UW Division of Gastroenterology - Gut Course Syllabus (HuBio 551)

	Updated: 03/13/08 12:05 PM

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Authors: D.R. Saunders, C.E. Rubin, and J.D. Ostrow
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C. Embryology and Structure
Clinical problems from the vitelline duct		The vitelline duct which connects the yolk-sac with the primitive gut in early embryonic life may fail to obliterate, leaving a connection between the lower ileum and the umbilicus. Most commonly this forms a small blind sac or diverticulum of the ileum (Meckel's) which can become inflamed and mimic appendicitis. Islands of gastric mucosa in Meckel's diverticulum can be associated with a local peptic ulcer, a source of bleeding and perforation, especially in small children. The obliterated vitelline duct may become a fibrous band, extending from the ileum to the umbilicus; a bowel loop may twist around this band obstructing its lumen (volvulus) and even shutting off its blood supply, causing obstruction or even infarction, requiring emergency surgery for survival.
Congenital intestinal obstructions		During normal intestinal development, the lumen is temporarily occluded with proliferating epithelial cells before it recanalizes to form a permanent lumen. Partial persistence of one of these areas of occlusion can cause a web-like narrowing which may become obstructed by food residues at any time in future life. Complete persistence of luminal occlusion (atresia) necessitates surgical repair soon after birth to ensure survival. Outpouchings from the foregut normally will develop into the liver and pancreas. Persistent pockets of developing epithelium after luminal recanalization may become diverticula or isolated masses of pancreatic tissue within the gastric or duodenal wall (pancreatic rests); they rarely cause symptoms. On the other hand, incomplete luminal recanalization can produce cysts or side-by- side reduplications of the gastrointestinal lumen; these can lead to obstruction, volvulus or intussusception (invagination of one part of the intestine into another during peristalsis).
1. Gross Anatomy
		The small intestine is a convoluted tube which begins at the pylorus and ends approximately twenty feet further down at the ileocecal valve. The small intestine is made up of the short fixed duodenum and the longer more mobile jejunum and ileum.
Figure 1 The four parts of the duodenum with relationships to the stomach, pancreas, & biliary tree.
Importance of the duodenal bulb		The duodenum is a C-shaped segment which begins at the pylorus and then wraps around the head of the pancreas and finally crosses to the left of the spine to join the jejunum. The conical first two inches of the duodenum is called the duodenal "cap" or bulb; its small size belies its importance as the most common site of peptic ulcer. An ulcer penetrating through the posterior wall of the duodenal bulb can erode the pancreaticoduodenal artery, penetrate and inflame the pancreas or perforate into the lesser omental sac which may confine the resulting inflammation and infection. An ulcer perforating through the anterior wall of the duodenal bulb may gain access to the general peritoneal cavity and cause peritonitis. The gallbladder rests on the bulb's anterosuperior surface so that gallstones can occasionally ulcerate through, forming a connection (fistula) between the biliary tract and intestine, and if the stone is large enough, even obstruct the intestinal lumen (gallstone ileus). The descending second portion of the duodenum is four inches long and usually lies retroperitoneally along the right side of the vertebral column; it receives pancreatic and biliary drainage through the medially-located papilla of Vater. The third portion of the duodenum then crosses the spine from right to left and the fourth portion inclines slightly upward to join the jejunum at the level of the ligament of Treitz (a suspensory ligament passing from the connective tissue around the celiac artery to the duodenojejunal junction).
The intestinal fan		Unlike the duodenum, the jejunum and ileum are supported on a long, frilled, fan like mesentery which attaches to the posterior abdominal wall by the mesenteric root. The convoluted edge of the mesentery, where it attaches to the intestine, is twenty times longer than it is at its origin in the mesenteric root. The mesenteric root follows an imaginary line which would connect the duodenojejunal junction with the ileocecal valve. The root and its attached mesentery thus form a diagonal shelf stretching from the left upper abdomen to the right iliac fossa.
