Small Bowel

Development of Small Intestine

The small intestine includes the duodenum, jejunum, and ileum. During development of the gastrointestinal system, the duodenum comes from the distal portion of the foregut, whereas the jejunum and ileum come entirely from the midgut. The duodenum moves to the right of the midline as the stomach rotates and shifts to the left side of the abdomen during weeks 4 to 6 of fetal life. As development proceeds, the common bile duct moves to the posterior side of the gut tube as the stomach rotates and the liver enlarges. One aspect of duodenal development that is clinically important is that during weeks 5 and 6, the epithelial lining of the duodenum, derived from the endoderm, proliferates to the point that it completely blocks the lumen of the duodenum. However, the lumen of the duodenum typically recanalizes so that the fetus can begin swallowing amniotic fluid. If the lumen of the duodenum does not recanalize or opens incompletely, duodenal atresia or stenosis will occur. As a region of gut that links the foregut and midgut, the duodenum is supplied by branches of both the celiac and superior mesenteric arteries. The descending and horizontal portions of the duodenum are the regions where this anastomosis occurs, and these are also the regions in which atresia or stenosis is most likely to be manifested.

The jejunum and ileum are, in their entirety, midgut structures and are supplied by branches of the superior mesenteric artery. As it elongates, a loop of midgut herniates into the umbilical cord, with the superior mesenteric artery extending between the loop's proximal limb (cranial) and distal limb (caudal). The vitelline duct extends off the apex of the loop, connecting the midgut temporarily to the secondary yolk sac. The proximal limb of the midgut loop will become the jejunum and ileum, and the distal limb will become the terminal ileum, cecum, appendix, ascending colon, and transverse colon. Although it may sound as though the proximal and caudal portions are unbalanced, the jejunum and ileum elongate tremendously, creating many loops within the umbilicus. While in the umbilicus, the midgut rotates 90 degrees in a clockwise motion (when viewed from the perspective of the embryo) and also becomes elongated. This rotation moves the proximal limb to the right and the distal limb to the left side of the cord. During the 10th week, the midgut begins to return to the abdominal cavity, which has grown more expansive as the relative size of the liver and kidneys decreases. As the loop of midgut finishes returning to the abdomen in the 11th week, it undergoes a further 180-degree rotation around the superior mesenteric artery, with the proximal limb moving to the left side of the body (where most of the jejunum will be found) and the distal limb moving to the right side of the body (where you will typically find the distal ileum, cecum, appendix, and ascending colon). During this process, the ileum loses its connection to the vitelline duct, unless it remains as a blind pouch ( ileal or Meckel diverticulum ).

The dorsal mesentery of the duodenum lays back and fuses with the parietal peritoneum of the posterior body wall to become secondarily retroperitoneal. The jejunum and ileum retain the posterior mesentery; it allows these mesenteric organs a degree of freedom within the abdominal cavity. Because the stomach and the proximal jejunum have a mesentery, the first and fourth portions of the duodenum may have a small mesentery. The morphologic changes of the midgut during development are largely complete at this time, apart from growth as the individual grows during childhood and adolescence. The further development of the large colon will be covered in the next section.

Topography and Relations of Small Bowel

The small intestine consists of a retroperitoneal portion, the duodenum, and a mesenteric portion made up of the coils of the jejunum and ileum. The total length of the mesenteric portion of the small intestine varies considerably. The average for adults is roughly 5 m. The proximal jejunum forms approximately two fifths of the mesenteric portion, and the ileum forms the remaining three fifths. The jejunum commences at the duodenojejunal flexure on the left side of the second lumbar vertebra or, occasionally, somewhat more cranially. The ileum terminates when it joins the large intestine in the right iliac fossa. Although the division between the jejunum and ileum is not grossly visible (the appearance of the arteries and histologic structure can be used to distinguish the two regions), the coils of the jejunum tend to be on the superior left side of the abdomen and those of the ileum on the inferior right side.

The duodenojejunal flexure is situated at the superiormost end of the region covered by the mesentery of the transverse colon. It may sometimes be partially concealed by the parietal line of attachment of the transverse mesocolon. From the duodenojejunal flexure to the ileocolic junction, the line of attachment of this mesentery runs obliquely from superior left to inferior right, passing across the lumbar portion of the spine, aorta, inferior vena cava, right psoas major, and right ureter. The mesentery is formed by two layers of peritoneum that reflect off the posterior body wall and become continuous as they cover the intestinal surface. The space between the two layers of peritoneum is filled with connective tissue and adipose cells, the quantity of the latter varying greatly from one individual to another. Sandwiched between the two layers of peritoneum and embedded in this tissue are blood and lymph vessels running between the intestine and the posterior abdominal wall, as well as nerves and mesenteric lymph nodes. The mesentery is only about 15 to 20 cm in length as it attaches to the body wall, compared with several meters (corresponding to the length of the intestine) along its intestinal attachment, so you can conceptualize the mesentery fanning outward as it approaches the intestines. The existence of the mesentery affords the intestinal coils a wide range of movement.

The various portions of the large intestine form a horseshoe-shaped frame enclosing the coils of the small intestine. This frame may be overlapped anteriorly by the coils of the small intestine, particularly the descending colon on the left side. Similarly, depending on their filling and on their relationship with the pelvic organs, the coils of the small intestine may extend inferiorly into the true pelvis or, if the pelvic organs are greatly distended (e.g., in pregnancy), may be displaced superiorly.

Greatly varying in shape and highly mobile, the greater omentum hangs down apronlike from the greater curvature of the stomach and spreads between the anterior abdominal wall and the coils of the small intestine. This large sheet of connective tissue, adipose tissue, and outer coating of the peritoneum frequently obscures the small intestines but can often be reflected, so that its free end is lifted superiorly. However, it also may form adhesions to the anterior and lateral abdominal wall, which would make it difficult to reflect.

Most of the coils of the jejunum lie superiorly to the left, whereas those forming the ileum are situated inferiorly to the right. Because it is suspended from the body wall by a mesentery, the small intestine is capable of considerable movement, and its individual coils vary greatly in position. This is true between individuals and even in one and the same subject at different times, depending on the state of intestinal filling and peristalsis and the position of the body. The only portion that, in line with its progressively shortened mesentery, has a more or less constant position is the terminal ileum, which passes to the right, across the right psoas major muscle, to the site of the ileocolic junction.

Structure of Small Intestine

The freely mobile portion of the small intestine, which is attached to the mesentery, extends from the duodenojejunal flexure to the ileocolic orifice, where the small intestine joins the large intestine. This portion of the small intestine consists of the jejunum and the ileum. They run imperceptibly into each other, the transition being marked by a gradual change in the diameter of the lumen and by several structural alterations.

The walls of the jejunum and ileum are virtually identical in structure but have slight modifications that make them histologically distinct. Like the rest of the gastrointestinal tract, the jejunum and the ileum each has four layers: the mucosa, submucosa, muscularis externa, and serosa. The innermost layer, the mucosa, is thickly plicated by macroscopically visible circular folds (plicae circulares, Kerckring folds). These folds vary in height, projecting into the lumen by 3 to 10 mm. Some of these plicae extend all the way around the internal circumference, some of them extend only halfway or two thirds of the way around the circle, and still others spiral around the circle twice or even more times. The circular folds projecting into the lumen slow down the progression of the luminal contents to a slight degree, but their most important function is to increase the absorptive surface area of the intestinal lumen. The visible increase in surface area created by the circular folds is mirrored on the microscopic level by tiny fingerlike projections, intestinal villi.

In fact, the entire mucosal surface of the small intestine, over and between the circular folds, is covered with intestinal villi, projections that are 0.5 to 1.5 mm long (just barely visible to the naked eye). The mass of these villi (estimated at 4 million altogether in the jejunum and ileum) accounts for the velvety appearance of the mucosa. They are somewhat longer and broader in the jejunum than they are in the ileum. The valleys or indentations between the villi form nonramified pits, each of which harbors tubular structures, the intestinal glands (crypts of Lieberkühn). Along the villi, the entire inner surface of the small intestine is covered by a single layer of epithelial cells, the majority of which are enterocytes, highly prismatic columnar cells with a surface covered by microvilli, microscopic projections from these cells' apical surfaces. Between these columnar cells are interspersed three other types of cells: goblet cells, Paneth cells , and enteroendocrine cells. The goblet cells secrete an alkaline, mucous fluid that coats the whole mucosa. Most goblet cells are found lining the crypts or along the lower parts of the villi, but a considerable number of them are located near the apex of the villi, where they seem to be squeezed between neighboring enterocytes. The Paneth cells are found almost exclusively near the base of the glands. They are easily identified histologically due to the eosinophilic granules they contain. Paneth cells are primarily involved in moderating the bacterial normal flora of the small intestine. They do so by secreting the antimicrobial enzyme lysozyme, as well as α-defensins. They are able to phagocytose bacteria and other invaders within the intestinal lumen. Lastly, the enteroendocrine cells (argentaffin cells, yellow cells, cells of Schmidt or of Kultschitzky) contain basal-staining granules with a high affinity for silver and chromium. These cells are typically found at the bottom of intestinal glands but can migrate upward. They regulate the activity of the digestive system by releasing hormones such as cholecystokinin (stimulates secretion of the gallbladder and pancreas and inhibits gastric emptying), secretin (stimulates pancreatic secretion and inhibits gastric secretion), motilin (stimulates peristalsis), and gastric inhibitory peptide (stimulates insulin secretion and inhibits gastric secretion) into the bloodstream. Enteroendocrine cells in the small intestine may also secrete somatostatin (inhibits release of gastrin and gastric secretion) and histamine (stimulates gastric secretion from parietal cells) in a paracrine fashion, affecting nearby tissues. Lymphocytes, eosinophils, neutrophils, macrophages, mast cells, and plasma cells are also sometimes seen in the epithelial lining of the small intestine, but these have generally migrated from the underlying layer of the mucosa, the lamina propria.

The lamina propria lies deep to the epithelial surface of the mucosa, but it extends into both the circular folds and intestinal villi, forming the core of each villus. This diffuse reticular connective tissue allows for the easy diffusion of nutrients and gasses to and from the epithelial lining of the intestine. The lamina propria frequently assumes a lymphatic character owing to the large number of lymphocytes that migrate through it. The lamina propria also contains thin fibers of smooth muscle that radiate from the muscularis mucosae and extend upward to the tips of the villi. When these fibers are relaxed, the villi have a smooth surface, whereas they become jagged or indented when the fibers contract. These muscular fibrils are assumed to act as motors that maintain the pumping function of the villi. At the core of each villus is a lymphatic vessel, the central lacteal, which transports fat-soluble substances and lymph to the cisterna chyli and from there to the venous circulation. The muscularis mucosae, which separates the lamina propria from the submucosa, is composed of two thin layers of smooth muscle, which keep the movable mucosal layer in place. The outer longitudinal layer is thinner than the inner circular layer, from which the muscular fibers in the core of the villi, mentioned above, emanate.

