (arrow), which are characterized by granular eosinophilic cytoplasm. (Hematoxylin and eosin, ×250.)

The mucosa also contains specialized cells that because of their specific endocrine function are called enteroendocrine or neuroendocrine cells.

These neuroendocrine cells historically have been divided into argentaffin cells (granules able to reduce silver nitrate) and argyrophilic cells (granules that reduce silver nitrate only in the presence of a chemical reducer). Argentaffin cells stain positive with bichromate salts and also are called enterochromaffin cells. These cells are oval or triangular (also called “halo cells”) and have a basal position in relation to the remaining epithelial cells (Fig. 96-6A) and a pale cytoplasm filled with dark-stained granules. Variation in shapes and cell types has been detected with immunohistochemical staining. The unifying APUD concept—amine precursor, uptake, and decarboxylation—ascribes common characteristics to these neuroendocrine cells. APUD cells are a group of cells with a common embryonic neural crest origin and with similar cytochemical and electron microscopic features; however, embryologic and morphologic data support an endodermal origin of these cells.

Figure 96-6. Microscopic characteristics of neuroendocrine cells of the small intestine. A, Features include clear cytoplasm and a round nucleus (arrow). (Hematoxylin and eosin, ×250.) B, Neurosecretory granules are seen as electron-dense, round black bodies (arrow) on electron microscopic examination, ×20,000. C, Granules in neuroendocrine cells are stained black with the Grimelius stain (arrow), ×150. D, Cells stained with synaptophysin have brown cytoplasm (arrow), ×250.

(B, Courtesy of S. Teichberg, PhD.)

Ultrastructurally, enteroendocrine cells contain membrane-bound granules with variably sized electrodense cores (see Fig. 96-6B), averaging 100 to 250 nm in diameter, and consisting of large dense-core vesicles and smaller, synaptic-type microvesicles. Neurosecretory granules can be demonstrated with the Grimelius stain by light microscopy as dark granules (see Fig. 96-6C), or, more specifically, by immunofluorescence, and with immunohistochemical stains such as neuron-specific enolase, chromogranin, and synaptophysin. Chromogranin enables visualization of the large dense-core vesicles, and synaptophysin targets the small synaptic-like microvesicles (see Fig. 96-6D).⁶ Vesicular monoamine transporter 1 (VMAT1) and 2 (VMAT2) are two isoforms of the adenosine triphosphate (ATP)–dependent vesicular monoamine transporters. These antigens, derived from both the large and small dense-core vesicles, are expressed differentially in small dense-core vesicles. Both are expressed in neuroendocrine cells, but VMAT1 is restricted to serotonin-producing enterochromaffin cells, and VMAT2 is expressed in histamine-producing cells, enterochromaffin-like cells, and pancreatic islet cells.⁷ Specific immunohistochemical stains allow for identification of individual protein products of the neuroendocrine cells.

Besides releasing hormones in the blood, neuroendocrine cells also regulate secretion, absorption, motility, mucosal cell proliferation, and possibly immunobarrier control.⁶ Electron microscopy and immunohistochemistry have led to the identification of a variety of cell types (Table 96-1). Designation according to the nature of the stored peptide is preferable to characterization of neuroendocrine cells by letters. Serotonin-producing enterochromaffin cells, vasoactive intestinal polypeptide (VIP), and somatostatin D cells are distributed throughout the small and large intestine. Gastrin-, ghrelin-, gastric inhibitory peptide (GIP)-, secretin-, and cholecystokinin-producing cells are found predominantly in the stomach and proximal small intestine; peptide YY-, glucagon-like peptide (GLP)-1-, GLP-2-, and neurotensin-secreting cells are found in the ileum.⁸

Table 96-1 Enteroendocrine Cells of the Intestinal Tract: Cell Types and Products, Vesicle Markers, and Distribution

Neuroendocrine cells originate from a common precursor cell in the intestinal crypt. The earliest cell fate is regulated by the Notch signaling pathway (see earlier). Math1 is the first factor involved in endocrine specification, followed by neurogenin3.⁸ Pax4 and Pax6, paired ox homeodomain transcription factors, and Nkx2.2 also are required for neuroendocrine differentiation.^8,9 As mature neuroendocrine cells migrate to the tip of the villi, they undergo apoptosis and are extruded into the lumen.

M cells are specialized epithelial cells overlying lymphoid follicles in the small intestine and colon. M cells selectively bind, process, and deliver pathogens directly to lymphocytes, macrophages, or other components of the mucosal lymphoid system.

Interstitial cells of Cajal (ICC) are present in both the small intestine and the colon and are mesenchymal cells, located in the myenteric plexus, the muscularis propria, and the submucosa (Fig. 96-7). The distribution of the ICC is similar in children and in adults although a difference in their distribution is seen in fetuses of different gestational ages.¹⁰ Recognized as the pacemaker cells of the intestine, the ICC regulate intestinal motility by generating slow waves and determining frequency of smooth muscle contraction; they also amplify the neuronal signals, mediate neurotransmission from enteric motor neurons to smooth muscle cells, and set the smooth muscle membrane potential gradient. The ICC are spindle shaped or stellate, with long ramified processes, and have large, oval light-staining nuclei with sparse perinuclear cytoplasm. The ICC express the receptor for tyrosine kinase (c-Kit) or CD117 which is necessary for their maintenance. Serotonin regulates the number of the ICC by increasing their proliferation.¹¹ Immunohistochemical stains that use antibodies against c-Kit allow the ICC to be labeled. The distribution and onset of appearance of these cells in the gastrointestinal tract have been described.¹⁰

Figure 96-7. Photomicrograph showing the interstitial cells of Cajal in the small intestine. Brown-staining, elongated cells are evident around the myenteric plexus (arrow). (CD117 immunostain, ×250.)

Muscularis or Muscularis Propria

The muscularis propria, mainly responsible for contractility, consists of two layers of smooth muscle: an inner circular coat and an outer longitudinal coat arranged in a helicoidal pattern. A prominent nerve fiber plexus called the myenteric plexus, or Auerbach’s plexus, is found between these two muscle layers (Fig. 96-8). Parasympathetic and postganglionic sympathetic fibers terminate in parasympathetic ganglion cells, and postganglionic parasympathetic fibers terminate in smooth muscle.

Figure 96-8. Photomicrograph of the muscularis propria of the small intestine. The myenteric plexus (mp) is seen as a pale area with ganglion cells between the inner and outer layers (il, ol) of the muscularis propria (arrow). (Hematoxylin and eosin, ×250.)

Small Intestine

The mucosa of the small intestine is characterized by mucosal folds (plicae circulares, or valves of Kerckring) and villi. The mucosal folds are composed of mucosa and submucosa. Villi are mucosal folds that decrease in size from the proximal to distal small intestine and are of different shapes in the various segments of the small intestine: they may be broad, short, or leaf-like in the duodenum; tongue-like in the jejunum; and finger-like more distally (Fig. 96-9A). The villous pattern also may vary in different ethnic groups. Thus, for example, biopsy specimens from Africans, Indians, South Vietnamese, and Haitians have shorter and thicker villi, an increased number of leaf-shaped villi, and more mononuclear cells in comparison with specimens from North Americans.

Figure 96-9. Photomicrograph of the duodenal mucosa. A, Villi are seen as finger-like projections. B, Brunner glands (bg) are found below the mucosa. (Hematoxylin and eosin. A, ×250; B, ×150.)

