AN UNDERRATED ORGAN

The small intestine is the raison d'tre of the GI tract as it is the principle site of nutrient digestion and
absorption.1 The small intestine is also the body's largest reservoir of immunologically active and
hormone-producing cells, and hence can be conceptualized as the largest organ of the immune and
endocrine systems, respectively. It achieves this diversity of action through unique anatomical features
that provide it with a massive surface area, a diversity of cell types, and a complex neural network to
coordinate these functions.
Despite its size and importance, diseases of the small intestine are relatively infrequent, and present
diagnostic and therapeutic challenges. Treatments for common conditions such as postoperative ileus are
hardly more effective than those used at the dawn of the last century. Mortality rates associated with
acute mesenteric ischemia have not improved during the past 50 years.
Despite the introduction of novel imaging techniques such as capsule endoscopy and double balloon
endoscopy, diagnostic tests lack sufficient predictive power to definitively guide clinical decision making
for individual patients. Furthermore, few high-quality, controlled data on the efficacy of surgical
therapies for small bowel diseases are available.
Therefore, sound clinical judgment and a thorough understanding of anatomy, physiology, and
pathophysiology remain essential to the care of patients with intestinal disorders.

GROSS ANATOMY

The small intestine is a tubular structure that extends from the pylorus to the cecum. The estimated
length of this structure varies depending on whether radiologic, surgical, or autopsy measurements are
made. In the living, it is thought to measure 4 to 6 m. The small intestine consists of three segments
lying in series: the duodenum, jejunum, and ileum. The duodenum, the most proximal segment, lies in
the retroperitoneum immediately adjacent to the head and inferior border of the body of the pancreas.
The duodenum is demarcated from the stomach by the pylorus and from the jejunum by the ligament of
Treitz. The jejunum and ileum lie within the peritoneal cavity and are tethered to the retroperitoneum by
a broad-based mesentery. No distinct anatomic landmark demarcates the jejunum from the ileum; the
proximal 40% of the jejunoileal segment is arbitrarily defined as the jejunum and the distal 60% as the
ileum. The ileum is demarcated from the cecum by the ileocecal valve.
The small intestine contains mucosal folds known as plicae circulares or valvulae conniventes that are
visible upon gross inspection. These folds are also visible radiographically and help in the distinction
between small intestine and colon, which does not contain them, on abdominal radiographs. These folds
are more prominent in the proximal intestine than in the distal small intestine. Other features evident on
gross inspection that are more characteristic of the proximal than distal small intestine include a larger
circumference, thicker wall, less fatty mesentery, and longer vasa recta (Fig. 28-1). Gross examination
of the small intestinal mucosa also reveals aggregates of lymphoid follicles. Those follicles, located in the
ileum, are the most prominent and are designated Peyer's patches.
Most of the duodenum derives its arterial blood from branches of both the celiac and the superior
mesenteric arteries. The distal duodenum, the jejunum, and the ileum derive their arterial blood from
the superior mesenteric artery. Their venous drainage occurs via the superior mesenteric vein. Lymph
drainage occurs through lymphatic vessels coursing parallel to corresponding arteries. This lymph drains
through mesenteric lymph nodes to the cisterna chyli, then through the thoracic duct, and ultimately
into the left subclavian vein. The parasympathetic and sympathetic innervation of the small intestine is
derived from the vagus and splanchnic nerves, respectively.

HISTOLOGY

The wall of the small intestine consists of four distinct layers: mucosa, submucosa, muscularis externa,
and serosa (Fig. 28-2).
The mucosa is the innermost layer and it consists of three layers: epithelium, lamina propria, and
muscularis mucosae. The epithelium is exposed to the intestinal lumen and is the surface through which
absorption from and secretion into the lumen occurs. The lamina propria is located immediately external
to the epithelium and consists of connective tissue and a heterogeneous population of cells. It is
demarcated from the more external submucosa by the muscularis mucosae, a thin sheet of smooth
muscle cells.
The mucosa is organized into villi and crypts (crypts of Lieberkhn). Villi are finger-like projections of
epithelium and underlying lamina propria that contain blood and lymphatic (lacteals) vessels that extend
into the intestinal lumen. Intestinal, epithelial cellular proliferation is confined to the crypts, each of
which carries an average census of 250 to 300 cells. All epithelial cells in each crypt are derived from an
unknown number of the yet uncharacterized multipotent stem cells located at or near the crypt's base.
Their immediate descendants are amplified by undergoing several cycles of rapid division. These
descendants then make a commitment to differentiate along one of four pathways that ultimately yield
enterocytes and goblet, enteroendocrine, and Paneth cells. With the exception of Paneth cells, these
lineages complete their terminal differentiation during an upward migration from each crypt to adjacent
villi. The journey from the crypt to the villus tip is completed in 2 to 5 days and terminates with cells