The submucosa is a relatively stout layer that is located deep to the mucosa. It is made up of type I collagen bundles forming dense, irregular connective tissue. By altering the angles of its meshes, this submucosal network is able to adapt itself to changes in the diameter and length of the intestinal lumen. The submucosa contains a rich network of arteries, veins, and lymphatics that supply the submucosa and overlying mucosal structures. It also has a substantial network of viscerosensory and visceromotor axons; preganglionic parasympathetic axons terminating in the submucosa synapse on the submucosal plexus (Meissner plexus), a collection of ganglia (nerve cells) scattered throughout the small and large intestines that contribute to the enteric nervous system.

The muscularis externa is a large and powerful two-layered coat of smooth muscle that covers the submucosa. The thick inner circular layer and the thinner outer longitudinal layer are connected by convoluted transitional fascicles in the area where they border on each other. Between the two layers is a network of viscerosensory and visceromotor axons. As in the submucosa, preganglionic parasympathetic axons synapse with the myenteric plexus (Auerbach plexus), which are the ganglia located between the two layers of smooth muscle. The myenteric plexus and submucosal plexuses are major components of the enteric nervous system. The muscularis externa is responsible for creating the powerful movements of peristalsis that move intestinal contents progressively down the lumen, or in retrograde motion during vomiting.

Lining the outside surface of the small intestines is the final layer, the serosa (visceral peritoneum). This layer is composed of mesothelial cells on the surface that are connected to the muscularis externa by a thin layer of loose connective tissue. The mesothelial cells release fluid that lubricates the external surface of the small intestine and helps to prevent irritation and adhesions between the intestines and other peritoneal structures. The serosa covers the entire circumference of the small intestines, except for a narrow strip where the mesentery anchors the intestines to the posterior body wall.

Though very similar in many ways, the jejunum and ileum differ in several respects. The lumen of the ileum is narrower and the diameter of the total wall is thinner than that of the jejunum. The average diameter of the jejunum measures 3 to 3.5 cm and that of the ileum 2.5 cm or less. Due to this difference, the contents of the intestine are more visible through the wall of the ileum than the jejunum. Because of this, in the operative view, the jejunum typically has a whitish-red hue, whereas the ileum takes on a darker appearance. The circular folds within the lumen vary in frequency and height, as do the villi. They decrease in height and number as the small intestine approaches the cecum, and in the distal ileum the folds appear only sporadically.

In the jejunum, lymphatic tissue is encountered only in the form of solitary lymphoid nodules that appear as pinhead-sized elevations on the surface of the mucosa. They become more numerous and more pronounced as they near the large intestine. However, within the ileum, such nodules are very pronounced, forming aggregated lymphoid nodules (Peyer patches). They are invariably situated opposite the attachment of the mesentery and are generally of an elongated oval or ellipsoid shape, their longest diameter always coinciding with the longitudinal axis of the intestinal lumen. Their average width is 1 to 1.5 cm and they vary in length from 2 cm up to 10 or 12 cm or, occasionally, even more. They differ in number from one individual to another, the average total fluctuating from 20 to 30. Another difference between the jejunum and ileum concerns the fat content of their mesenteries. In the adult, the mesentery of the ileum contains more fatty tissue and appears to be thicker than that of the jejunum. The blood vessels that supply each region also have a different appearance, which is described in Plates 1-1 and 1-2 .

The principal task of the gastrointestinal tract is to supply the body with its caloric requirements and metabolic material. The structures of the entire gastrointestinal tract, from the mouth to the large intestine, are optimized to accomplish this task. It is within the small intestines, especially the jejunum and ileum, where the majority of absorption occurs through the long row of epithelial cells, enterocytes, which coat the inner surface of the small intestine. These epithelial cells, together with the villi they cover, should properly be considered the organ of absorption. The surface area available for absorption is maximized in several ways. The circular folds of the small intestine (including the epithelial cells, lamina propria, muscularis mucosae, and submucosal layers) increase the surface area grossly. The villi that project from the lumen and circular folds further increase the surface area available for absorption. Finally, the apical surfaces of the enterocytes themselves have a striated border, which is actually composed of microvilli extending from each enterocyte into the lumen. It has been calculated that each epithelial cell is provided with about 1000 microvilli, which increase the cellular surface approximately 24 times. The microvilli seem to vary only a little in size (average length, 1 micron; width, 0.07 micron) and have a core of actin microfilaments extending down their length to attach to a network of fibrils, the terminal web, at the apical edges of the cells. Contraction or relaxation of this web can widen or narrow the space between adjacent villi.

At some time after the ingestion of a meal containing fat, fine lipid droplets can be observed in the intermicrovillous spaces; slightly later, the droplets appear in the area of the terminal web, where they accumulate in minute vesicles, which owe their existence to a pinocytotic activity, probably of the intermicrovillous plasma membrane. The droplets then can be found in the main body of the epithelial cell, where they coalesce to form larger units in vesicles or cisternae, which are connected with each other by intracellular tubules. The fat droplets pass toward the lateral cell surfaces. From the intercellular spaces, the droplets traverse the basement membrane and the interstitial spaces of the lamina propria to enter the central lacteals of the villi. The lacteals carry fats and fluid proximally via lymphatic channels that ultimately drain to the cisterna chyli, thoracic duct, and, finally, left subclavian vein. For this reason, fat-soluble substances can bypass the liver, which receives the substances from the lumen that are transported to it via the hepatic portal vein.

The nucleus of the enterocytes is typically located in its basal region, near the Golgi apparatus. Mitochondria and other organelles of the cell body show no particular or specific features. To maintain a separation between the lumen of the intestines (which is technically outside the body) and the extracellular space within the body, the apical region of enterocytes and other cells of the intestinal epithelium are bound to each other by junctional complexes in the vicinity of the terminal web. The enterocytes are anchored to the underlying connective tissue of the lamina propria by tight junctions. This allows the enterocytes to be selective about the substances that are released into the lamina propria and, thereafter, the bloodstream.

Blood Supply of Small Intestine

For the typical pattern of arterial branching of the small intestines, please refer to Plates 1-1 and 1-2 . In this section, we will describe the variations concerning the origin, course, anastomoses, and distribution of the vessels supplying the small intestine. These variations are so frequent that conventional textbook descriptions are inadequate for anyone attempting procedures in the area. Typically, the superior mesenteric artery supplies almost all of the small intestine aside from the proximal duodenum, which receives blood from the supraduodenal and superior pancreaticoduodenal arteries. These arteries are branches of the gastroduodenal artery, a branch of the common hepatic artery, which is itself a branch of the celiac trunk.

The distance between the celiac trunk and the superior mesenteric artery varies from 1 to 23 mm but is typically between 1 and 6 mm. These major vessels branch from the abdominal aorta; in rare cases, the vessels form a single massive vessel, a celiacomesenteric trunk , that gives off the common hepatic, splenic, left gastric, and superior mesenteric arteries. However, in some cases of celiacomesenteric trunk the left gastric artery is a small separate branch arising directly from the abdominal aorta (A). A far more frequently encountered variation (0.4% to 6% of the population, Kahraman and associates 2002) of these vessels is a hepatomesenteric trunk. This occurs when the superior mesenteric trunk fuses with the common hepatic, right hepatic, or left hepatic artery (B, C, D, and E). If the hepatomesenteric trunk includes the common hepatic artery, there will also be a gastrosplenic trunk giving rise to the splenic and left gastric arteries (B). If the hepatomesenteric trunk gives rise to a right hepatic artery (C) or an accessory right hepatic artery (D and E), there will be either an incomplete celiac trunk or a complete celiac trunk contributing the remaining hepatic vessels (C and D). The cystic artery may arise from either the right hepatic artery or accessory right hepatic artery (C, D, and E).

Variations that are even less frequent have been described. A splenomesenteric trunk develops when the superior mesenteric and splenic arteries arise from a common trunk (F). In such cases, there will be a separate hepatogastric trunk branching into common hepatic and left gastric arteries. If the superior mesenteric, splenic, and common hepatic arteries come from a common trunk of the abdominal aorta (G), the result is a hepatosplenomesenteric trunk, with a separate left gastric artery arising from the aorta or from the left inferior phrenic artery, creating a gastrophrenic trunk. Occasionally, the right gastroomental artery may branch from the superior mesenteric artery (H) instead of taking its normal departure from the gastroduodenal artery.

The first jejunal branch of superior mesenteric origin may be very large (6 mm in diameter), but in many instances, it is very small (1 to 2 mm) and forms anastomoses with the inferior pancreaticoduodenal artery or has a common origin with it. The distribution, as well as the caliber, of all the following intestinal branches of the superior mesenteric artery varies considerably, and smaller branches may alternate without any general rule or order. An odd situation may be faced during gastric resection, when the right gastroomental artery and the first jejunal branch arise from a common pancreaticoduodenal trunk coming from the superior mesenteric artery. Closer to the small intestine itself, small (4- to 6-cm) segments may be vascularized by straight arteries derived from a separate anterior and posterior arcade, each serving the anterior and posterior surface of the same region of the gut. Though numerous other examples of variations concerning the origin and communication of the first jejunal branches could be enumerated, those cited seem sufficient to justify the requirement of a careful inspection of these vessels while operating in this region.

Lymph Drainage of Small Intestine

The lymph vessels of the small intestine begin with the central lacteals of the villi. At the base of the villi, each central lacteal joins with lymph capillaries, draining the nearby intestinal crypts. These lymph capillaries form a fine network within the lamina propria, in which the first lymphatic valves are already encountered. Many minute branches emerge from this network, penetrating through the muscularis mucosae into the submucosa, which hosts a sizable network of lymphatic vessels. The vessels of this network have conspicuous valves that prevent retrograde motion of the lymphatic fluid once it is inside the vessels. Progressively larger lymph vessels, receiving additional lymph from the layers of the muscularis mucosae and from the serosa and subserosa, pass toward the attachment of the mesentery to the small intestine. Within the mesentery, the lymph vessels travel alongside arteries and veins. These larger lymph vessels have been referred to as chyliferous vessels or lacteals because they transport emulsified fat absorbed from the intestines and appear as milky-white threads after the ingestion of fat-containing food. Lymph fluid traveling through these vessels encounters several juxtaintestinal (within the mesentery, alongside the intestines) superior mesenteric lymph nodes, which number some 100 to 200 and constitute the largest aggregate of lymph nodes in the body. They increase in number and size toward the root of the mesentery. In the root of the mesentery, larger lymphatic branches are situated, which lead into the central group of superior mesenteric nodes in the area where the superior mesenteric artery arises from the aorta.