Jejunal and ileal differences		The proximal half of the small intestine is arbitrarily designated jejunum and the distal half is designated ileum. Although the jejunum and ileum are different, the changes from one to the other are gradual. The jejunum is broader and has a thicker wall than the ileum. This is explained by the high circular folds of the jejunum (valvulae conniventes). The folds of the ileum are sparse and low, but it has distinctive patches of lymphoid tissue which are often several cm long and which can penetrate from the lamina propria into the submucosa (Peyer's patches). The coils of jejunum and ileum occupy most of the abdominal cavity except for the peripheral inverted U-shaped colon. If one draws a line from the right upper corner of the abdomen to its left lower corner, the jejunum generally lies above the line, and the ileum below it. The distal ileum occupies the true pelvis and its distal portion (terminal ileum) ascends out of the pelvis to join the cecum in the right iliac fossa. The 3 fixed points in the small bowel are the second (retroperitoneal) portion of the duodenum, the duodenojejunal junction, and the ileocecal valve. The mesenteric attachment permits considerable mobility of the rest of the intestinal coils and this is useful in accommodating to food, gas, position change, the changing volume of other hollow organs and the state of contraction of the abdominal and diaphragmatic muscles.
Figure 2 Microanatomy of the jejunum and its villi
Blood supply		The superior mesenteric artery comes from the aorta to supply the jejunum and ileum via a series of intercommunicating arcades which travel through the mesentery. The venous blood returns via corresponding venous arcades to the superior mesenteric vein which joins with the splenic vein to form the portal vein. Thus, nutrients absorbed directly into the portal blood pass initially through the liver. The nerves come from the superior mesenteric plexus and follow the blood vessels to the bowel; they originate from sympathetic spinal nerves and parasympathetic nerves of the vagus.
Visceral pain		Small bowel pain is poorly defined, as is all visceral pain; it is usually referred to the periumbilical area, although cecal, terminal ileal and appendiceal pain may be felt in the hypogastrium. The small bowel is not normally palpable to the examining hand and because of its mobility any mass within it must become rather large before it is palpable. If, for any reason, the bowel is distended with air, then the whole abdomen may be protuberant and sound like a drum (tympanitic) when percussed (tapped) with the fingers.
Surface area, theoretically it is the size of a tennis court		Although the small bowel is fifteen to twenty feet long during life, it has several anatomic adaptations which greatly increase the surface area available for absorption. First, there are the circular folds (Figure 2A); secondly, there are the innumerable 1 mm long slender villi covering these folds (Figure 2B,C); thirdly, there are the tiny microvilli (Figure 3) of one micron length which make up the luminal surface of the intestinal absorptive cells covering each villus. This surface area accounts for the absorptive capacity of the small intestine and for its functional reserve although we do not know how much of the epithelial cells lining the intervillous space participate in absorption. It is well to remember that the lining of the gastrointestinal tract is one of the three main areas of contact with the external environment, the skin and the lining of the respiratory tract being the others.
2. Microscopic Anatomy
4 layers		The intestinal wall is made up of four layers: the inner layer of mucosa (villi, crypts, lamina propria and muscularis mucosae); the middle layer of submucosa (loose connective tissue, blood vessels, lymphatics and nerves); and the outer layer of muscularis externa (inner circular and outer longitudinal smooth muscle coats) and the outer serosal covering. The inner mucosal layer faces the lumen and is the primary site of absorption. Its structure and its cell types will be described in greater detail. The mucosa glides freely on the loose connective tissue of the submucosa as its folds assume different configurations during the churning of intestinal contents accompanying digestion and absorption. The submucosa also serves as a conduit for blood vessels, lymphatics and nerves connecting the mucosa with the rest of the body. The main function of the outer muscularis externa is to provide the segmental contractions which churn the intestinal contents within the bowel, so that a meal is delivered to the cecum in 2 4 hours after leaving the stomach.