Various methods have been suggested to determine normal villus height. The height of the normal villus is 0.5 to 1.5 mm; villus height should be more than one half of the total thickness of the mucosa, and three to five times the length of the crypts. Villi are lined by enterocytes, goblet cells, and enteroendocrine cells.

Intestinal villus morphogenesis begins when mesenchymal aggregates impinge on the basal aspect of the epithelium to produce primitive folds. By nine to 10 weeks of gestation, the pseudostratified squamous epithelium converts to a single layer of columnar cells that lines mesenchymal stalks or the lamina propria.¹² During mid- to late gestation, the basic tissue architecture of the intestine is established through epithelial-mesenchymal interaction. Induced by signals from mesoderm-derived mesenchyme, the endoderm-derived epithelium evaginates to form villi and intervillus regions. The intervillus region eventually invaginates into the mucosa to form crypts.¹ Contractile subepithelial pericryptal myofibroblasts contribute mechanically to crypt formation and are the major source of instructive signals to the epithelium.³

Two types of glands are present in the small intestine: Brunner’s glands and crypts of Lieberkühn (intestinal crypts). Brunner’s glands are submucosal glands (see Fig. 96-9B) found primarily in the first portion of the duodenum and in decreased numbers in the distal duodenum; their function is to secrete a bicarbonate-rich alkaline secretion that helps neutralize gastric chyme. In children these glands also may be present in the proximal jejunum. Brunner’s glands open into the intestinal crypts and morphologically resemble pyloric glands.

Crypts of Lieberkühn are tubular glands that extend to the muscularis mucosae (see Fig. 96-5). The crypts are occupied mainly by undifferentiated cells and Paneth cells. Cells are generated at the crypt base and proceed to migrate toward the villus. During this migration, these cells mature and differentiate into a secretory lineage (goblet cells, enteroendocrine cells, Paneth cells) and enterocytes. The commitment of the stem cells to differentiate is acquired in the upper third of the crypt, where cells lose their ability to divide. The constant renewal of enterocytes is regulated by human acyl-coenzyme A synthetase.¹³

Paneth and columnar cells predominate in the base of the crypt. Above the base are absorptive cells and oligomucin cells; the latter originate from undifferentiated cells and differentiate into goblet cells. Goblet cells predominate in the upper half of the crypt. Enteroendocrine cells are admixed with goblet cells. A certain number of CD3⁺ intraepithelial T lymphocytes (up to 30 per 100 epithelial cells) normally are present in the villi. Smooth muscle is found in the lamina propria of the small intestinal villus, extending vertically up from the muscularis mucosae. Plasma cells containing primarily immunoglobulin A (IgA), and mast cells also are present. Lymphoid tissue is prominent in the lamina propria as solitary nodules and as confluent masses—Peyer’s patches—and is seen in the submucosa. Peyer’s patches are distributed along the antimesenteric border and are most numerous in the terminal ileum; their numbers decrease with age.

Most types of enteroendocrine cells are present in the duodenum. Cells that produce ghrelin, gastrin, cholecystokinin, motilin, neurotensin, GIP, and secretin are restricted to the small intestine.⁶

The proportions of these cells differ in the villi and crypts, as well as in different segments of the intestine. Ninety percent of the villus epithelial cells are absorptive cells intermingled with goblet and enteroendocrine cells. The proportion of goblet to absorptive cells is increased in the ileum. The ICC are more abundant in the myenteric plexus of the small bowel than in the colon.¹⁰

Colon

Colonic epithelial cells are generated from stem cells at the base of the crypts and migrate toward the intestinal lumen after three to five days, on initiation of apoptosis. Most epithelial cells undergo apoptosis when they lose contact with the extracellular matrix and are shed into the lumen through caspase activation. Caspase activation is responsible for the cleavage of essential intracellular proteins leading to apoptosis and therefore loss of anchorage.¹⁴

The mucosa of the large intestine is characterized by the presence of crypts of Lieberkühn, associated predominantly with goblet cells intermixed with a few absorptive and enteroendocrine cells. Glucagon-like immunoreactant (GLI), pancreatic polypeptide-like peptide (PYY) with N-terminal tyrosine amide–producing L cells predominate in the large intestine. Enterochromaffin, enterochromaffin-like, and pancreatic polypeptide–producing cells also are found. Paneth cells are scarce and normally are noted only in the proximal colon. The lamina propria of the large intestine contains solitary lymphoid follicles extending into the submucosa. Lymphoid follicles are more developed in the rectum and decrease in number with age. Confluent lymphoid tissue is present in the appendix. Macrophages (muciphages) predominate in the subepithelial portion of the lamina propria. These cells are weakly PAS positive and are associated with stainable lipids.

Anal Canal

Microscopically the anal canal is divided into three zones: proximal, intermediate or pectinate, and distal or anal skin. The proximal zone is lined by stratified cuboidal epithelium, and the transition with the rectal mucosa, which is lined by high columnar mucus-producing cells, is called the anorectal histologic junction (Fig. 96-10A). The intermediate or pectinate zone is lined by stratified squamous epithelium but without adnexae (e.g., hair, sebaceous glands) and also is referred to as anoderm. Its proximal margin, in contact with the proximal zone, is called the dentate line; its distal margin, in contact with the anal skin, constitutes the pectinate line, also referred to as the mucocutaneous junction (see Fig. 96-10B). The anal skin is lined by squamous stratified epithelium and contains hair and sebaceous glands.

Figure 96-10. Photomicrograph of the anal canal. A, Anorectal histologic junction. Transition from rectal glandular mucosa (rg) to proximal anal mucosa lined by stratified squamous epithelium (ep) is evident. B, The pectinate line is characterized by anal mucosa with stratified squamous epithelium (ep) and anal skin (as) containing adnexae (arrow). (A and B, Hematoxylin and eosin, ×150.)

Vasculature

Large arterial branches enter the muscularis propria and pass to the submucosa, where they branch to form large plexuses.

In the small intestine, two types of branches arise from the submucosal plexuses: some arteries branch on the inner surface of the muscularis mucosae and break into a capillary meshwork that surrounds the crypts of Lieberkühn. Other arteries are destined for villi, each receiving one or two arteries, and set up the anatomic arrangement that allows a countercurrent mechanism during absorption. These vessels enter at the base of the villus and form a dense capillary network immediately underneath the epithelium of the entire villus structure. One or several veins originate at the tip of each villus from the superficial capillary plexus, anastomose with the glandular venous plexus, and then enter the submucosa joining the submucosal venous plexus.

In the colon, branches from the submucosal plexus extend to the surface, giving rise to capillaries supplying the submucosa, and there branch to form a capillary meshwork around the crypts of Lieberkühn. From the periglandular capillary meshwork, veins form a venous plexus between the base of the crypts and the muscularis mucosae. From this plexus, branches extend into the submucosa and form another venous plexus, from which large veins follow the distribution of the arteries and pass through the muscularis propria into the serosa.

Lymph Vessels

The lymphatics of the small intestine are called lacteals and become filled with milky-white lymph called chyle after eating. Each villus contains one central lacteal, except in the duodenum, where two or more lacteals per villus may be present. The wall of the lacteal consists of endothelial cells, reticulum fibers, and smooth muscle cells. The central lacteals anastomose at the base of the villus with the lymphatic capillaries between the crypts of Lieberkühn. They also form a plexus on the inner surface of the muscularis mucosae. Branches of this plexus extend through the muscularis mucosae to form a submucosal plexus. Branches from the submucosal plexus penetrate the muscularis propria, where they receive branches from plexuses between the inner and outer layers. Lymphatic vessels are absent in the colonic mucosa, but the distribution of lymphatics in the remaining colonic layers is similar to that in the small intestine.