The proximal duodenum and nearby pancreas receive blood from branches of the celiac trunk; its distal sections are supplied by the superior mesenteric artery; lymphatic drainage from the duodenum can pass to either celiac or superior mesenteric lymph nodes. Lymphatic fluid from the duodenum and the nearby pancreatic head pass fluid to lymph nodes lying inferior, superior, and posterior to the head of the pancreas. The inferior nodes are the already-encountered central group of superior mesenteric nodes. The superior group of lymph nodes is known as the subpyloric and right suprapancreatic nodes, and the posterior group is known as the retropancreatic nodes. Lymphatic fluid from the latter two groups of nodes drains parallel to branches of the celiac trunk to reach the celiac lymph nodes.

From the superior mesenteric nodes and the celiac nodes, lymphatic fluid passes through the short intestinal or gastrointestinal lymph trunk, which is sometimes divided into several smaller parallel trunks, and enters the cisterna chyli, a saclike expansion at the beginning of the thoracic duct. The intestinal trunk drains not only the whole of the small intestine but also all organs, the lymph of which is collected in the celiac and superior mesenteric lymph nodes (especially the stomach, liver, pancreas, and extensive portions of the large intestine). The cisterna chyli also receives much of the lymphatic fluid drained from the lower limbs, pelvic organs, and hindgut organs. From the cisterna chyli, lymph drains superiorly through the thoracic duct. This large lymphatic vessel has prominent valves in its wall and is found in the posterior mediastinum between the aorta and esophagus. It travels posterior to the arch of the aorta to ultimately drain the lymphatic fluid into the venous system at the left subclavian vein near its junction with the left internal jugular vein.

Motility of Small Intestine

The digestive status (fed versus fasting) is a key component of small bowel motility. Fasting small intestinal motility follows four cyclic phases, referred to as the migratory motor complex. The migratory motor complex consists of waves of electrical activity that sweep through the intestine every 90 to 120 minutes. In addition to facilitating the transport of indigestible substances from the stomach to the colon, the migratory motor complex also transports bacteria from the small intestine to the large intestine and inhibits the reflux of colonic bacteria to the terminal ileum. It has thereby been termed the “intestinal housekeeper.”

Phase I of the migratory motor complex lasts 5 to 20 minutes and is characterized by a prolonged period of quiescence. Phase II lasts 10 to 40 minutes and is defined by an increased frequency of random contractions. Phase III lasts 3 to 6 minutes and is characterized by bursts of prolonged high-amplitude contractions. In phase IV, there is a rapid decrease in contractions. In the duodenum, phase III contractions have a frequency of 1 to 12 contractions per minute and last for at least 3 minutes. The velocity progressively decreases from the proximal duodenum to the distal jejunum. Alterations in the migratory motor complex have been implicated in small intestinal bacterial overgrowth, IBS, functional dyspepsia, gastroparesis, Chagas disease, intestinal pseudoobstruction, obesity, anorexia nervosa, and aging.

The postprandial phase is defined as the time from meal intake until the return of phase III of the migratory motor complex. When nutrients enter the small bowel, transit is initially rapid and chyme is distributed throughout the bowel. During digestion, transit slows down to promote absorption by increasing contact time of the chyme with the small bowel wall. Pressure waves after a meal are similar to those occurring during the migratory motor complex, but they propagate on average half the distance of phase III pressure waves. Most postprandial pressure waves propagate less than 2 cm and serve to mix and grind nutrient chyme. Flow rates during this period are highly variable and rely on caloric content and the nature of the meal. In addition, the enteric nerves, hormonal function, and level of paracrine mediators, including gastrin, cholecystokinin, neurotensin, peptide YY, pancreatic polypeptide, and motilin play a role.

The stationary pressure waves of the postprandial period favor absorption, as does phase I of the migratory motor complex. The stationary pressure waves work in two ways: (1) by stirring intestinal contents and (2) by providing propulsive pressure waves to spread and expose the chyme to a larger absorptive surface. This type of activity is also referred to as rhythmic segmentation. Intestinal peristalsis is generated by the contraction of the muscularis propria, made up of outer longitudinal and inner circular layers, forming a continuous tube that lengthens, shortens, twists, and constricts so that the enclosed contents are constantly agitated and propelled. A meal generally traverses the small bowel in approximately 5 hours, a period that is shortened by the intake of another meal.

The initiation and cycling of the migratory motor complex is under the control of the enteric nervous system. Smooth muscle cells of the gastrointestinal tract undergo periodic depolarization of their membrane potential. These are called slow waves, and they are generated by the interstitial cells of Cajal, which act as pacemakers and produce spontaneous electrical slow waves with a frequency of 12 per minute in the duodenum and 10 per minute in the ileum. A contraction is achieved when a slow wave occurs at the same time that an excitatory neurotransmitter is released from a motor neuron of the enteric nervous system.

Motility studies (manometry) and transit studies are used to investigate small bowel motor physiology. Manometry studies are conducted using a catheter that measures intraluminal pressure induced by smooth muscle contractions. Transit studies include hydrogen breath testing, small bowel scintigraphy, and wireless motility capsule testing. The wireless motility capsule measures transit time, pressure, pH, and temperature from the mouth to the anus. It correlates well with scintigraphy. Patients can resume normal daily activities while data are being collected by the capsule. It also eliminates radiation exposure and provides a complete transit profile of the gastrointestinal tract.

The junction of the small intestine with the colon is sometimes referred to as the ileocecal valve partly because of its structural appearance in some anatomic specimens and partly because the end of the ileum, being wedged into the wall of the colon, seems to function, in some individuals, in the manner of a flutter valve. The ileocecal junction functions as a true sphincter, meaning that it regulates the flow of material from the ileum to the cecum, as well as preventing its retrograde passage. Thus the contact of the intestinal contents with the terminal ileal mucosa is prolonged, favoring maximal intestinal absorption. The sphincter opens when a peristaltic wave, passing along the terminal ileum, builds up enough pressure to overcome the resistance of the sphincter. The cecum at first manifests receptive relaxation. Increasing pressure in the cecum, either by overdistention or by a peristaltic contraction, causes a reflex contraction of the sphincter, preventing overfilling of the cecum and cecoileal reflux.

Gastrointestinal Hormones

The epithelium of the gastrointestinal tract contains multiple cell types, including specialized cells termed enteroendocrine cells that number less than 1% of the cell population and yet form the largest endocrine system of the body. Enteroendocrine cells synthesize, store, and release chemical transmitters that are involved in gastrointestinal motility, secretion, and absorption and in regulation of appetite. These transmitters are predominantly small polypeptides that are also found in the enteric nervous system and the central nervous system. There are more than 30 gut peptide hormone genes identified, which express more than 100 bioactive peptides. They are grouped into “families” according to their primary structure. In this section, the pancreatic polypeptide family will be discussed.

Peptide YY is one of the gut peptides that belongs to the pancreatic polypeptide family of peptides, which also includes pancreatic polypeptide and neuropeptide Y. Despite sharing structural similarities and the same 36 amino acid lengths, the gut peptides vary in their biologic functions and locations. Peptide YY, neuropeptide Y, and pancreatic polypeptide bind to a family of G-protein–linked receptors (called Y receptors). At present, five receptor subtypes have been identified.

Peptide YY is secreted from L cells in the ileum and H cells in the colon in response to an oral nutrient load. Peptide YY levels start to rise within 15 minutes of any caloric ingestion, long before the nutrients themselves reach the distal gut, implying that other neural or hormonal mechanisms are involved in its release. The actions of peptide YY are largely inhibitory. It inhibits gastrointestinal motility, pancreatic and gastric secretion, and chloride secretion, causing a delay in intestinal transit, or the so-called ileal brake. This allows for a longer contact time between nutrients and the small intestine. Peptide YY is also believed to be involved in the regulation of food intake and satiety, acting mainly via the Y ₂ receptors in the hypothalamus.

Pancreatic polypeptide is secreted by specialized pancreatic islet cells and inhibits gallbladder contraction and pancreatic exocrine secretion. It may influence food intake, energy metabolism, and the expression of gastric ghrelin and hypothalamic peptides. Neuropeptide Y is a neurotransmitter predominantly found in sympathetic neurons and is the most potent known stimulant of food intake.

Pathophysiology of Small Intestine

The most important functions of the small intestine are digestion and absorption of nutrients. They are achieved by an interaction between intact small bowel motility and gastrointestinal hormones. Clinically recognizable disturbances of small bowel function arise mainly from alterations in the motor activities or interference with digestion and absorption.

Tests for Small Bowel Function

Congenital Intestinal Obstruction: Intestinal Atresia, Malrotation of Colon, Volvulus of Midgut

Intestinal obstruction in newborn infants is caused by a variety of congenital anomalies, and prompt diagnosis and treatment can be life-saving. The causes of such intestinal obstructions may be atresia of the esophagus, diaphragmatic hernia, annular pancreas, malrotation of the colon with volvulus of the midgut, peritoneal bands mostly compressing the duodenum, internal or mesentericoparietal herniations, meconium ileus, aganglionic megacolon, imperforate anus, and atresia or congenital stenosis of the bowel.

Atresia refers to the complete congenital obstruction of the lumen of a hollow viscus, and stenosis refers to luminal narrowing of varying degrees. The most common site of intestinal atresia is the small bowel, particularly the jejunum and ileum; the colon is least commonly affected. Intestinal atresia results from an interruption in the normal development of the gastrointestinal tract, commonly during the second and third months of fetal life. In the proximal small bowel, this is often caused by failure of the intestine to recanalize. As the intestine changes from a solid structure to a hollow tube, one or more septa may persist, leaving a diaphragm of tissue with only a minute opening and setting up a stenosis. If such persisting septa leave an intact diaphragm across the lumen, or if, during the solid stage, the intestine divides to form two or more blind segments entirely separate from each other or connected by threadlike fibrous bands, atresia ensues. In the middle and distal small bowel, atresia often results from vascular disruption, leading to ischemic necrosis of the fetal intestine. Because the fetal bowel is sterile, the necrotic tissue is resorbed, leaving blind proximal and distal ends, often with a gap in the mesentery.

Intestinal atresia can be classified into four types based on the anatomic arrangement. In type 1, there is no discontinuity of bowel but rather obstruction of the lumen by a diaphragm composed of mucosa and submucosa. In type 2, the proximal and distal segments are connected by a short band and bowel discontinuity is evident. In type 3, there is complete discontinuity. Type 4 is a combination of types 2 and 3.