Intestinal crypts		The main function of the mucosal villi, and especially of the upper third of the villus, is absorption. The main function of the mucosal crypts is to provide new cells to keep the epithelial "escalator" moving up the villus to normally replace this epithelium every 5 days on an average. The intestinal crypt is called the crypt of Lieberkuhn.
Intercellular junctions bind enterocytes together		The absorptive cell (enterocyte) is the most numerous cell type covering the jejunal villus. The enterocytes form a carpet of cells, held together by a web of intercellular junctions, a structure analogous to a 6-pack, in which the cylindrical cans are held together by the plastic sheet at the upper edges.
Figure 3 Ultrastructure of an enterocyte and its underlying vascular channels
Absorptive cells have an apical brush border, consisting of microvilli. Paracellular absorption Endoplasmic reticulum makes chylomicrons		By light microscopy, the main identifying feature of the enterocyte is its refractile brush border covering its luminal (apical) surface; by electron microscopy this brush border is made up of numerous finger-like microvilli (Figure 3) covered by a unique plasma membrane which contains enzymes that hydrolyze oligo- and disaccharides and certain oligopeptides to monosaccharides and smaller peptides or amino acids. Other light microscopic features of the absorptive cell are its tall columnar shape, its basal nucleus and its homogeneous cytoplasm. By electron microscopy there are "tight junctions" between adjacent absorptive cells at the level of the terminal web. These were thought to be a belt encircling the cell, that formed an effective seal between the gut lumen and the mucosa. It is now realized that these tight junctions are not so tight after all, since they allow small solutes to be absorbed by a paracellular route into the large, lateral intercellular spaces. Again, at the higher magnifications of electron microscopy, it is evident that the absorptive cell cytoplasm is rich in mitochondria and contains an interconnecting network of tubular smooth endoplasmic reticulum (SER). The SER functions in the synthesis and degradation of many compounds, both of luminal and endogenous origin; triglyceride is synthesized within the SER and made into the packages that are transportable in the blood, the chylomicrons and the VLDL (very low density lipoproteins). The SER connects with the supranuclear Golgi cisternae which is an area where various cell products like chylomicrons are prepared for export from the cell. The rough endoplasmic reticulum (RER) is studded with ribosomes, and it is an area where proteins are synthesized. The apoproteins essential for synthesis and transport of chylomicrons and VLDL are probably synthesized within the RER. The RER tubules connect with the SER.
Goblet cells secrete acidic mucus Lymphoid tissue samples antigens		The goblet cells are easily recognized with the light microscope because their mucous granules are contained within a space shaped like a brandy goblet which fills most of the cell and flattens the nucleus basally. Intestinal goblet cell mucus is acidic and therefore stains deeply with certain basic dyes. Goblet cells are regularly seen in both the crypt and on the villus. Goblet cells secrete mucus which may have a lubricating and protective function for the intestinal mucosa. They are progressively more numerous from midjejunum to terminal ileum and this plus Peyer's lymphoid patches differentiates jejunal from ileal mucosa. Among the absorptive and goblet cells covering the Peyer's patches of the ileum are the M cells. These cells transport various luminal antigens and toxins to the underlying lymphoid cells so that they can initiate an immune response.
Mucosal regeneration from the crypt stem cells.		Undifferentiated epithelial cells predominate in the crypts of Lieberkuhn. They are occasionally observed to be undergoing mitosis; these multipotent cells will become goblet and absorptive cells as they migrate up the crypt onto the villus. Although these undifferentiated cells are columnar, they are shorter than the absorptive cells and have a more basophilic cytoplasm, which reflects the abundance of free ribosomes in their cytoplasm. Paneth cells are located at the blind basal end of the crypts and are easily recognized by their large acidophilic secretory granules, the largest in the gastrointestinal tract; these granules are released into the lumen of the crypt where their component proteins (defensins) have roles in host defense.