being removed by apoptosis and/or exfoliation. Thus, the small intestinal epithelium undergoes
continuous renewal, making it one of the body's most dynamic tissues. The high cellular turnover rate
contributes to mucosal resiliency but also makes the intestine uniquely susceptible to certain forms of
injury such as that induced by radiation and chemotherapy.
Enterocytes are the predominant absorptive cell of the intestinal epithelium. Their apical (lumen-facing)
cell membrane contains specialized digestive enzymes, transporter mechanisms, and microvilli that are
estimated to increase the absorptive surface area of the small intestine by up to 40-fold. Goblet cells
produce mucin believed to play a role in mucosal defense against pathogens. Enteroendocrine cells are
characterized by secretory granules containing regulatory agents and are discussed in greater detail
below in the Endocrine Function section. Paneth cells are located at the base of the crypt and contain
secretory granules containing growth factors, digestive enzymes, and antimicrobial peptides. In addition,
the intestinal epithelium contains microfold (M) cells and intraepithelial lymphocytes. These two
components of the immune system are discussed below.
The submucosa consists of dense connective tissue and a heterogeneous population of cells, including
leukocytes and fibroblasts. The submucosa also contains an extensive network of vascular and lymphatic
vessels, nerve fibers, and ganglion cells of the submucosal (Meissner's) plexus.
The muscularis propria consists of an outer, longitudinally oriented layer and an inner, circularly oriented
layer of smooth muscle fibers. Located at the interface between these two layers are ganglion cells of
the myenteric (Auerbach's) plexus.
The serosa consists of a single layer of mesothelial cells and is a component of the visceral peritoneum.

DEVELOPMENT

The first recognizable precursor of the small intestine is the embryonic gut tube, formed from the
endoderm during the fourth week of gestation. The gut tube is divided into foregut, midgut, and
hindgut. Other than duodenum, which is a foregut structure, the rest of the small intestine is derived
from the midgut. The gut tube initially communicates with the yolk sac; however, the communication
between these two structures narrows by the sixth week to form the vitelline duct. The yolk sac and
vitelline duct usually undergo obliteration by the end of gestation. Incomplete obliteration of the vitelline
duct results in the spectrum of defects associated with Meckel's diverticula.
Also, during the fourth week of gestation, the mesoderm of the embryo splits. The portion of mesoderm
that adheres to the endoderm forms the visceral peritoneum, while the portion that adheres to the
ectoderm forms the parietal peritoneum. This mesodermal division results in the formation of a coelomic
cavity that is the precursor of the peritoneal cavity.
At approximately the fifth week of gestation, the bowel begins to lengthen to an extent greater than that
which can be accommodated by the developing abdominal cavity, resulting in the extracoelomic
herniation of the developing bowel. The bowel continues to lengthen during the subsequent weeks and is
retracted back into the abdominal cavity during the tenth week of gestation. Subsequently, the
duodenum becomes a retroperitoneal structure. Coincident with extrusion and retraction, the bowel
undergoes a 270 counterclockwise rotation relative to the posterior abdominal wall. This rotation
accounts for the usual locations of the cecum in the right lower quadrant and the duodenojejunal
junction to the left of midline (Fig. 28-3).
The celiac and superior mesenteric arteries and veins are derived from the vitelline vascular system,
which, in turn, is derived from blood vessels formed within the splanchnopleuric mesoderm during the
third week of gestation. Neurons found in the small intestine are derived from neural crest cells that
begin to migrate away from the neural tube during the third week of gestation. These neural crest cells
enter the mesenchyme of the primitive foregut and subsequently migrate to the remainder of the bowel.
During the sixth week of gestation, the lumen of the developing bowel becomes obliterated as bowel
epithelial proliferation accelerates. Vacuoles form within the bowel substance during the subsequent
weeks and coalesce to form the intestinal lumen by the ninth week of gestation. Errors in this
recanalization may account for defects such as intestinal webs and stenoses. Most intestinal atresias,
however, are believed to be related to ischemic episodes occurring after organogenesis has been
completed rather than to errors in recanalization.
During the ninth week of gestation, the intestinal epithelium develops intestine-specific features such as
crypt-villus architecture. Organogenesis is complete by approximately the twelfth week of gestation.
Elucidation of the fundamental mechanisms regulating patterned intestinal development is an area of
active investigation.