The diagnosis of intestinal atresia or stenosis can be made with prenatal ultrasound. Findings that suggest intestinal atresia on ultrasound include bowel dilatation or ascites. Prenatal diagnosis can lead to prompt treatment of the infant shortly after birth and avoids the complications associated with intestinal obstruction.

Postnatally, the diagnosis of intestinal atresia should be suspected in newborns that develop abdominal distention, vomiting, or an abdominal mass with or without obstipation. However, the timing of these signs is variable and depends on the location of the obstruction as well as its nature, whether it is a stenosis or an atresia. X-ray study of the abdomen is indicated in any newborn suspected to have intestinal obstruction. The presence of persisting bile-stained vomitus in the absence of meconium stools for more than 4 hours is often a common initial finding in proximal obstruction. A double-bubble sign on plain x-ray with no distal gas strongly suggests duodenal atresia. If an enema is indicated, it should be a diagnostic barium enema, unless meconium ileus is suspected, in which case water-soluble Gastrografin should be used. It may be necessary to aspirate air from the stomach because it might distort or obscure the pattern of gas distribution in the small bowel, or it may be advisable to introduce 20 mL of gas into the stomach, if no gas is present, in cases of obstruction in the higher parts of the small intestine. Differentiation between the shadows of the small and large intestines is often difficult to make, because of an underdeveloped state of the circular folds of the jejunum as well as of the colonic haustrations. For this reason, the point of obstruction in an infant is commonly assumed to be lower than it actually is. Total absence of air in the abdomen is indicative of esophageal atresia without tracheoesophageal communication. Other obstructive lesions in the alimentary tract are, as a rule, marked by air distention above and complete absence of air below the point of obstruction, so, for example, in duodenal atresia the stomach and duodenum above the block are considerably dilated, with no air below.

The management of intestinal atresia is primarily surgical and depends on the location of the obstruction. In all cases, the mandatory principle is to preserve as much of the small intestine as possible. Unfortunately, in many instances the atretic portion of the intestine is so great that lack of an adequate absorptive surface will sometimes bring about insurmountable difficulties in maintaining nutrition postoperatively. Preoperatively, feedings should be withheld, the proximal segment should be decompressed after placement of a nasoenteric tube, and fluid and electrolyte resuscitation should be instituted promptly.

Surgery can be performed laparoscopically; the possibility that multiple sites of atresia may be present should be entertained and properly evaluated preoperatively, however.

The prognosis of intestinal atresia is very good. Most deaths occur in infants who are premature or have associated anomalies.

Volvulus is the term generally used to indicate the torsion and/or coiling of an organ about its attachment, which, in the specific case of the intestines, is the mesentery. It may occur at all ages when, for one reason or another, an intestinal segment becomes longer and the mesentery narrower. In the newborn, volvulus of the midgut, which leads to serious intestinal obstruction, is a complication of a malrotation of the colon. Normally, around week 10 of fetal life, the ileocecal area rotates in a counterclockwise direction, bringing the cecum into the lower right abdominal quadrant and permitting the mesentery of the ascending colon to be fixed posteriorly and laterally to the parietal peritoneum. Genetic mutations that disrupt signaling result in the arrest of this process. The attachment of the mesentery from the duodenojejunal junction to the middle of the transverse colon is lacking, causing this long mass of intestine to remain suspended between the two points of fixation. It may become twisted, producing not only intestinal obstruction but also occlusion of the superior mesenteric vessels. The cecum may be held in this abnormal position in the upper right quadrant by adventitious peritoneal bands and be fixed to the liver, parietal peritoneum, or posterior abdominal wall in such a way as to compress the duodenum. Peritoneal bands, not associated with malrotation of the colon, may occasionally cause obstruction of the duodenum or, still more rarely, of other parts of the small bowel.

The clinical signs of these conditions are the same as those of any other cause of intestinal obstruction in the newborn. The x-ray appearance often resembles a typical intestinal obstruction with dilated loops proximally with completely gas-free segments distal to the obstruction. In cases of volvulus, however, residual air bubbles may be observed distal to the obstruction due to air that passed along the intestinal tract before the volvulus occurred. During operation for these cases of volvulus of the midgut, the twisted portion of the bowel is unwound and the Ladd procedure is carried out on the malrotated portion. Upon severing the obstructing adventitious bands or abnormal attachments, the colon will drop to the left side of the abdomen, leaving the small bowel on the right side.

Internal (e.g., paraduodenal, duodenojejunal) hernia may also be responsible for intestinal obstruction in infants. A loop of bowel may become incarcerated, or perhaps even strangulated, by entering a defect in the mesentery or by passing between adventitious bands of peritoneum. The herniation is generally diagnosed either by exclusion or on the operating table. The obvious procedure is to reduce any existing hernia and to divide any obstructing adventitious bands.

Congenital Intestinal Obstruction: Meconium Ileus

The condition known as meconium ileus develops exclusively in infants born with cystic fibrosis, which is a lethal autosomal recessive disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This mutation primarily interferes with chloride transport in various acinar structures of the intestinal, bronchial, salivary, and sweat glands, as well as those of the pancreas. Pancreatic damage can occur in utero; 85% to 90% of these patients develop severe pancreatic insufficiency. Subsequently, the meconium becomes thick and tenacious, adhering to the intestinal mucosa and causing impaction in the ileum and intestinal obstruction.

Meconium ileus can cause complete obstruction, with an empty, collapsed segment distally and a dilated segment proximally. The ileum frequently resembles a strand of beads, as the bowel wall conforms to the contour of the aggregations of meconium, which is gray in color and of a dried, puttylike consistency. Just proximal to the occlusion, the bowel is slightly larger in caliber, and the meconium sticking to the wall is less firm but still so viscous as to prevent peristaltic propulsion. It is here still gray-green to green-black, and it contains so little fluid that it leaves no stain when held in the hand. Meconium ileus has typical radiographic findings. Some of the loops seem moderately enlarged, some are enormously ballooned, others appear normal, and some are even smaller than normal. This is in marked contrast to intestinal obstruction from atresia, stenosis, or aganglionic megacolon, where all the loops are likely to be extended with gas to the same extent. The inspissated meconium is seen on the x-ray film as a radiopaque mass, with a mottled appearance due to air bubbles that have been forced into it. It is important to remember, however, that inspissated meconium may also be visualized in aganglionic megacolon (see Plate 3-30 ) and that both conditions, meconium ileus and aganglionic megacolon, may exist without any evidence of fecal shadows on x-ray examination. Flecks of calcium, either scattered throughout the abdomen or attached to the bowel wall, are diagnostic of meconium peritonitis caused by rupture of the intestine in utero.

The management of meconium ileus depends on the degree of obstruction and the presence of complications. Patients with uncomplicated meconium ileus can be treated nonoperatively by methods that help disimpact the inspissated mucus. In this approach, dilute water-soluble contrast or N -acetylcysteine (Mucomyst) can be infused transanally via catheter into the dilated portion of the ileum. This procedure should be performed by an experienced team, and the use of fluoroscopy is recommended. These agents help dissolve the impacted meconium by absorbing fluid from the bowel wall into the intestinal lumen; therefore, these infants are at risk of fluid and electrolyte abnormalities, and expectant and adequate resuscitation is mandatory. This approach can be followed for several days provided no complications occur; if there is no success, surgical intervention should be considered. Operative irrigation can be attempted using the same agents delivered through a purse-string suture. Alternatively, the distended terminal ileum should be resected with the meconium pellets flushed from the distal small bowel. An end ileostomy is created, with the distal bowel brought up as a mucous fistula or sewn to the side of the ileum. Reanastomosis can be carried out at a later time after appropriate deflation of the dilated proximal bowel has occurred and pancreatic enzymes have been instituted. Distal intestinal obstructive syndrome is a similar phenomenon that occurs later in life and is more commonly seen in cystic fibrosis patients with a history of meconium ileus as an infant.

Diaphragmatic Hernia

Diaphragmatic hernia in the newborn is a not uncommon defect and seems to be reported increasingly, in one to four neonates per 10,000 births. This probably reflects earlier diagnosis and more prompt treatment rather than increased incidence. If the diaphragmatic defect is not surgically repaired, most of these infants die within the first month of life as a result of respiratory compromise.

The most usual site of a congenital diaphragmatic hernia is the foramen of Bochdalek in the posterolateral portion. Herniation most often occurs in the left side and usually involves the stomach and the bowels. Right-sided hernias are rare and may contain the liver. Less common hernias occur at the esophageal hiatus and at the foramen of Morgagni in the retrosternal portion of the diaphragm. Herniation through these latter defects usually does not produce severe respiratory distress. Diaphragmatic eventration must be distinguished from diaphragmatic herniation. The former refers to elevation of a portion of the diaphragm that is thin and membranous due to incomplete muscularization. The diaphragm in this case forms a sac that covers abdominal contents that are displaced into the thorax. In rare cases, the diaphragm may completely or partially fail to develop (diaphragmatic or hemidiaphragmatic agenesis). The cause of congenital diaphragmatic hernia has not been clearly elucidated; most occur sporadically. Failure of normal closure of the pleuroperitoneal folds during the fourth to tenth weeks following fertilization appears to be the initial step in formation of these hernias; genetic or environmental factors are believed to trigger disruption of mesenchymal cell differentiation during formation of the diaphragm, however.

Most cases of congenital diaphragmatic hernia are diagnosed prenatally on routine ultrasound screening at approximately 24 weeks of gestation. Visualization of a chest mass with or without mediastinal shift is suggestive of a diaphragmatic hernia. Fetal MRI can confirm the finding and estimate lung volumes, as well as identify associated anomalies, which frequently occur with diaphragmatic hernias. Fetal genetic studies should also be performed. In utero therapy is investigational at this time and involves fetal tracheal occlusion, which averts pulmonary hypoplasia and pulmonary hypertension by increasing transpulmonic pressure. The birth should take place at a tertiary care center via vaginal delivery induced at term.

Although routine prenatal ultrasound examination is able to identify most congenital diaphragmatic hernias, the diagnosis may not be made until after delivery. The characteristic signs include a barrel-shaped chest with a left-sided respiratory lag (if the hernia is on the left, as it is in most instances) and a small and frequently scaphoid abdomen. The heart is displaced to the right, often to an extreme degree. Breathing sounds are absent over the left chest and are heard only over the upper right thorax portion, where they are harsh in character. Gas fills the herniated bowel usually only later, so that the percussion sounds over the chest are not necessarily tympanitic directly after birth. Auscultatory findings, suggestive of peristaltic movements in the chest, may be present but are not reliable. Some infants, able to compensate for the presence of abdominal viscera in the chest, exhibit signs and symptoms only when the gas-filled intestines cause a greater mediastinal shift. Though the diagnosis can be made on physical findings alone, chest x-ray confirms the clinical impression, except when the severity of the infant's respiratory distress does not allow time for such a procedure.