Nerves

The intrinsic nervous system (enteric nervous system) consists of subserosal, muscular, and submucosal plexuses. The subserosal plexus contains a network of thin nerve fibers, without ganglia, that connects the extrinsic nerves with the intrinsic plexus. The myenteric plexus, or Auerbach’s plexus, is situated between the outer and inner layers of the muscularis propria (see Fig. 96-8); it consists of ganglia and bundles of unmyelinated axons that connect with the ganglia forming a meshwork. These axons originate from processes of the ganglion cells and extrinsic vagus and sympathetic ganglia. The deep muscular plexus is situated on the mucosal aspect of the circular muscular layer of the muscularis propria. It does not contain ganglia; it innervates the muscularis propria and connects with the myenteric plexus. The submucosal plexus, or Meissner’s plexus, consists of ganglia and nerve bundles. The nerve fibers of this plexus innervate the muscularis mucosae and smooth muscle in the core of the villi. Fibers from this plexus also form a mucosal plexus that is situated in the lamina propria and provides branches to the intestinal crypts and villi. The ganglion cells of the submucosal plexus are distributed in two layers: one is adjacent to the circular muscular layer of the muscularis propria; the other is contiguous to the muscularis mucosae. Ganglion cells are large cells, isolated or grouped in small clusters called ganglia (Fig. 96-11). Ganglion cells have an abundant basophilic cytoplasm, a large vesicular round nucleus, and a prominent nucleolus. Ganglion cells are scarce in the physiologically hypoganglionic segment 1 cm above the anal verge.

Figure 96-11. Photomicrograph showing a normal submucosal plexus of the colon. The ganglia (g) are identified by their oval structure and the nerve trunks are thin (arrow). (Hematoxylin and eosin, ×150.)

Duodenum

The duodenum originates from the terminal portion of the foregut and cephalic part of the midgut. With rotation of the stomach, the duodenum becomes C-shaped and rotates to the right; the fourth portion becomes fixed in the left upper abdominal cavity. The mesoduodenum fuses with the adjacent peritoneum; both layers disappear, and the duodenum becomes fixed in its retroperitoneal location. The lumen of the duodenum is obliterated during the second month of development by proliferation of its cells; this phenomenon is shortly followed by recanalization. Because the foregut is supplied by the celiac artery and the midgut by the superior mesenteric artery, the duodenum is supplied by both arteries and therefore is relatively protected from ischemic injury.¹⁶

Midgut

In a 5-week embryo, the midgut is suspended from the dorsal abdominal wall by a short mesentery and communicates with the yolk sac by way of the vitelline duct. The midgut gives rise to the duodenum distal to the ampulla, to the entire small bowel, and to the cecum, appendix, ascending colon, and the proximal two thirds of the transverse colon. The midgut rapidly elongates with formation of the primary intestinal loop. The cephalic portion of this loop, which communicates with the yolk sac by the narrow vitelline duct, gives rise to the distal portion of the duodenum, the jejunum, and a portion of the ileum; the distal ileum, cecum, appendix, ascending colon, and proximal two thirds of the transverse colon originate from the caudal limb. During week 6 of embryonic development, the primary intestinal loop enters the umbilical cord (physiologic umbilical herniation) (Fig. 96-13), and by week 10 it re-enters the abdominal cavity. The proximal portion of the jejunum is the first portion of the intestine to re-enter the abdominal cavity and becomes located on the left side; the subsequent loop that re-enters the abdominal cavity locates to the right. The cecal bud is the last segment to re-enter the abdominal cavity. The cecum originates as a small dilatation of the caudal limb of the primary intestinal loop by approximately 6 weeks of development. Initially it lies in the right upper quadrant; then it descends to the right iliac fossa, placing the ascending colon and hepatic flexure in the right side of the abdominal cavity. The appendix originates from the distal end of the cecal bud. Because the appendix develops during descent of the colon, its final position frequently is retrocecal or retrocolonic.

Figure 96-13. Physiologic umbilical herniation of the intestinal loop during normal development. Coiling of the small intestinal loops and formation of the cecum occur during the herniation. The first 90 degrees of rotation occur during herniation; the remaining 180 degrees occur during the return of the intestine to the abdominal cavity.

(From Sun B, editor. Langman’s Medical Embryology. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2004.)

The primary intestinal loop rotates counterclockwise for approximately 270 degrees around an axis formed by the superior mesenteric artery. This rotation occurs in three stages (Fig. 96-14): the first stage occurs between six and eight weeks (90 degrees), the second stage is at nine weeks (180 degrees), and the third stage is at 12 weeks of gestation (270 degrees). Elongation of the bowel continues, and the jejunum and ileum form a number of coiled loops within the peritoneal cavity.¹⁶

Figure 96-14. The three stages of normal intestinal rotation (see text for details).

(From Gosche JR, Touloukian RJ. Congenital anomalies of the midgut. In: Wyllie R, Hyams JS, editors. Pediatric Gastrointestinal Disease. Pathophysiology, Diagnosis, Management. 2nd ed. Philadelphia: WB Saunders; 1999.)

Mesentery

When the caudal limb of the primitive intestine moves to the right side of the abdominal cavity, the dorsal mesentery twists around the origin of the superior mesenteric artery. After the ascending and the descending portions of the colon reach their final destinations, their mesenteries fuse with the peritoneum of the posterior abdominal wall, and they become retroperitoneal organs. The appendix, cecum, and descending colon retain their free mesentery. The transverse mesocolon fuses with the posterior wall of the greater omentum. The mesentery of the jejunum and ileum at first is in continuity with the ascending mesocolon; after the ascending colon becomes retroperitoneal, the mesentery only extends from the duodenum to the ileocecal junction.¹⁶

Hindgut

The distal third of the transverse colon, the descending colon and sigmoid, the rectum, and the upper part of the anal canal originate from the hindgut. Initially the urinary, genital, and rectal tracts empty into a common channel, the cloaca. They become separated by the caudal descent of the urorectal septum into an anterior urogenital sinus and a posterior intestinal canal. The lateral fold of the cloaca moves to the midline, and the caudal extension of the urorectal septum develops into the perineal body. In a man, the lateral genital ridges coalesce to form the urethra and scrotum; in a woman, no fusion occurs, and the labia minora and majora evolve. The cloaca is lined by endoderm and covered anteriorly by ectoderm. The most distal portion of the hindgut enters into the posterior region of the cloaca, the primitive anorectal canal. The boundary between the endoderm and the ectoderm forms the cloacal membrane. This membrane ruptures by the seventh week of embryonic development, creating the anal opening for the hindgut. This portion is obliterated by the ectoderm but recanalizes by week nine. Thus, the distal portion of the anal canal originates from the ectoderm and is supplied by the inferior rectal artery; the proximal portion of the anal canal originates from the endoderm and is supplied by the superior rectal artery. The pectinate line is situated at the junction of the endoderm and the ectoderm.