Endocrine cells Carcinoid syndrome		The gastrointestinal mucosa is an important endocrine organ. The easiest endocrine cell to identify is the argentaffin or entero-chromaffin cell which is distributed throughout the gastrointestinal tract. Their granules are stained by silver because of their ability to reduce silver salts. They are roughly triangular cells. The argentaffin granules, which typically have a wide variability in density by electron microscopy, contain 5 hydroxy-tryptophan - the precursor of serotonin. These cells are most abundant in the crypts. They are most numerous also in the ileum and appendix and can form secretory neoplasms, called carcinoids. Flushing, diarrhea and asthma all are features of carcinoid syndrome and indicate excessive secretion of serotonin and other vasoactive substances into the blood.
		Studies using immunofluorescence and electron microscopy indicate that there are a variety of other endocrine cells intermixed with the epithelium covering the villus and lining the crypts. The different types of endocrine cells cannot be differentiated from one another by routine light microscopy.
Epithelial surface replaced every 5 days Flat mucosa from increased exfoliation of villus tip cells or impaired regeneration from crypt stem cells.		The intestinal epithelium is one of the most rapidly replaceable cell populations in man and normally renews itself completely every five days. Mitoses near the bases of the crypts produce new cells which migrate up the sides of the villus to replace the cells which are continually being extruded from the upper end of the villus. This rapid rate of cell replacement makes the epithelium of the intestinal mucosa especially vulnerable to various influences which adversely affect cell proliferation. Thus, slowing of replacement from the bottoms of the crypts by mitotic poisons will shorten the length of the villi above, or eliminate them entirely, i.e., flatten the mucosa. When the rate of exfoliation is greatly augmented by injury at the luminal surface, the increased rate of cell replacement in response to this injury may be inadequate to maintain the length of the villi and again a flat mucosa may result. In the first example above we are dealing with a reduced rate of proliferation and in the second example with an increased rate of proliferation and replacement; nevertheless, the structural end result may be the same - a flat mucosa devoid of villi.
Figure 4 Migration of labeled enterocytes from crypt to villus tip
Cells of the L.P.		The lamina propria is the connective tissue core of the villus. It fills the space between the basement lamina of the epithelial cells and the muscularis mucosae. The lamina propria core of each villus contains a tongue of smooth muscle with surrounding capillaries and a central lacteal, the blind end of which is only two-thirds up the villus. The usual connective tissue elements and various lymphoid round cells are also present. Plasma cells predominate and synthesize mostly immunoglobulins, especially IgA, which help protect the gut from infection and toxic substances. Lymphocytes, eosinophils, macrophages, fibroblasts, collagen and nerves are also scattered within the lamina propria.
Transport of nutrients		The structures beneath the epithelium support it. They must be traversed before an absorbed nutrient can be removed via the portal venules or lymphatics. The basal halves of the absorptive cells in the upper portions of the villus are separated from one another by intercellular spaces (Figure 3). The intercellular spaces are separated from the lamina propria by an underlying basement lamina. An absorbed nutrient or electrolyte usually passes through the lateral or basal plasma membrane of the absorptive cell and enters the intercellular space. It must then traverse the basement lamina to reach the lamina propria. Soluble substances easily reach the capillaries which are located immediately subjacent to the basement lamina. These solutes must traverse the intact basement lamina of the capillary and the fenestrated capillary endothelium to enter its lumen. Lipid particles must take a longer extracellular journey through the lamina propria to reach the blind end of the lacteal, whose lumen they enter via gaps between overlapping endothelial cells of the lacteal wall. The pumping movement of the smooth muscle within the villus may well provide some of the energy for this long extracellular journey. Solutes in the capillaries reach the liver via the portal vein and lipid particles in the lacteals reach the systemic circulation via the thoracic duct which empties into the left subclavian vein.
Brunner's glands → alkaline mucus		In the proximal duodenum, one finds Brunner's glands which are downgrowths from the crypts through the muscularis mucosae into the submucosa. They are branched, coiled, mucous glands which secrete a biocarbonate-rich, alkaline mucus which may assist in reducing the acidity of the gastric chyme, thus preventing duodenal ulceration.
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