Once the diagnosis of a diaphragmatic hernia is made, the management encompasses preoperative medical management followed by surgical repair. Aggressive preoperative medical management has improved survival rates to well over 90% and involves ventilatory support after immediate endotracheal intubation. Use of extracorporeal membrane oxygenation is reserved for infants who fail to respond to conventional ventilatory support. Echocardiography is performed to evaluate pulmonary hypertension and identify underlying cardiac anomalies. The circulatory system is maintained by administration of fluids and inotropic agents. To avoid additional distention of the abdominal viscera, nasogastric tube placement before anesthesia is recommended. Premature infants with respiratory distress syndrome should receive surfactant therapy.

In the past, surgical repair of these types of hernias was considered an emergency and infants underwent surgery shortly after birth. It is now accepted that emergent surgery is not necessary, and the timing of surgical repair depends on the severity of pulmonary hypoplasia and pulmonary hypertension. Infants requiring minimal support with no evidence of pulmonary compromise can undergo surgical repair within 72 hours. In infants with some degree of pulmonary hypoplasia and reversible pulmonary hypertension, surgery should be delayed until pulmonary compliance improves and pulmonary hypertension is reversed.

Surgical repair of the diaphragmatic hernia can be performed using an abdominal or a transthoracic approach via either open or minimally invasive techniques.

The repair of the diaphragmatic defect may be accomplished by primary closure; however, larger defects often need a synthetic patch repair to allow a tension-free closure. The abdominal cavity may also be too small and underdeveloped to accommodate the intestine and permit closure of the abdominal wall muscle and fascial layers. In such cases, a temporary abdominal wall silo or mobilization of abdominal wall skin flaps may be necessary to allow for gradual visceral reduction and concomitant abdominal cavity expansion, so that a staged closure of the abdominal wall is possible.

Complications following repair can be seen immediately after surgery with persistent pulmonary hypertension or can occur late with chronic respiratory disease, recurrent hernia, patch infection, spinal or chest wall abnormalities, and gastroesophageal reflux.

Intussusception

Intussusception occurs when a proximal segment of the bowel telescopes into an adjacent distal segment. It is one of the most common abdominal emergencies in children but is rare in adults. Intussusception commonly occurs near the ileocecal junction, where the intussusceptum telescopes into the intussuscipiens, dragging the associated mesentery with it. This leads to the development of venous and lymphatic congestion with resulting intestinal edema, which can ultimately lead to ischemia, perforation, and peritonitis. Rarely, the proximal bowel is drawn into the lumen of the distal bowel (retrograde intussusception); this phenomenon is seen in Roux-en-Y gastric bypass surgery. The majority of cases in children are idiopathic, although evidence points to a preceding viral infection triggering the intussusception in some of these cases. On the other hand, adults usually have a distinct underlying pathologic lead point, which can be malignant in half of cases. Intermittent abdominal pain is the most common presentation in both children and adults. Symptoms progress over time and are accompanied by nausea and vomiting. In children, a sausage-shaped abdominal mass may be felt in the right side of the abdomen accompanied by the “currant jelly” stool mixed with blood and mucous.

An intussusception is sometimes discovered incidentally during an imaging study performed for other reasons or for nonspecific symptoms. If these intussusceptions are short and if the patient has few symptoms, intervention may not be required.

Ultrasonography is the method of choice for detecting intussusception in children and can demonstrate layers within the intestine (target sign). Plain abdominal x-rays are less sensitive and are used to exclude other causes and confirm the presence of small bowel obstruction. In adults, CT scanning is the investigation of choice, on which the target sign is also seen.

The treatment approach differs in pediatric and adult populations. In stable children with no signs of bowel perforation, nonoperative reduction using either hydrostatic or pneumatic enema is preferred to surgery. With this approach, the recurrence rate reaches 10%. In adults, surgical resection of the involved segment is recommended. Pathologic evaluation is needed to rule out underlying malignant disease.

Omphalocele

An omphalocele, or exomphalos, is a midline abdominal wall defect covered by a membrane of amnion and peritoneum containing bowel, and, occasionally, spleen and liver at the base of the umbilical cord. When the defect is less than 4 cm, it is termed a hernia of the umbilical cord; when it is greater than 10 cm, it is termed a giant omphalocele. It results from the persistence of the physiologic midgut herniation beyond the 12th postmenstrual week. Associated abnormalities occur in 30% to 70% of infants and include chromosomal abnormalities (trisomy 13, 18, 21), congenital heart disease, Beckwith-Wiedemann syndrome, and prune belly syndrome. The diagnosis of an omphalocele can usually be made by inspection, but if the omphalocele is small, it may appear to be a normal part of the umbilical cord. The major differential diagnosis to consider is gastroschisis. Gastroschisis is a defect in the abdominal wall that usually occurs to the right of the normal insertion area of the umbilical cord; it is believed to arise at the site of involution of the right umbilical vein. The absence of a membranous sac with free-floating loops of bowel distinguishes gastroschisis from omphalocele; if the membranous sac of the omphalocele ruptures in utero, however, other clues should be sought, such as the location of the liver and site of the cord insertion.

When omphalocele is identified prenatally, fetal genetic studies, including amniocentesis and fetal echocardiography, should be offered because of the high risk of aneuploidy and other congenital and genetic disorders. Fetal growth should subsequently be monitored closely. Precluding other obstetric indications, spontaneous labor and delivery should be allowed to occur. However, referral to a tertiary care center is highly recommended.

In the delivery room, neonatal management involves covering the defect with gauze dressings soaked in thermally neutral sterile saline, covering the dressing with clear plastic wrap, inserting an orogastric tube to decompress the stomach, stabilizing the airway to ensure adequate ventilation, and establishing peripheral intravenous access. The primary goal of surgery is to return the viscera to the abdominal cavity and close the defect; with an intact sac, emergency operation is not necessary, however. Small defects (<2 cm) can generally be managed by primary direct closure, whereas medium to large defects require a staged procedure.

A staged repair aims to create a protective extraabdominal extension of the peritoneal cavity (termed a silo ), allowing gradual reduction of the viscera and gradual abdominal wall expansion. This is achieved by using two parallel sheets of reinforced Silastic sheeting sutured to the fascial edges or a preformed one-piece silo with a collapsible ring at its base for ease of insertion. A prosthetic patch repair bridges the fascial gap with a synthetic material (e.g., polytetrafluoroethylene), and the skin is closed over the patch. The silo is progressively compressed to invert the amniotic sac and its contents into the abdomen and to bring the edges of the linea alba together by stretching the abdominal wall muscles. This usually requires 5 to 7 days, after which the defect is primarily closed. The intraabdominal pressure produced by the silo should not exceed 20 cm of water to avoid impairing venous return from the bowel and kidneys. When abdominal relaxation is sufficient to allow the rectus muscles to come together, the silo is removed, the amnion is left inverted into the abdominal cavity, and the defect is closed.

Management of an omphalocele may be complicated by rupture of the omphalocele sac either in utero or during delivery. The frequency of multiple congenital anomalies in these infants must also be borne in mind. Some variety of intestinal obstruction is common, especially anomalies of rotation and fixation of the colon. Obviously, if intestinal obstruction is suspected from x-ray studies or other signs, such as vomiting, failure to pass a stool, or distention, the proper corrective intraabdominal procedure must be undertaken before the closure is completed.

The survival rate for infants with small omphaloceles is excellent. The overall survival rate is 90%. Death is associated with wound dehiscence in larger omphaloceles, with subsequent infection, or with associated anomalies.

Duplications of Alimentary Tract

Alimentary tract duplications, also referred to as mesenteric cysts, giant diverticula, or enteric cysts, are rare congenital malformations that develop during fetal life. These spherical or tubular structures may be single or, more frequently, multiple, and are equipped with all the layers of that part of the alimentary tract to which they are intimately attached, including the muscular coat. This is in distinction to diverticula, which lack a muscular coat. Gastrointestinal duplication cysts may or may not communicate with the adjacent lumen of the gastrointestinal tract.

Most intestinal duplications are diagnosed in newborn infants and children, but some can remain silent and present in adulthood. With the routine use of prenatal ultrasound, however, many are being diagnosed in utero. Associated anomalies are present in one third of cases and involve the spine and gastrointestinal tract.

Several theories have been proposed to explain the origin of the duplications, but no single hypothesis can explain all possible combinations of duplications, locations, and associated anomalies. Failure of recanalization can explain duplications located in the gastrointestinal tract, which passes through a “solid” stage with temporary occlusion of the lumen around the 5th week of life. Other theories include intrauterine vascular accidents leading to duplications similar to intestinal atresia and incomplete twinning, which can explain duplications of the hindgut associated with genitourinary malformations.

Duplications can occur in all parts of the alimentary canal, from the tongue to the rectum, but are most frequently encountered in the jejunoileal area (65%), followed by the colon (20.5%), gastric region (8%), and duodenal region (6.5%). Small intestinal duplications are typically located on the mesenteric border and share a blood supply with the adjacent intestine.

The walls of the two structures (i.e., of the intestine and its corresponding duplication) are not sharply separated but have muscular fibers in common; hence, it is difficult to remove the duplicated segment without damaging the blood supply or the wall of the contiguous intestine.

Intestinal duplications may remain asymptomatic, and the diagnosis may be made incidentally by physical examination or during a radiologic or endoscopic procedure. Alternatively, abdominal pain, vomiting, and an abdominal mass are the most common symptoms and signs. Ectopic gastric mucosa is present in 24% of intestinal duplications, potentially leading to penetrating ulcers and severe gastrointestinal bleeding. Rarely, these cysts can serve as a lead point and cause intussusception or superinfection of the cyst. Malignant diseases arising from alimentary tract duplications, especially hindgut duplications, have also been reported.

The diagnosis is confirmed by radiologic imaging, including ultrasound, barium studies, CT scanning, or MRI studies. Abdominal sonography typically shows a cystic structure situated next to the intestine with a “double wall,” consisting of a hyperechoic inner layer produced by the mucosa and a relatively hypoechoic outer layer produced by smooth muscle. The presence of peristalsis is also a helpful sign. When ectopic gastric mucosa is suspected, ^99m technetium pertechnetate scintigraphy should be performed to confirm the finding.