Arterial System

Vascular endothelial growth factor (VEGF)-A and its receptors, VEGFR-1 and VEGFR-2, are important for endothelial cell proliferation, migration, and sprouting. Angiopoietins and their receptors, Tie1 and Tie2, play a role in remodeling and maturation of the developing vasculature. Mutation in Tie2 has been reported in vascular dysmorphogenesis. Vascular malformation is briefly discussed in Chapter 36.

Arteries of the dorsal mesentery, originating from fusion of the vitelline arteries, give rise to the celiac, superior mesenteric, and inferior mesenteric arteries. Their branches supply the foregut, midgut, and hindgut, respectively.

Venous System

Vitelline veins give rise to a periduodenal plexus that develops into a single vessel, the portal vein. The superior mesenteric vein originates from the right vitelline vein that receives blood from the primitive intestinal loop. The left vitelline vein disappears. The umbilical veins become connected to the hepatic sinusoids after which the right umbilical vein disappears and the left umbilical vein joins the inferior vena cava; ultimately the umbilical vein is obliterated and forms the ligamentum teres. The cardinal veins are involved with forming the inferior vena cava as is the proximal portion of the right vitelline vein.

Lymphatic System

Lymphatics originate from endothelial budding of veins, after which the peripheral lymphatic system spreads by endothelial sprouting into the surrounding tissues and organs. Flt4 (also known as VEGFR-3), a receptor for VEGF, plays a role in development of the vascular as well as the lymphatic systems. Overexpression of VEGF-C, a ligand of Flt4, results in hyperplasia of lymphatic vessels in transgenic mice. The homeobox gene Prox1 is essential for normal development of the lymphatic system based on animal studies. Homeobox genes contain a conserved sequence of 183 nucleotides. The proteins encoded by homeobox-containing genes act as regulatory molecules that control the expression of other genes. Several families of homeobox-containing genes are known, including the murine Hox family, which has been implicated in pattern formation during embryogenesis. Disruption of this gene in mice causes chyle-filled intestine. Abnormalities in the development of the lymphatic system can result in lymphangiectasia (see Chapter 28).

Enteric Nervous System

The enteric nervous system originates from vagal, truncal, and sacral neural crest cells. Most of the enteric nervous system cells derive from the vagal and truncal neural crest, enter the foregut mesenchyma, and colonize the developing intestine in a cephalocaudal direction. The truncal neural crest gives rise to ganglia of the proximal stomach, whereas the vagal neural crest supplies ganglia to the entire intestine including the rectum; this colonization is complete by 13 weeks of embryonic development. A small component of the enteric nervous system originates from sacral neural crest cells. These cells form extraintestinal pelvic ganglia that colonize the hindgut mesenchyma before the arrival of the vagal-derived neural crest cells.¹⁸ The normal development of the enteric nervous system depends on the survival of cells developed from the neural crest, and their proliferation, movement, and differentiation into neurons and glial cells. Microenvironmental, genetic, or molecular mechanisms may intervene in these processes (see “Disturbance in the Enteric Nervous System”).

Omphalocele

Current theories suggest that a teratogenic event during the first three weeks of gestation prevents return of the bowel to the abdomen and causes failure of lateral embryonic fold development, which results in an omphalocele. Omphalocele occurs with a frequency of 2.5 in 10,000 births. Associated anomalies (e.g., sternal defects) result from failure of closure of the cephalic folds; failure of caudal fold development results in exstrophy of the bladder and, in extreme cases, exstrophy of the cloaca.

Omphalocele is a congenital hernia involving the umbilicus. It is covered by an avascular sac composed of fused layers of amnion and peritoneum (Fig. 96-15). The umbilical cord usually is inserted into the apex of the sac, and the blood vessels radiate within the sac wall. Although a central defect is present in the skin and the linea alba, the remainder of the abdominal wall is intact, including the surrounding musculature. Because a small occult omphalocele of the umbilical cord may not be observed at birth, it is recommended that the umbilical cord be tied at least 5 cm from the abdominal wall at the time of delivery. Close inspection of the umbilical cord before clamping will avoid clamping an occult omphalocele.

Figure 96-15. A newborn with an omphalocele. Note the translucent sac-like structure with its attached umbilical cord.

With a large omphalocele, the liver and spleen frequently are outside the abdominal cavity. Associated anomalies occur in about 75% of children with omphalocele and include chromosomal abnormalities such as trisomy 13 or 18, nonchromosomal syndromes such as Beckwith-Wiedemann syndrome (mental retardation, hepatomegaly, large body stature, hypoglycemia), fetal valproate syndrome, exstrophy of the bladder or cloaca, and OEIS (omphalocele, exstrophy of the bladder, imperforate anus, spinal defect). Malformations of the musculoskeletal, cardiovascular, and central nervous systems, also can occur.^21,22

Prenatally, increased levels of maternal serum alpha fetoprotein suggest the possible presence of an omphalocele. Ultrasound examination during pregnancy allows the diagnosis of this abdominal wall defect in most infants.

Fetal management, including possible termination of pregnancy, is determined by the physician in consultation with the family. If pregnancy is continued, mode of delivery and provision for care of a child with possibly coexisting anomalies should be considered before labor and delivery. Operative treatment is required in all patients with omphalocele. The size of the omphalocele determines whether a primary repair or delayed primary closure is selected. Escharification of the intact omphalocele sac has been used. Reoperation is necessary in up to 25% of cases of omphalocele, either for reclosure of stomas or for subsequent bowel obstruction.

Gastroschisis

Gastroschisis is an abdominal wall defect most commonly located to the right of an intact umbilical cord (Fig. 96-16). The incidence of gastroschisis is approximately 1 in 10,000 births overall, but approaches 7 in 10,000 among mothers younger than 20 years of age. Gastroschisis occurs more frequently in whites and in Hispanic infants than in other races or ethnicities. In gastroschisis, a sac is absent, and the extruded bowel is “padded” and thickened along its length from its extended exposure to the amniotic fluid. Histologically, the bowel usually is normal. Atresia occurs in 10% to 15% of children with gastroschisis. Almost all infants with gastroschisis also exhibit malrotation. Whereas prematurity is more common in children born with gastroschisis than it is in children with omphalocele, extraintestinal anomalies are much more common with omphalocele than they are with gastroschisis. The morbidity and mortality in patients with gastroschisis are largely related to intestinal atresia; other congenital anomalies also have been reported in a small number of patients.^21,22 Gastroschisis may be complicated by necrotizing enterocolitis, with all its attendant short-term and long-term complications.

Figure 96-16. Gastroschisis. In this newborn, there are full-thickness disruption of the abdominal wall and protruding viscera without accompanying peritoneum.

(From Feldman’s Online Gastro Atlas, Current Medicine.)

Increased maternal levels of alpha fetoprotein are suggestive of gastroschisis, as well as omphalocele.

Most children with gastroschisis can undergo primary closure safely; however, for the child with significant intestinal atresia as a complication of gastroschisis, bowel exteriorization and secondary closure often are preferred treatment. It is crucial to conserve intestinal length in these children. Adhesive small bowel obstruction is a frequent and a serious complication, especially in the first year of life.²³

Omphalomesenteric (or Vitelline) Cyst

Omphalomesenteric (or vitelline) cyst is more common in men and is characterized by a mucosa-lined intestinal cystic mass within the center of a fibrous cord.²⁴ Infection of the cyst or intestinal obstruction may result.

