CHAPTER 96 Anatomy, Histology, Embryology, and Developmental Anomalies of the Small and Large 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.
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.
(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 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.
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.)
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.
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.
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.)
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
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
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.)
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
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
The submucosa, between the muscularis mucosae and the muscularis propria, is a fibrous connective tissue layer that contains fibroblasts, mast cells, blood and lymphatic vessels, and a nerve fiber plexus—Meissner’s plexus—comprised of nonmyelinated, postganglionic sympathetic fibers, and parasympathetic ganglion cells.
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.
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.
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.
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
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.
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.)
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.
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.
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.
The embryo begins the third week of development as a bilaminar germ disk. During week three, in a process called gastrulation, this disk becomes a trilaminar disk. The surface facing the yolk sac becomes the definitive endoderm; the surface facing the amniotic sac becomes the ectoderm. The middle layer is called mesoderm. The long axis and left-right axis of the embryo also are established at this time. The oral opening is marked by the buccopharyngeal membrane; the future openings of the urogenital and the digestive tracts become identifiable as the cloacal membrane. At four weeks of gestation, the alimentary tract is divided into three parts: foregut, midgut, and hindgut.
The endoderm forms the intestinal tube, which communicates only with the yolk sac. Narrowing of the communication of the yolk sac with the endoderm forms the vitelline duct. With folding of the embryo during the fourth week of development, the mesodermal layer splits. The portion that adheres to endoderm forms the visceral peritoneum, whereas the part that adheres to ectoderm forms the parietal peritoneum. The space between the two layers becomes the peritoneal cavity.
The induction of endoderm appears to be governed by nodal or transforming growth factor-β signaling.15 Specification is initiated by transcription factors expressed in the different regions of the intestinal tube. Thus, PDX1 specifies the duodenum, CDXC the small intestine, and CDXA the large intestine and rectum.16 Differentiation of the gastrointestinal tract depends on the interaction between the endoderm and mesoderm through the Hox code. Signaling from the mesoderm to endoderm is regulated by the Hox genes that encode homeodomain-containing transcription factors. Induction of the Hox code in the mesoderm results from expression of Shh through the endoderm of the midgut and hindgut. Shh is a signaling molecule that acts as a morphogen or form-producing substance in a variety of organ systems. When prompted by this code, the mesoderm instructs the endoderm to form the various components of the midgut and hindgut regions, for example, the small bowel, cecum, colon, and cloaca.16 As indicated by animal studies, Hox genes contribute to the subdivision of the intestine, and formation of the ileocecal valve that separates the small and the large intestine. Shh also plays a crucial role in the development of the hindgut.17
The primitive gut results from incorporation of the endoderm-lined yolk sac cavity into the embryo, following embryonal cephalocaudal and lateral folding. The primitive gut is composed of a blind-ended tube in the cephalic and caudal portions of the embryo, which is the progenitor of the foregut and hindgut; the midgut (Fig. 96-12) is connected to the yolk sac by the vitelline duct. The endoderm gives rise to the epithelial lining of the gastrointestinal tract; muscle, connective tissue, and peritoneum originate from the splanchnic mesoderm. During the ninth week of development, the epithelium begins to differentiate from the endoderm with villus formation and differentiation of epithelial cell types. Organogenesis is complete by 12 weeks of gestation.
(From Sun B, editor. Langman’s Medical Embryology. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2004.)
Initially the foregut, midgut, and hindgut are in broad contact with the mesenchyma of the posterior abdominal wall. The intraembryonic cavity is in open communication with the extraembryonic cavity. Subsequently the intraembryonic cavity loses its wide connection with the extraembryonic cavity. By week five of embryonic development, splanchnic mesoderm layers are fused in the midline and form a double-layered membrane, the dorsal mesentery, between the right and left halves of the body cavity. The mesoderm surrounds the intestinal tube and suspends it from the posterior body wall, allowing it to hang into the body cavity. The caudal portions of the foregut, the midgut, and most of the hindgut thus are suspended from the abdominal wall by the dorsal mesentery extending from the duodenum to the cloaca. The dorsal mesentery forms the mesoduodenum in the duodenum, the dorsal mesocolon in the region of the colon, and the mesentery proper in the region of the jejunum and ileum.16
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
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
(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.)
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
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.
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.
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.