The definitive management of intestinal duplications is surgical resection, which is indicated even if the cysts are asymptomatic because the potential complications can be grave. Total resection of the duplication along with the adjacent bowel is preferred, if feasible. If the patient is in poor condition or if the procedure is technically unfeasible, the cyst may be excised or “shelled out” or mucosal stripping may be performed. Additionally, a simple exteriorization by the Mikulicz technique can be performed, with the final repair postponed to a later date. Minimally invasive surgery has been successfully employed, with a low rate of complications, including laparoscopic simple cyst excision and resection with end-to-end or end-to-side anastomosis. Endoscopic resection of duodenal duplications has been reported, but the long-term outcome has not been documented. Thoracoabdominal enteric duplications may require combined transdiaphragmatic thoracolaparoscopy.

Meckel Diverticulum

The vitelline, or omphalomesenteric, duct connects the yolk sac with the primitive tubular gut in the early embryonic stages and normally involutes at about the 7th week of fetal life, leaving no trace of its existence. Failure of the vitelline duct to disappear in its entire extension results in a variety of remnants, which include a diverticulum (Meckel diverticulum) attached to the ileum, omphalomesenteric cysts (enterocysts), omphalomesenteric fistulae that drain through the umbilicus, and fibrous bands from the diverticulum to the umbilicus that predispose to bowel obstruction. The most common form is Meckel diverticulum.

Meckel diverticulum is the most frequent congenital anomaly of the gastrointestinal tract and is classically described by the rule of twos. It is prevalent in approximately 2% of the population, is usually located within 2 feet of the ileocecal valve, and measures approximately 2 inches in length. It is two times as prevalent in males as in females, with approximately 2% of patients developing a complication, usually within the first 2 years of life. This diverticulum is always attached to the antimesenteric side of the ileal wall, and it varies in length (from 1 to 10 cm) and also in width (from 1 to 4 cm in diameter), though its shape usually resembles that of a finger of a glove. The artery supplying the diverticulum, the vitelline artery , is a branch of the superior mesenteric artery. It crosses over the ileal wall along the diverticulum to its tip.

Meckel diverticulum is a “true” or “complete” diverticulum composed of all the layers of the small bowel (the mucosal, muscular, and serosal layers), in contrast to an acquired intestinal diverticula, in which the mucosa and submucosa herniate through the muscle layer, covered only by serosa. The mucosal lining of a Meckel diverticulum corresponds to that of the ileum, but occasionally islands of heterotopic (jejunal, duodenal, or gastric) mucosa and nodules of pancreatic tissue may be present and can give rise to serious complications (see below).

The opening of a Meckel diverticulum is funnel-like and, as a rule, wide enough not to give rise to occlusions, as do the “false diverticula” with a narrow neck. In the majority of individuals with Meckel diverticulum, the rest of the former vitelline duct becomes completely obliterated, but in some cases, a nonpatent fibrous cord may remain, which attaches the blind end of the diverticulum to the umbilical site of the abdominal wall. Occasionally, the diverticulum or the fibrous cord may be affixed to another intestinal loop or to another viscus. Rarely, a rudiment of the vitelline duct persists permanently in the form of a solid fibrous cord without development of a diverticulum, resulting in fixation of an ileal loop to the umbilicus. This can lead to intestinal obstruction and strangulation of bowel loops.

The persistence of the entire vitelline duct as a permanent tube leads to an umbilicointestinal fistula, which should be easily discovered soon after birth. The umbilical cord in such relatively rare cases is usually thicker at its base at birth than is normal, and when its external structures have regressed and sloughed off, a reddish mass with a small opening in its center will be noted in the umbilicus. The fistula may discharge intestinal contents depending on the caliber of the duct and the changes in the abdominal pressure. The discharge can vary from occasional drainage of small amounts of mucus to continuous loss of enteric contents. In such cases, an umbilical polyp frequently forms at the external opening of the fistula. The most serious complication of an umbilicointestinal fistula, however, is prolapse of the ileum through a fistulous tube of large caliber. Increased abdominal pressure, when the infant cries or coughs, may cause such a prolapse, which presents itself as a dark-red, protruding, sausagelike mass, with a portion of the bowel turned inside out, and intestinal mucosa appearing at the external mouth of the fistula.

Another anatomic variant of a vitelline duct remnant is an umbilical sinus. In these cases, the vitelline duct may remain open only at its outer portion, resulting in a sinus rather than a fistula. In such instances, the proximal part of the duct closer to the ileum is usually transformed into a fibrous cord attached on one end to the sinus and on the other to the ileum. Finally, the vitelline duct may undergo fibrosis on the outer end as well as on the inner end, while a central portion persists as a patent part that develops into a cyst (enterocyst), causing, in later life, a variety of symptoms.

Meckel diverticulum, as well as other variants of vitelline duct remnants, may remain quiescent and may not be discovered for a lifetime, but they can also give rise to a variety of clinical syndromes. Acute inflammation of a diverticulum may be produced by nonspecific infections, foreign bodies, parasites, or trauma. This can range from mild inflammatory changes to gangrene with subsequent perforation and peritonitis. Clinical and pathologic findings in these cases resemble appendiceal inflammation and are often difficult to differentiate. The onset of symptoms with this diverticulitis is usually sudden. Severe pain of colicky character is localized around the umbilicus and accompanied by nausea, persistent vomiting, and fever. The abdomen may be distended, with an area of tenderness around the umbilicus or in the right or left lower quadrant. An inflamed Meckel diverticulum may be very difficult to distinguish from acute appendicitis on physical examination or preoperative imaging and may require exploratory laparotomy. Other diagnoses to consider include acute cholecystitis, colonic diverticulitis, and acute salpingitis.

Ectopic tissue is present in up to 21% of patients with Meckel diverticulum and commonly involves gastric tissue; however, duodenal and pancreatic tissues can also be present. Gastrointestinal bleeding can occur as a result of peptic ulceration caused by heterotopic gastric mucosa in the lining of a diverticulum. The ulcer usually forms adjacent to or away from the diverticulum, and not on the mucosa or ectopic tissue within the diverticulum, and may resemble the marginal jejunal ulcer occurring after gastrojejunal anastomosis. Bleeding is more likely to occur in symptomatic patients and can be chronic and insidious or present with massive hemorrhage. The diagnosis should be suspected in children who develop painless rectal bleeding or in younger adults who present with obscure gastrointestinal bleeding. The gastric mucosa, even when ectopic, is able to concentrate and secrete ^99m technetium-labeled pertechnetate; this test is often diagnostic and can be used to localize ectopic gastric mucosa in symptomatic Meckel diverticulum. Mesenteric arteriography can also be used to localize a bleeding diverticulum. Additionally, endoscopic procedures such as double-balloon enteroscopy and capsule endoscopy have been described. If diagnostic testing is unrevealing or if the patient is hemodynamically unstable, abdominal exploration may be necessary to determine whether a Meckel diverticulum is the source of bleeding.

Intestinal obstruction can be a complication of a Meckel diverticulum; it may result from intussusception, volvulus, or incarceration in an abdominal hernia. Intussusception occurs when the diverticulum serves as the lead point of ileal or ileocolonic intussusception. A nodule of heterotopic tissue or a tumor situated near the fundus of the diverticulum may become the predisposing factor of an inversion, which, however, can be complete only when the diverticulum is in no way adherent to other structures. Volvulus can occur as a result of twisting of the intestines around a fibrous cord or band related to a Meckel diverticulum. Strangulation of the diverticulum may also occur when it enters the sac of an inguinal hernia (Littre hernia) and most commonly is seen in inguinal hernias followed by femoral and then umbilical hernias.

Benign tumors (myoma, lipoma, adenoma, and neurogenic neoplasm), as well as malignant ones, develop occasionally in a Meckel diverticulum. Different types of carcinoma, sarcoma, and carcinoid tumors have been observed, as in other parts of the small intestine.

Management of a Meckel diverticulum depends on the clinical presentation. Asymptomatic patients diagnosed incidentally on imaging may not undergo elective resection; however, management of a diverticulum identified on abdominal exploration in an asymptomatic patient is more controversial. Symptomatic Meckel diverticulum should be resected; either open laparotomy or laparoscopy techniques can be employed.

Diverticula of Small Intestine

A diverticulum is a blind outpouching of a hollow viscus, consisting of one or more layers of the part involved. Small intestinal diverticula usually occur in the duodenum and occur less frequently in the jejunum and ileum. The true incidence is not known, because diverticula may remain asymptomatic and the diagnosis is usually incidental; duodenal diverticula have been reported in 7% of those undergoing endoscopic retrograde cholangiopancreatography. In about 20% of cases, they are associated with diverticula in other parts of the digestive tract.

Diverticula of the small intestine may be single or multiple. Jejunal diverticula are usually multiple and are frequently associated with disorders of intestinal motility, such as progressive systemic sclerosis, visceral neuropathies, and myopathies. The multiple diverticula can be so numerous as to involve nearly the entire small intestine. They are located almost always along the line of mesenteric attachment, with sizes varying from a few millimeters up to several centimeters in diameter. The “complete” diverticula, formed by all the layers of the intestinal wall, are believed to be of congenital origin and are frequently associated with other malformations. The “incomplete” diverticula, consisting only of mucosa and serosa, are caused by herniation through a defect caused by the entrance of large vessels.

Diverticula of the small intestine are frequently symptomless and are found incidentally on imaging or endoscopy or at autopsy. In some cases, the symptoms are limited to a vague abdominal pain and flatulence appearing a certain time after meals and attributed to retention of fecal matter in the diverticula. Small intestinal diverticula may, however, give rise to serious complications, such as acute inflammation, intestinal obstruction, perforation, and hemorrhage. Acute diverticulitis is usually the consequence of food residue or parasites becoming trapped in the pouch and may present with symptoms similar to those of acute appendicitis. Intestinal obstruction may occur by strangulation, compression by an inflammatory tumor, or, more rarely, intussusception. Perforation of a diverticulum is usually the consequence of acute inflammation or trauma produced by a foreign body that found its way into the pouch. The perforation may occur in the free abdominal cavity, the mesentery, or another intestinal loop, resulting in generalized peritonitis, a walled-off abscess, or an intestinal fistula. A few cases are recorded in which aberrant pancreatic tissue and benign or malignant tumors were located in an intestinal diverticulum.

The presence of massive diverticulosis of the small intestine may lead to bacterial overgrowth, which can seriously interfere with absorption, causing steatorrhea, megaloblastic anemia, and other symptoms that characterize the malabsorption syndrome (see Plate 2-29 ). Diverticula of the small intestine can be diagnosed only by endoscopic imaging or x-ray studies. X-ray demonstration is, however, rendered difficult when the wide neck of the diverticulum makes it empty readily or when the intestinal contents fill the diverticulum and prevent the entrance of the barium. In patients with asymptomatic diverticula, no treatment is required; management of acute diverticulitis and diverticular bleeding is similar to that for colonic diverticular disease. Small intestinal bacterial overgrowth can be treated with oral antibiotics, but this is rarely curative unless the underlying risk factor (diverticulosis) is removed, and patients require intermittent antibiotic therapy.