Patent Omphalomesenteric (Vitelline) Duct

Patent omphalomesenteric (vitelline) duct represents a persistent connection between the distal ileum and the umbilicus. This fistula has a male-to-female ratio of 5 : 1, and accounts for 6% to 15% of omphalomesenteric duct remnants. The diagnosis usually is made in the first few weeks of life after separation of the umbilical cord from the newborn umbilicus. Foul-smelling discharge from the umbilicus occurs.²⁷ Examination of the umbilicus reveals either an opening or a polypoid mass resulting from limited prolapse of the patent omphalomesenteric duct. Definitive diagnosis can be made by fistulography. Complications of this type of fistula include prolapse of the patent duct, or of the duct and the attached ileum, through the umbilicus, which may lead to partial intestinal obstruction. Prolapse should not be mistaken for an umbilical polyp, because excision of involved tissue might result in perforation. Resection is warranted.²⁷

Omphalomesenteric Band

In omphalomesenteric band, the solid cord connecting the ileum to the umbilicus remains intact. This cord may result in intestinal obstruction from an internal hernia or volvulus.

Vitelline Blood Vessel Remnants

Failure of involution of vitelline blood vessel remnants results in complications similar to those seen with a retained fibrous cord within the peritoneal cavity. Intestinal obstruction occurs when a portion of the small intestine wraps itself around the band. Treatment of all vitelline duct abnormalities is surgical.

Classification

Anomalies of rotation usually are characterized by the stage in the rotational process at which normal embryonic development of the midgut has been interrupted. Most anomalies of midgut rotation occur during the second stage of rotation and have been characterized as nonrotation, reverse rotation, and malrotation (Fig. 96-18). Of these, nonrotation is most common and reflects a complete failure of the second stage of rotation. With this anomaly the intestinal tract occupies the same position in the abdomen as it does in an eight-week-old embryo; the small intestine is located to the right of the midline and the colon is positioned to the left.

Figure 96-18. Rotation defects. A and B, Two examples of nonrotation. A, Ladd’s bands are seen crossing the duodenum; some authors would refer to this as a “mixed rotation.” B, In nonrotation, the small intestine is located to the right of the midline, and the colon is to the left of the midline. C, Reverse rotation. The transverse colon passes behind the duodenum. D, Malrotation with volvulus characterized by a clockwise twist of the mesentery and strangulation. E, Radiologic appearance of malrotation depicting the duodenum to the right of the spine, with a volvulus.

A and B, from Gosche JR, Touloukian J. Congenital anomalies of the midgut. In: Wyllie R, Hyams JS, editors. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 2nd ed. Philadelphia: WB Saunders; 1999. C, From Sun B, editor. Langman’s Medical Embryology. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2004. D, From Netter FH. The Netter Collection of Medical Illustration. vol 3. Teterboro, NJ: Icon Learning System; 2002. (D, Courtesy of Dr. J. Levenbrown.)

Defects in the first and third stages of rotation are uncommon. Abnormalities in the first stage are associated with extroversion of the cloaca; abnormalities of the third stage cause failure of cecal elongation, and the cecum remains in the right upper quadrant.

In adults, reverse rotation of the midgut loop is the most commonly diagnosed defect of the midgut. Reverse rotation of the midgut loop is rare, however, and accounts for only 4% of all rotational anomalies. In reverse rotation, the midgut rotates 180 degrees clockwise during the second stage of rotation, resulting in a net 90 degrees of clockwise rotation. This may produce either the retroarterial colon type (the colon is located behind the superior mesenteric artery) or the liver and entire colon ipsilateral type of reverse rotation.

Malrotation of the midgut loop, a developmental anomaly of intestinal fixation and rotation, occurs when the proximal midgut fails to rotate around the mesenteric vessels during the second stage of rotation. The distal midgut does rotate 90 degrees in a counterclockwise direction, however, with the result that the jejunum and ileum remain to the right of the superior mesenteric artery and the cecum is situated in the subpyloric region. With the potential for the small intestine and cecum to twist around the superior mesenteric artery and each other, this is the rotation anomaly in adults most frequently associated with ischemic damage, therefore mandating surgical correction.

Associated Abnormalities

Associated anomalies are seen in 30% to 60% of patients with defects in intestinal rotation. Nonrotation of the midgut is a significant finding in patients with omphalocele, gastroschisis, and diaphragmatic hernia. Rotation defects are seen in approximately 30% to 50% of infants with duodenal or jejunal atresia and in 10% to 15% of children with intestinal pseudo-obstruction; they also are associated with a variety of other conditions including Hirschsprung’s disease, esophageal atresia, biliary atresia, annular pancreas, meconium ileus, intestinal duplications, mesenteric cysts, Meckel’s diverticulum, urologic anomalies, and imperforate anus.²⁹

Anomalies of rotation can cause acute or chronic intermittent obstruction from volvulus (see Fig. 96-18D,E). Venous and lymphatic obstruction, also from volvulus, can lead to malabsorption and abnormalities in intestinal motility. Patients may fail to thrive and present with chylous ascites and other symptoms and signs of lymphangiectasia resulting from chronic lymphatic obstruction.

Duodenal obstruction can occur as the result of midgut volvulus, and as the result of peritoneal bands between a malpositioned cecum in the subpyloric region and the peritoneum. These bands, called Ladd’s bands, cross the second or third portion of the duodenum and cause obstruction by compression or kinking. Ladd’s bands are an anomaly of peritoneal embryogenesis and persist throughout life.

Diagnosis and Management

If time allows, diagnosis can be made by upper gastrointestinal contrast examination and delineation of the site of the duodenojejunal junction. Findings on ultrasonography may suggest malrotation if the superior mesenteric vein is seen located to the left of the superior mesenteric artery, in contradistinction to the normal anatomy. In the child with acute onset of bilious vomiting and peritoneal signs, no diagnostic studies should be performed if they delay surgical intervention. In the full-term infant with bilious emesis, anomalies of rotation should be considered first and foremost, to avoid the morbidity and mortality associated with these lesions. Ladd’s procedure, including dividing Ladd’s bands, if present, widening of the mesentery, appendectomy, and fixation of the small intestine on the right and the colon on the left side of the abdomen, is the operation of choice.³⁰

Enteric Duplication

Enteric duplications are rare with an incidence of 1 in 4500 births. Enteric duplications are either tubular or spherical; the tubular type communicates with the normal intestinal tract, whereas the spherical type does not. Tubular duplications may join the intestine at one or at both of its ends. Except for duodenal duplications, duplications occur on the mesenteric side of the bowel, and a common blood supply and muscular coat are shared by the duplicated segment and the adjacent bowel. Duplication cysts may be completely isolated and have their own exclusive blood supply. Small bowel duplications often contain pancreatic tissue or gastric mucosa; the latter can be diagnosed by ^99mTc radioisotopic imaging.³¹

The etiology of duplications is unclear, but may involve a defect in intestinal recanalization. Enteric duplications occur throughout the gastrointestinal tract but are most common in the ileum.³¹ Gastric duplications occur least commonly. Depending on the site of the duplication, and whether ectopic gastric mucosa is present (seen in approximately 50% of the cases), complications include intestinal hemorrhage, ulceration, perforation, intestinal obstruction, volvulus, intussusception, infection, pancreatitis, jaundice, hematobilia, and cutaneous enteric fistulas. Duplication of the rectum is the most common of the large bowel duplications and may be associated with constipation or obstipation. Colonic duplications frequently involve the entire colon. Occasionally, large bowel duplications affect several segments of the colon, leaving “skip areas” of normal colon. A high percentage of children with duplications have associated malformations. Adenocarcinoma, neuroendocrine carcinoma, and squamous carcinoma have been documented with gastric, small bowel, and colonic duplications,^31,32 and carcinoid has been described in duplications of the rectum.

Neuroenteric cysts attach posteriorly to the spinal cord, are associated with asymptomatic hemivertebrae, and may occur at any level of the gastrointestinal tract.

An intra-abdominal mass may be appreciated in a child with intestinal duplication, either by abdominal palpation or on rectal examination. Stool may contain occult blood from ulcerated ectopic gastric mucosa or ischemic damage. Other symptoms and signs include abdominal distention, constipation, vomiting, and respiratory distress.³³ Generalized peritonitis can be the first manifestation of a perforated duplication cyst. In adults, acute abdomen, intra-abdominal mass, symptoms of colonic diverticulitis and chronic abdominal pain have been observed.³⁴

Preoperative diagnosis by radiographic evaluation is problematic, but radioisotope studies may prove diagnostic if ectopic mucosa is present in sufficient quantities.

Anocutaneous Fistula

In anocutaneous fistula, the rectum traverses normally through most of the anal sphincter, but its lower portion deviates anteriorly and ends as a perineal, cutaneous fistula anterior to the center of the external anal sphincter (anocutaneous or perineal fistula). These anomalies are similar in the male and the female child. Perineal fistula is the most benign of anorectal defects, and associated urologic defects are uncommon (10%). All patients achieve bowel control after proper surgical treatment. Examination of the perineum may demonstrate features indicative of a perineal fistula, including a prominent midline skin ridge (“bucket-handle” malformation) and subepithelial midline raphe fistula having the appearance of a black ribbon because of its meconium content. Surgery consists of a simple anoplasty, usually done without a protective colostomy.

Rectourethral Fistula

In rectourethral fistula, by far the most frequent anorectal malformation in male children, the rectum descends through a portion of the pelvic floor musculature but focally deviates anteriorly and communicates with the posterior urethra. This fistula may end in the lower posterior (bulbar) or in the upper posterior (prostatic) urethra.⁴⁹ Prenatal echogenic calcifications within the bowel, due to a mixture of meconium and urine, should suggest an anorectal malformation with rectourinary fistula and bladder outlet obstruction.⁵⁰ Children with prostatic urethral fistulas more commonly have sacral and urologic defects (60%) than do children with bulbar prostatic fistula (30%). Eighty-five percent of children with rectourethral bulbar fistula achieve fecal continence after repair, compared with 60% of children with rectoprostatic fistula.

Rectovesical Fistula

In rectovesical fistula, the most proximal anorectal defect in male children, the rectum opens into the bladder neck. Ninety percent of these malformations are associated with significant urologic defects, and only 15% of children achieve bowel control after surgical repair.

Vestibular Fistula

In vestibular fistula, the most common anorectal defect of female children, the rectum opens into the vestibular bulb of the clitoris. The vesticular bulbs are erectile structures situated on either side of the vulvovaginal orifice. The rectum and the vagina share a thin common wall. Thirty percent of affected children have associated urologic defects, and approximately 90% of these children achieve bowel control after surgery. In the vaginal fistula, the rectum opens in the lower or, less frequently, the upper half of the vagina.

Anorectal Agenesis (Imperforate Anus) Without Fistula

In anorectal agenesis the rectum ends blindly without a fistula approximately 1 to 2 cm above the perineum. Sphincter function usually is preserved, with 80% of these patients achieving bowel control after surgery. Approximately 50% of children with imperforate anus have Down syndrome. Conversely, 95% of children with Down syndrome who have anorectal malformations will have this specific type of defect.

Rectal Agenesis (Atresia)

Rectal agenesis occurs more frequently in female than in male children, and consists of complete (atresia) or partial (stenosis) interruption of the rectal lumen between the anal canal and the rectum. On visual inspection of the perineum, the anus appears normal; however, an obstruction can be found 1 to 2 cm above the mucocutaneous junction of the anus. Sphincter function is normal in these patients, and associated urologic defects are rare. In these children, prognosis is excellent, with 100% achieving full bowel control after anorectoplasty.

Anal Stenosis

Anal stenosis, a fibrous ring located at the anal verge, causes constipation and gives the stool a ribbon-like appearance. Response to dilation or surgical disruption is excellent.

Persistent Cloaca

In the complex defect of persistent cloaca, the rectum, vagina, and urethra are fused into a single common channel that opens into one perineal orifice situated at the site of what should be the opening of the normal urethra. Prognosis depends on the intactness of the sacrum and the length of the common channel. Prognosis is better in those children with a shorter common channel (less than 3 cm) than in those with a common channel longer than 3 cm; the latter have a higher incidence of urologic anomalies.⁵¹ Associated urologic problems are an important consideration with persistent cloaca. For example, urologic emergencies from obstructive uropathy are common, and hydrocolpos may compress the opening of the ureters, resulting in bilateral megaureters and massive vesicoureteral reflux.

Associated Abnormalities

Other associated abnormalities have been reported in 70% of children with anorectal malformation (Table 96-4).^42,43 Anorectal malformations occur in malformation syndromes and with chromosomal anomalies.^43,52

Table 96-4 Common Abnormalities Associated with Anorectal Malformations

Data adapted from Cho S, Moore SP, Fangman T. One hundred three consecutive patients with anorectal malformations and their associated anomalies. Arch Pediatr Adolesc Med 2001; 155:587-91.

The higher and more complex the anorectal defect, the greater the chance of severe urologic anomalies (72%); sacral abnormalities also are frequent. Children with a persistent cloaca or rectovesical fistula have a 99% chance of having an associated genitourinary anomaly, whereas less than 10% of children with low fistula have such abnormalities. Overall, patients with additional anomalies are more likely to have high lesions than are patients with isolated anorectal malformations.⁴³ Boys with low and high anorectal malformation have a high incidence of genital and gastrointestinal anomalies, whereas urologic anomalies are more frequent in girls with high anorectal malformations.⁵³ Long-term bowel dysfunction occurs in one third of boys with perineal fistula.

In the first 24 hours of life, a decision should be made whether a child needs a colostomy or simple anoplasty. The presence of an associated defect, either urologic or cardiac, that might be life threatening requires immediate evaluation. A cloaca with a common channel shorter than 3 cm can be repaired by posterior sagittal intervention, whereas a common channel longer than 3 cm requires a laparotomy.⁵¹

Hirschsprung’s Disease

Hirschsprung’s disease (HD) is due to a congenital absence of ganglion cells in both the submucosal (Meissner’s) and myenteric (Auerbach’s) plexuses. Aganglionosis extends continuously for a variable distance proximal to the internal sphincter. Short-segment HD is most common with a transition zone from aganglionic colon to ganglionic colon at the level of the sigmoid. In long-segment HD the entire colon and even the small intestine may lack ganglia. With an incidence of 1 in 5000 live births, approximately 700 new cases of HD occur each year in the United States. The incidence is lowest in Hispanic and highest in Asian individuals. Approximately 10% of babies with Down syndrome have HD. Deletion of 17q21 and other chromosomal anomalies also have been reported.⁵⁴ Familial occurrence has been reported in about 7% of cases. Familial cases have a male predominance with an increased incidence of long-segment aganglionosis. Affected families carry a high risk of familial recurrence of long-segment HD.⁵⁵ HD is seen most commonly in full-term infants but on occasion does occur in premature births. In the short-segment type, a 4 : 1 male preponderance is observed, and in the long-segment type, the ratio is reduced to about 2 : 1. Short-segment HD accounts for nearly 90% of cases in childhood, and long-segment HD accounts for the remainder. It is rare that ultrashort-segment HD manifests in the pediatric population, but it does explain certain cases of chronic constipation that come to attention in adulthood.