Celiac Disease

Celiac disease, also known as gluten-sensitive enteropathy or nontropical sprue, is a chronic immune-mediated enteropathy triggered by exposure to dietary gluten. The primary target of the disease is the small intestine; celiac disease can affect multiple systems, however.

It is primarily seen in individuals of European descent but is increasingly recognized on almost every continent. The overall prevalence in the general population of the United States and Europe is nearly 1%; only 10% to 15% of patients have been diagnosed and treated, however. The prevalence appears to increase with age.

Celiac disease develops in genetically predisposed individuals as a result of the influence of environmental factors. First-degree relatives of patients with celiac disease have a 10% to 15% risk of developing the disease.

The HLA class II genes HLA-DQ2 and HLA-DQ8, which are normally expressed on the surface of antigen cells in the gut, are the most important genetic susceptibility factors in celiac disease. HLA-DQ2 is found in 90% to 95% of patients with celiac disease, with HLA-DQ8 found in most of the remaining patients. These molecules are necessary variables predisposing a patient to the disease, which means that celiac disease is unlikely if neither molecule is present. The molecules are not, however, sufficient to cause celiac disease; they occur in 30% to 40% of the general population.

Gluten is a storage protein of wheat. The alcohol-soluble fraction of gluten, gliadin, is toxic in celiac disease, along with similar proteins in barley (hordeins) and rye (secalins). These proteins are rich in glutamine and proline residues that even the healthy human intestine cannot fully digest. As a result, intact gliadin peptides are left in the lumen, but few cross the intestinal barrier. In individuals with celiac disease, these fragments come into contact with tissue transglutaminase, a ubiquitous intracellular enzyme that is released by inflammatory and endothelial cells and fibroblasts in response to mechanical irritation or inflammation. Upon contact, tissue transglutaminase cross-links with these glutamine-rich proteins and deamidates them. This process modifies glutamine residues into glutamic acid residues, which are ideally suited to interact with the HLA-DQ2 or HLA-DQ8 molecules. Once bound to HLA-DQ2 or HLA-DQ8, gliadin peptides are presented to the CD4+ T cells, triggering the inflammatory reaction. The end result is an inflammatory state of the small intestine, causing a derangement in the architecture of the mucosa, with flattening of the villi, and infiltration of lymphocytes into the epithelium.

The clinical presentation of celiac disease has been traditionally classified based on signs and symptoms. Most patients are asymptomatic and the disease is discovered incidentally upon testing; others present with atypical extraintestinal signs and symptoms.

Chronic or intermittent diarrhea, often bulky and foul smelling, is one of the most common gastrointestinal symptoms. Abdominal pain, bloating, and flatulence are other common symptoms; however, chronic constipation has been reported.

A variety of extraintestinal manifestations have been described in celiac disease and are often the presenting symptom. Iron deficiency anemia, resistant to oral iron supplementation, is the most common extraintestinal sign and is considered the most frequent presentation among teenagers and adults. Neurologic symptoms such as headaches as well as psychiatric issues including depression and anxiety have been reported in association with celiac disease. Nonerosive, polyarticular, or oligoarticular arthritis that promptly resolves with a gluten-free diet has been documented. Metabolic bone diseases, including osteopenia, osteoporosis, and, rarely, osteomalacia, are common in celiac disease and can present in the absence of gastrointestinal symptoms.

Dermatitis herpetiformis is an uncommon cutaneous manifestation of celiac disease and presents as an intensely pruritic inflammatory papular and vesicular skin eruption involving the extensor surfaces of the elbows, forearms, knees, buttocks, back, and scalp. Direct immunofluorescence microscopy of a punch biopsy is the gold standard test for the diagnosis of dermatitis herpetiformis. Treatment consists of dietary gluten restriction and pharmacotherapy with dapsone. Long-term treatment lasting several years may be required to achieve complete remission.

The diagnosis of celiac disease requires a high index of suspicion and the identification of risk factors associated with the disease. Testing should be carried out for those with gastrointestinal symptoms and those with unexplained iron deficiency anemia, folate deficiency, or vitamin B ₁₂ deficiency. The presence of unexplained persistent elevation in serum aminotransferases, short stature, delayed puberty, recurrent fetal loss, reduced fertility, persistent aphthous stomatitis, dental enamel hypoplasia, idiopathic peripheral neuropathy, nonhereditary cerebellar ataxia, or recurrent migraine headaches also merits testing for celiac disease. Testing should be considered for first-degree relatives of individuals with celiac disease and for individuals with disorders known to coexist with celiac disease, such as type 1 diabetes mellitus and Down syndrome.

Testing the serum levels of anti–tissue transglutaminase IgA is generally acknowledged as the first choice in screening for celiac disease, displaying the highest levels of sensitivity (98%) and specificity (96%). Anti–endomysium IgA testing has a specificity of close to 100% and a sensitivity exceeding 90%, but this test has high interobserver variability. Antibodies to deamidated gliadin peptides (DGP-IgA and DGP-IgG) are also used as screening tools, and they seem to be especially useful in very young children. In fact, DGP testing may be more sensitive than anti–tissue transglutaminase IgA in children younger than 2 years. IgA deficiency is more common in celiac disease (2% to 5%) than in the general population (<0.5%), leading to falsely negative IgA tissue transglutaminase and IgA endomysium serology tests. In cases where there is a high pretest probability, total serum IgA can be measured in addition to IgA tissue transglutaminase and IgA endomysium. If the serum IgA is low, IgG-based assays should be used to test for celiac disease. Negative results on testing for HLA-DQ2 or HLA-DQ8 can also help to exclude the diagnosis in this setting.

In addition to serologic markers, the diagnosis of celiac disease still rests on the demonstration of histologic changes in the small intestinal mucosa as documented by biopsy specimens from the duodenum via endoscopy. The classic finding on endoscopy is an atrophic duodenal mucosa with loss of the folds with or without scalloping or a nodular appearance. Such findings, however, are not universally present and the mucosa can appear normal. Histologic findings range from mild alteration characterized only by increased intraepithelial lymphocytes to crypt hyperplasia and complete villous atrophy and are reported using the Marsh-Oberhuber and Corazza classifications.

Adherence to a strict gluten-free diet remains the only available treatment for patients with celiac disease and typically results in a complete return to health. Compliance with a gluten-free diet, however, is difficult at all ages but particularly for teenagers and younger adults. Dietary counseling with a skilled dietitian is one of the most important aspects of the treatment and should be recommended to all patients with celiac disease. Patients should be monitored for deficiencies of vitamins, particularly A, D, E, and B ₁₂ , iron, and folic acid, while copper and zinc should be supplemented. Deficiency of magnesium and selenium may also occur, and signs or symptoms of a deficiency should be sought. Constipation can occur as consequence of a gluten-free diet because the diet is low in roughage; regular use of psyllium seed husks is often beneficial.

If symptoms persist or serologic and/or histologic abnormalities develop while a patient is on a gluten-free diet, this usually indicates poor compliance with the diet or inadvertent gluten ingestion. Alternative or concurrent disorders such as bacterial overgrowth, pancreatic insufficiency, and microscopic colitis should be considered and excluded appropriately. Refractory sprue is the persistence of symptoms and villous atrophy despite a strict gluten-free diet for at least 2 years. The cause is unknown, but the course can be severe, with progressive malabsorption and even death. Aggressive nutritional support is required, including parenteral nutrition if needed and pharmacotherapy focused on immunosuppression.

In patients unresponsive to immunosuppression, ulcerative jejunitis and lymphoma should be considered. Patients with ulcerative jejunitis have multiple chronic, benign-appearing ulcers, most frequently in the jejunum, which can rarely form strictures. These can be identified on cross-sectional abdominal imaging or on upper endoscopy and capsule endoscopy. Ulcerative jejunitis has an unfavorable prognosis, with a 30% mortality rate.

Distinction between ulcerative jejunitis and lymphoma is challenging because both have very similar symptoms and findings on imaging. Enteropathy-associated T-cell lymphoma is a rare but aggressive neoplasm that arises in the gastrointestinal tract as a sequela of untreated celiac disease. Most patients present with stage IV disease. Treatment consists of chemotherapy with or without autologous hematopoietic cell transplantation.

Various malignant diseases are associated with celiac disease, and the gluten-free diet is considered to be protective against the development of certain malignant diseases. These include esophageal, head, and neck squamous carcinoma, small intestinal adenocarcinoma, and non-Hodgkin lymphoma.

Tropical Sprue

Tropical sprue is a chronic diarrheal disease seen in certain, but not all, tropical areas and characterized by small intestinal damage causing malabsorption and nutritional deficiencies, including deficiencies of folate and vitamin B ₁₂ .

Tropical sprue occurs in specific locations in the tropics within a narrow 30-degree band north and south of the equator. It is particularly prevalent in southern India, the Philippines, and several Caribbean islands (Haiti, the Dominican Republic, Puerto Rico, and Cuba), but is rarely observed in Jamaica, Africa, the Middle East, or Southeast Asia. It affects both native populations as well as visitors to the tropics who stay for more than a month.

It is widely believed that infectious agents are responsible for the development of tropical sprue. Multiple microorganisms, including Klebsiella pneumoniae, Enterobacter cloacae, and Escherichia coli, have been identified in jejunal aspirates, but there is little consistency among studies. Bacterial overgrowth has also been documented in patients with tropical sprue, which can contribute to significant small bowel structural damage, by elaboration of toxins and fermentation products.

Intestinal injury causes loss of brush-border disaccharidase enzymes, which leads to malabsorption of dietary carbohydrates. The loss of normal villous architecture impairs fat absorption and causes steatorrhea. Vitamin B ₁₂ and folate malabsorption lead to deficiencies of these two vitamins, in contrast to small intestinal bacterial overgrowth, where the serum folate concentration is actually increased. This may be related to a difference in the bacterial species colonizing the small bowel in the two conditions. Facultative anaerobic toxigenic coliforms in tropical sprue produce fermentation products such as ethanol that diminish folate absorption, whereas anaerobic nontoxigenic flora in the small bowel overgrowth generate folic acid.

The diagnosis of tropical sprue should be entertained in any individual with chronic diarrhea who is either residing in or has recently returned from a prolonged visit to a tropical country. Steatorrhea is often present and is accompanied by cramping abdominal pain, gas, and fatigue. Malabsorption is evident, with progressive weight loss, megaloblastic anemia, and signs of a low-protein state.