Diagnosis

The child with symptomatic HD usually demonstrates signs and symptoms of bowel obstruction. The diagnosis may be made by one or a combination of the following tests: contrast enema, rectal biopsy, and anal manometry. Flexible sigmoidoscopy plays a complementary role in diagnosis.

A contrast enema performed on an unprepared colon will show the distal narrowed hypertonic segment of bowel (usually seen best in a lateral projection). The transition zone between the narrowed distal and dilated proximal intestine will be seen in the most common form of HD—the rectosigmoid form (Fig. 96-22A)—but may not be seen with long- or ultrashort-segment intestinal involvement. In ultrashort-segment HD, a radiologic picture indistinguishable from that in functional constipation with dilated bowel extending to the anus usually is seen. The transition zone may not be evident in rectosigmoid HD if the patient has undergone cleansing enemas or colonic irrigation before the study. Although it has been suggested that the transition zone may not be evident in the first six weeks of life, it almost always is noted in the neonate with partial bowel obstruction.

Figure 96-22. Hirschsprung’s disease. A, Film from a barium enema examination showing the transition zone between the narrowed distal aganglionic segment (na) and the proximal dilated ganglionic segment (dg). B, Anal manometry. Left tracing illustrates normal function. In the right tracing note the lack of relaxation of the internal sphincter on rectal distention in a patient with Hirschsprung’s disease. C, Photomicrograph of a rectal suction biopsy specimen showing the absence of ganglion cells and the presence of thickened nerve trunks (nt) characteristic of Hirschsprung’s disease. (Hematoxylin and eosin, ×125.) D, Acetylcholinesterase-positive fibers stained brown (arrows) in the muscularis mucosae and lamina propria, ×250.

(A, Courtesy of Dr. J. Levenbrown; B, from Markowitz J. Gastrointestinal motility. In: Silverberg M, Daum F, editors. Textbook of Pediatric Gastroenterology. 2nd ed. Chicago: Year Book Medical Publishers; 1988.)

Flexible sigmoidoscopy typically reveals a normal but empty rectum. The dilated proximal bowel, if within reach of the scope, is traversed easily, unless there is abundant feces in the lumen; occasionally stercoral ulcers may be seen.

Anal manometry is the most reliable method by which the gastroenterologist can make the diagnosis of ultrashort-segment HD. A normal physiologic response to distention of the rectum is relaxation of (smooth muscle) internal sphincter pressure. In HD, not only does rectal distention fail to induce internal sphincter relaxation, but a paradoxical rise in external sphincter pressure often is seen (see Fig. 96-22B). Sufficient volumes of air must be used to stimulate rectal distention for a reliable study. A false-positive result most commonly is caused by a capacious rectum in a constipated child or with megacolon, in which case balloon distention may not stimulate the reflex. Up to 20% of normal children have a falsely absent reflex, especially if they are premature or of low birth weight. Nonetheless, a positive response such as internal sphincter relaxation is strong evidence against HD.

Suction biopsy of the rectal mucosa is the most reliable method of diagnosis, except in patients with ultrashort-segment HD. The biopsy capsule should be placed at least 2 cm above the mucocutaneous junction in infants and 3 cm above the junction in older children to avoid the physiologic hypoganglionic zone. To be certain of the absence of ganglion cells in the submucosal plexus, an experienced pathologist may need to review many serial sections. Hyperplastic sympathetic nerve fibers and proliferating Schwann cells are associated findings (see Fig. 96-22C), but can be absent in total aganglionosis.

Controversy exists regarding the type of stains necessary to make a diagnosis of HD. Because acetylcholinesterase is increased in the muscularis mucosae and lamina propria in the aganglionic segment (see Fig. 96-22D), staining for this enzyme has been used for many years. This technique requires fresh, non–formalin-fixed tissue and technical expertise; at best, this stain is confirmatory. False-positive and false-negative reports have been documented in total colonic aganglionosis.⁶⁰ A variety of histochemical staining methods have been proposed for the identification of ganglion cells, but all are expensive, time-consuming, and unnecessary.

In the neonate, considerations in the differential diagnosis of HD include other causes of intestinal obstruction, such as meconium ileus, ileal atresia, meconium plug syndrome, and the microcolon seen in infants of diabetic mothers. When symptoms and signs of enterocolitis are present, diagnostic possibilities in the neonate also include primary necrotizing enterocolitis, HD-associated enterocolitis, milk protein–induced colitis (see Chapter 9), and sepsis with possible disseminated intravascular coagulation.

In the toddler or older child, HD must be differentiated from functional constipation (stool withholding, fecal retention). In the latter condition, history indicates that the child did pass meconium in the newborn nursery and that clinical problems did not arise until the child usually was at least 18 months of age. Fecal impaction almost always is present in fecal retention, and fecal soiling is characteristic. Children with anterior displacement of the anus may be more prone to fecal retention. Idiopathic pseudo-obstruction and intestinal neuronal dysplasia generally can be distinguished from HD by rectal biopsy.

Intestinal Neuronal Dysplasia

Intestinal neuronal dysplasia (IND) is a motility disorder that manifests with intestinal obstruction or severe chronic constipation; characteristic biopsy findings include an increased number of enlarged ganglia and neural hypertrophy (Fig. 96-23A).⁶² In addition, acetylcholinesterase activity is increased in the lamina propria and muscularis mucosae. A full-thickness surgical biopsy specimen is often necessary to diagnose IND. IND has been reported as an isolated lesion affecting especially premature infants, or infants with a history of formula protein intolerance, ileal stenosis, or small left colon–meconium plug syndrome.

Figure 96-23. Photomicrographs of a rectal biopsy specimen from a patient with intestinal neuronal dysplasia. A, Increased number of enlarged ganglia (arrows). B, Active inflammation of the rectal mucosa with a crypt abscess (arrow). (A and B, Hematoxylin and eosin, ×250.)

Three types of IND have been defined. IND type A usually manifests acutely in the neonatal period as severe constipation and enterocolitis. Biopsy features include mucosal inflammation (see Fig. 96-23B), ulceration with hyperplastic neural changes limited to the myenteric plexus, and increased acetylcholinesterase activity in the lamina propria and muscularis mucosae. The submucosal plexus in this type of intestinal neuronal dysplasia is histologically normal.

IND type B usually is seen in children between six months and six years of age who have chronic constipation and megacolon. Histopathologic findings include hyperplastic submucosal ganglia with increased acetylcholinesterase-positive fibers in the muscularis mucosae and lamina propria. Ectopic ganglion cells in the muscularis mucosae and lamina propria also have been described. No changes are seen in the myenteric plexus. Significant interobserver variation has been documented for the pathologic diagnosis of IND type B by rectal suction biopsies. Some reports have speculated that some of the morphologic features described in type B are normal age-related phenomena. A third, mixed type of IND has an acute presentation and involves both the submucosal and the myenteric plexuses.

The pathogenesis of IND is controversial. In some patients it is congenital malformation, whereas in others it is an acquired phenomenon. IND also can be seen in association with other syndromes such as neurofibromatosis or MEN-IIB, in proximal-segment HD, and with congenital anomalies predominantly of the gastrointestinal tract.⁶³ Other associated conditions include cystic fibrosis, microvillus inclusion disease, congenital anomalies, lipoblastomatosis, and inflammatory bowel disease. Therefore, IND may not represent a well-defined entity but rather may constitute a secondary phenomenon related either to age or to obstruction or inflammation.⁶⁴ IND can resolve with age.

Chronic Intestinal Pseudo-obstruction

Congenital forms of neuropathic and myopathic pseudo-obstruction are rare and sporadic, perhaps representing new mutations (see Chapter 120). In these situations, a family history of pseudo-obstruction is lacking, as are any associated syndromes and evidence of other predisposing factors such as toxins, infections, ischemia, or autoimmune disease. Children with chromosomal abnormalities such as Down syndrome, as well as those with MEN-III or with Duchenne’s muscular dystrophy, may suffer from pseudo-obstruction.

Microvillus Inclusion Disease

Congenital microvillus atrophy, also known as microvillus inclusion disease, is an autosomal recessive disorder that may manifest with severe diarrhea shortly after birth and is characterized by atrophy of the intestinal villi and characteristic electron microscopic findings.⁶⁵ Although the prevalence of microvillus inclusion disease is not known, it is reported to be the most common cause of familial intractable diarrhea.⁶⁶ A female gender predominance has been observed, and consanguinity is reported in 20% of cases. The incidence of microvillus inclusion disease may be higher among Navajo Indians and persons from the Middle East. Defective protein trafficking and abnormal cytoskeletal and microfilament function have been proposed as possible etiologies.⁶⁷ A blockage in the transport pathway from the Golgi apparatus leads to fusion of the small vesicles into microvillus inclusions.⁶⁸ Secretory diarrhea is severe, with intolerance to oral feeding and unresponsiveness to most therapeutic modalities.

Three variants of microvillus inclusion disease are recognized: congenital, the most frequent and severe, manifesting within the first week of life; late-onset, starting at six to eight weeks; and atypical, with either early or late onset.

The wall of the small intestine is paper-thin in microvillus inclusion disease. The mucosa of the duodenum and small bowel is characterized by villus atrophy, hypoplastic or normal crypts, and normal or decreased cellularity of the lamina propria (Fig. 96-24A). The absence of the brush border membrane is demonstrated by lack of linear staining with PAS, carcinoembryonic antigen (CEA), and CD10.⁶⁹ These stains also visualize the microvillus inclusions on light microscopy.

Figure 96-24. Photomicrographs of the duodenum from a patient with microvillus inclusion disease. A, Villus atrophy with crypt hyperplasia (arrow) and decreased cellularity of the lamina propria (lp). (Hematoxylin and eosin, ×250.) B, On electron microscopy, lack of or shortened microvilli (arrow) and a cytoplasmic inclusion (i), composed of a vesicle lined by microvilli, can be seen. (×15,000.)

(Courtesy of S. Teichberg, PhD.)

Evaluation by electron microscopy reveals ultrastructural abnormalities of the microvillus membrane, including disruption or absence of the brush border membrane, shortening and absence of the microvilli, and microvillus inclusions (see Fig. 96-24B). Although these lesions are most commonly noted in biopsies from the small intestine, microvillus inclusions also may be seen in specimens from the rectum and colon.

Total parenteral nutrition must be used to prolong survival. The secretory diarrhea persists but becomes less voluminous. Small bowel transplantation should be considered because without it, microvillus inclusion disease is fatal.⁷⁰

Congenital Glucose and Galactose Malabsorption

Familial glucose and galactose malabsorption, transmitted as an autosomal recessive trait, due to mutation in the SGlLT1 gene, is characterized by an absence of the active transport carrier protein (Na⁺-glucose cotransporter) for glucose and galactose.⁷² Ingestion of any formula containing glucose or galactose results in severe life-threatening watery diarrhea in the newborn period. Stools are strongly positive for reducing substances. Neither blood nor white blood cells are present in the stool. Findings on biopsy of the small bowel and colon are normal. Discontinuation of formula containing glucose, galactose, or lactose (lactose is metabolized to glucose and galactose) and institution of a fructose-containing formula with resultant therapeutic benefit usually are sufficient to make a clinical diagnosis of glucose or galactose malabsorption. Diarrhea abruptly ceases and the newborn begins to thrive when fructose-containing formula feedings are instituted. Some reports indicate that the severity of the diarrhea from glucose or galactose malabsorption diminishes with age because of the increased capacity of the intestinal flora to metabolize glucose.

Congenital Sucrase and Isomaltase Deficiency

Because sucrose is not a common dietary carbohydrate during the first six months of life, watery stools generally do not develop in children with this disorder until sucrose is administered in baby food. An exception to this rule is in the newborn receiving a formula (usually with soy protein or casein hydrolysate) with sucrose as the carbohydrate. Because sucrose itself is not a reducing substance, to make the diagnosis, the stool must be hydrolyzed by boiling it with 1N hydrochloric acid for 20 minutes, thereby changing sucrose to glucose and fructose. Congenital sucrase or isomaltase deficiency, although extremely rare, is the most common congenital disaccharidase deficiency.

Congenital Lactase Deficiency

Congenital absence of lactase is extremely rare. Affected babies receiving a lactose-containing formula develop severe watery diarrhea, which resolves with the institution of a non–lactose-containing formula. Biopsy specimens of the small intestine are normal histologically, but assay for disaccharidases reveals diminished or absent lactase.

Congenital Chloride Diarrhea

Congenital chloride diarrhea is an autosomal recessive disorder of intestinal Cl-HCO₃ exchange caused by mutations of the SLC26A3 gene.⁷³ The chloride-bicarbonate exchange mechanism in the ileum and colon is reversed, and chloride is actively secreted, resulting in a chloride-rich diarrhea. The baby with congenital chloride diarrhea often is premature and may present with an ileus or absence of passage of meconium. Watery diarrhea with a high stool chloride content and low stool pH is lifelong. Increased absorption of bicarbonate may result in dehydration, a hypochloremic metabolic alkalemia, hyponatremia, and marked hypokalemia. The stool contains no blood, no white blood cells, and no reducing substances. Urinary chloride is low. Biopsy specimens of the small intestine and colon are normal. Treatment is fluid and electrolyte replacement. Acid reduction with proton pump inhibitors has been tried with variable results.

Congenital Sodium Diarrhea

Congenital sodium diarrhea is caused by defective sodium or proton exchange.⁷⁴ Patients have acidemia and hyponatremia. The stool concentration of HCO₃ and sodium are increased.

Cystic Fibrosis

Cystic fibrosis is an autosomal recessive disorder of cyclic adenosine monophosphate chloride transport that results from a defect in the cystic fibrosis transmembrane regulator (CFTR) (see Chapter 57).

Approximately 10% to 15% of newborns with cystic fibrosis present with neonatal meconium ileus or its complications. Meconium plug syndrome also may occur, resulting in colonic obstruction, rather than small bowel obstruction, as is seen with meconium ileus. Antenatally, small intestinal ischemia and perforation may occur, resulting in meconium cyst, intestinal atresia, or meconium peritonitis with intra-abdominal or scrotal calcifications.