Chronic diarrhea in a tropical environment has extensive etiologic possibilities, primarily of an infectious nature. Therefore, exclusion of these causes of diarrhea is necessary before invasive endoscopic studies can be performed. Careful stool and serologic testing should be performed to exclude infection with Entamoeba histolytica, Giardia lamblia, Strongyloides stercoralis, Cryptosporidium parvum, Isospora belli, and Cyclospora cayetanensis, and serologic tests should be carried out to rule out celiac disease. In individuals with human immunodeficiency virus (HIV) risk factors, HIV infection and associated opportunistic infections should be ruled out.

If these are negative, upper endoscopy with biopsy of the small bowel should be performed. Gross findings at endoscopy are nonspecific and include flattening of duodenal folds and “scalloping.” The histologic features are nearly identical to those of celiac disease, with shortened, blunted villi and elongated crypts and increased inflammatory cells. However, in tropical sprue there appears to be less villous architectural alteration and more mononuclear cell infiltrate in the lamina propria, whereas in celiac disease, blunting of the villi is more severe with complete or nearly complete absence of villi.

Broad-spectrum antibiotics and folic acid are most often curative for this disease. Relapse or reinfection occurs in up to 20% of patients living in the tropics. Tetracycline, given for up to 6 months, completely reverses the intestinal and hematologic abnormalities of tropical sprue. Folic acid alone induces hematologic remission as well as improvement in appetite and weight gain. Because of marked folate deficiency, folic acid is most often given together with antibiotics. Coexistent B ₁₂ deficiency should be treated with intramuscular injections of cyanocobalamin.

Whipple Disease (Intestinal Lipodystrophy)

Whipple disease is a rare disease caused by an infection with Tropheryma whipplei , a gram-positive bacillus. The disease was first described in 1907 by G. H. Whipple, but the infectious agent was not identified until 1991.

It primarily affects middle-aged white males of European ancestry, suggesting an underlying genetic predisposition that leads to colonization of T. whipplei throughout the intestinal tract, lymphoreticular system, and central nervous system upon exposure to soil microbes.

Chronic carriers, which make up 2% to 11% of the general population in Europe, or infected individuals transmit the disease to others. The fecooral route appears to be the primary mode of transmission. Invasion or uptake of the bacillus is widespread throughout the body, including the intestinal epithelium, macrophages, capillary and lymphatic endothelium, colon, liver, brain, heart, lung, synovium, kidney, bone marrow, and skin. All of these sites show a remarkable lack of inflammatory response to the bacillus. In addition, the organism exerts no visible cytotoxic effects on host cells. These observations suggest an underlying host immune deficiency and, possibly, secondary immune down-regulation induced by the bacterium. This results in accumulation of massive numbers of organisms within the intestinal tract and resulting impairment of nutrient absorption.

The classical presentation is a 50-year-old Caucasian male who initially complains of intermittent migratory arthralgias and suffers from chronic intermittent diarrhea and weight loss. Nonspecific symptoms such as fatigue, cough, and myalgia can occur. The bacterium can affect nearly all organs, including the eye, skin, lung, and even epididymis and testes. Lymphadenopathy, mainly mediastinal, is present in over 50% of cases, and neurologic symptoms are present in nearly one quarter of patients. Cognitive changes such as dementia or memory impairment and psychiatric signs such as personality changes and depression are the most frequently observed signs. Whipple disease may rarely present as a chronic localized infection without intestinal and systemic involvement. This form can involve the endocardium, causing “culture-negative” endocarditis, or can infect the eye, causing “corticosteroid-resistant” uveitis. Additionally, T. whipplei has been implicated in acute infections of pneumonia, gastroenteritis, and even bacteremia.

Because of the rarity of Whipple disease, the diagnosis requires a high index of suspicion. Routine laboratory findings include anemia with both iron and vitamin B ₁₂ deficiency and hypoalbuminemia. Polymerase chain reaction testing of saliva and stool lacks sensitivity, and in most cases, upper gastrointestinal endoscopy with biopsies of the small intestine is necessary to make the diagnosis. Gross examination reveals thickened small intestinal folds studded with yellowish-white flecks. The corresponding mesentery and retroperitoneal lymph nodes are enlarged, are yellow or gray in color, and have a soft, doughy consistency; on section, they show many vacuolated spaces (Swiss cheese, or honeycombed, appearance), which are filled with a yellowish-white creamy material.

The duodenal villi may appear atrophied during examination; this is a nonspecific finding. Histologically, the small intestinal mucosa shows a thickened lamina propria containing a large number of mononuclear macrophages with foamy cytoplasm and eosinophilic granularity. Demonstration of extensive periodic acid–Schiff–positive material in the lamina propria of duodenal biopsies confirms the diagnosis. However, periodic acid–Schiff staining can be positive in other circumstances, such as Mycobacterium infection. Immunohistochemical analysis using specific antibodies allows the direct visualization of bacteria in samples and has a sensitivity and specificity superior to those of periodic acid–Schiff staining. It is also possible, in specialized research laboratories, to use polymerase chain reaction techniques to amplify the DNA, which can then be sequenced.

The treatment of Whipple disease has evolved over the past two decades. Prior to the use of antibiotics, the disease was uniformly fatal. With adequate treatment, however, most patients do well. Clinical improvement is often dramatic, occurring within 7 to 21 days. Current treatment regimens recommend use of a third-generation cephalosporin or penicillin followed by long-term maintenance with trimethoprim-sulfamethoxazole. The two major problems are central nervous system disease and relapsing infection. Central nervous system disease is difficult to manage and requires longer use of an antibiotic that readily enters the blood-brain barrier. Relapse has been reported in up to 35% of cases and indicates incomplete eradication of the organism during the initial therapy. Immune reconstitution inflammatory syndrome is sometimes observed and may be fatal. Therefore, close monitoring during therapy, especially during the initial period, is essential.

Bacterial Overgrowth

Small intestinal bacterial overgrowth refers to the excessive proliferation of native bacteria or the presence of colonic bacteria in the small bowel, leading to symptoms and interfering with absorption of nutrients. Although sterile at birth, the alimentary canal is populated by the maternal flora within a few hours after birth. The interaction among an infant's genes and microbiome and the nutrition the infant receives and environment surrounding the infant plays a role in the early establishment of the intestinal flora. The proximal small bowel normally contains few bacteria when compared with the colon. Lactobacilli, enterococci, gram-positive aerobes, or facultative anaerobes predominate in concentrations of 104 organisms/mL in the mid to distal jejunum. The concentration of coliforms rarely exceeds 103 organisms/mL; Bacteroides, the predominant organism in the colon, is rarely found in the proximal small bowel because several defensive mechanisms prevent excessive bacterial colonization of the small bowel. Gastric acid sterilizes ingested microorganisms, and proteolytic pancreatic and intestinal enzymes digest bacteria that escape into the small bowel. An intestinal mucous layer traps bacteria, and the sweeping action of small intestinal peristaltic movements prevents attachment to the mucosa. Gut immunity plays an important role through secretory IgA, which prevents bacterial proliferation. Lastly, an intact ileocecal valve prevents retrograde bacterial translocation. Therefore, disorders that disrupt any or all of these mechanisms permit the development of small intestinal bacterial overgrowth.

Anatomic abnormalities that lead to stasis, such as surgical blind loops, fistulas, and strictures related to Crohn disease; short bowel syndrome; and small intestinal diverticula, are common causes of small intestinal bacterial overgrowth. Small intestinal dysmotility, commonly seen in scleroderma, postirradiation enteropathy, and small intestinal pseudoobstruction, can cause functional stasis that allows bacterial proliferation. Certain endocrine disorders, such as diabetes mellitus and thyroid disease, can alter intestinal motility, and hypochlorhydria and immunodeficiency interfere with the host's ability to neutralize pathogens. Rarely, small intestinal bacterial overgrowth can occur in the absence of an underlying cause.

Once established, the bacterial overgrowth interferes with nutrient absorption and causes several untoward symptoms by elaboration of toxins or causes direct mucosal injury. Deconjugation of bile accompanied by premature fermentation of carbohydrates contributes to steatorrhea, diarrhea, and flatulence. Nutrient deficiencies can occur owing to malabsorption of vitamin B ₁₂ and fat-soluble vitamins.

The clinical manifestations of bacterial overgrowth are usually nonspecific and include loose stools, bloating, flatulence, and abdominal discomfort. In severe cases, steatorrhea may be seen. The ensuing malabsorption can lead to weight loss, hypoalbuminemia, and peripheral edema. Rarely, patients may present with xerophthalmia, perioral numbness, and neuropathy with paresthesias, reflecting severe underling deficiencies of vitamins A, D, and B ₁₂ , respectively.

The gold standard for the diagnosis of small intestinal bacterial overgrowth has traditionally been a jejunal aspirate culture demonstrating more than 105 colony-forming units per milliliter of jejunal aspirate. This test is cumbersome to perform and poorly reproducible, however. Breath tests rely on the principle that the premature fermentation of a test dose of carbohydrate in the presence of bacterial overgrowth leads to production and exhalation of hydrogen or methane. The sensitivity and specificity of breath tests as compared with jejunal aspirate cultures are low, and testing protocols are not standardized; they are safe and easy to perform, however, and are currently widely used for the diagnosis of small intestinal bacterial overgrowth. Lactulose and glucose are the most common substrates used.

Treatment of bacterial overgrowth involves the use of antibiotics, but when an underlying disease is present, it should be corrected. Surgical resection of a blind loop or discontinuation of agents that reduce motility or suppress acid secretion are such measures that eliminate and prevent relapse of bacterial overgrowth. Several broad-spectrum antibiotics have been used, including tetracycline, metronidazole, amoxicillin/clavulanic acid, and cephalosporins. Recently, the use of rifaximin, a nonabsorbable antibiotic that inhibits bacterial RNA synthesis, has been shown to be effective when given for 7 to 10 days.

Recurrence is common after treatment, especially in patients with underlying disorders that have not been corrected. For recurrent symptoms, several antibiotic treatment strategies exist, including intermittent courses or the use of rotating antibiotics during the first week of every month or every other week. Dietary prescriptions include a dairy-free diet that is low in fiber and low in carbohydrates but high in fat. This type of diet reduces symptoms and ensures a good source of calories.

Carbohydrate Malabsorption, Including Lactose Malabsorption

Carbohydrate malabsorption is a frequent clinical condition caused by fermentation of unabsorbed carbohydrates by colonic flora and giving rise to symptoms. Although lactose is the most commonly malabsorbed sugar, other carbohydrates, including oligosaccharides, disaccharides, and monosaccharides such as fructose, can cause symptoms related to malabsorption.