PHYSIOLOGY
Digestion and Absorption
The intestinal epithelium is the interface through which absorption and secretion occur. It has features
characteristic of absorptive epithelia in general, including epithelial cells with cellular membranes
possessing distinct apical (luminal) and basolateral (serosal) domains demarcated by intercellular tight
junctions, and an asymmetric distribution of transmembrane transporter mechanisms that promotes
vectorial transport of solutes across the epithelium.

Solutes can traverse the epithelium by active or passive transport. Passive transport of solutes occurs
through diffusion or convection and is driven by existing electrochemical gradients. Active transport is
the energy-dependent net transfer of solutes in the absence of or against an electrochemical gradient.
Active transport occurs through transcellular pathways (through the cell), whereas passive transport can
occur through either transcellular or paracellular pathways (between cells through the tight junctions).
Transcellular transport requires solutes to traverse the cell membranes through specialized membrane
proteins, such as channels, carriers, and pumps. The molecular characterization of transporter proteins
is evolving rapidly, with different transporter families, each containing many individual genes encoding
specific transporters, now identified. Similarly, understanding of the paracellular pathway is evolving. In
contrast to what was once believed, it is becoming apparent that paracellular permeability is substrate
specific, dynamic, and subject to regulation by specific tight junction proteins.

WATER AND ELECTROLYTE ABSORPTION AND SECRETION

Eight to 9 L of fluid enter the small intestine daily. Most of this volume consists of salivary, gastric,
biliary, pancreatic, and intestinal secretions. Under normal conditions, the small intestine absorbs over
80% of this fluid, leaving approximately 1.5 L that enters the colon (Fig. 28-4). Small intestinal
absorption and secretion are tightly regulated; derangements in water and electrolyte homeostasis
characteristic of many of the disorders discussed in this chapter play an important role in contributing to
their associated clinical features.
Water absorption is believed to be driven by osmotic gradients created primarily by active transepithelial
Na+ absorption. Intestinal water secretion, in contrast, is believed to be driven by osmotic gradients
created primarily by transepithelial Cl secretion. Most intestinal water transport is believed to occur
through the transcellular pathway.4 The specific transport mechanisms mediating water absorption are
incompletely characterized. Aquaporins (water channels) are expressed in the intestinal epithelium;
however, their contribution to overall intestinal water absorption appears to be relatively minor.5
The prevailing model for intestinal epithelial Na + absorption is shown in Fig. 28-5. Activity of the Na +/K+
ATPase enzyme, which is located in the basolateral membrane and exchanges three intracellular Na + for
every two extracellular K+ in an energy-dependent process, generates the electrochemical gradient that
drives the transport of Na+ from the intestinal lumen into the cytoplasm of enterocytes. Na + ions
traverse the apical membrane through several distinct transporter mechanisms including nutrientcoupled sodium transport (e.g., sodium-glucose cotransporter-1, SGLT1), sodium channels, and sodiumhydrogen exchangers. Absorbed Na+ ions are then extruded from enterocytes through the Na +/K+
ATPase located in the basolateral membrane. Similar mechanistic models that account for the transport
of other common ions such as K+ and HCO3 also exist.
Substantial heterogeneity, with respect to both crypt-villus and craniocaudal axes, exist for intestinal
epithelial transport mechanisms. For example, nutrient-coupled Na + transporters are expressed in
mature villus cells, but are absent in crypt cells. In contrast, the cystic fibrosis transmembrane regulator
(a chloride channel) is expressed to a greater extent in crypt cells. This spatial distribution pattern is
consistent with a model in which absorptive function resides primarily in the villus and secretory function
in the crypt.
Intestinal absorption and secretion are subject to modulation under physiologic and pathophysiologic
conditions by a wide array of hormonal, neural, and immune regulatory mediators (Table 28-1).

CARBOHYDRATE DIGESTION AND ABSORPTION

Approximately 45% of energy consumption in the average Western diet consists of carbohydrates,
approximately one half of which is in the form of starch (linear or branched polymers of glucose) derived
from cereals and plants. Other major sources of dietary carbohydrates include sugars derived from milk
(lactose), fruits and vegetables (fructose, glucose, and sucrose), or purified from sugar cane or beets
(sucrose). Processed foods contain a variety of sugars including fructose, oligosaccharides, and
polysaccharides. Glycogen derived from meat contributes only a small fraction of dietary carbohydrate.
Pancreatic amylase is the major enzyme of starch digestion, although salivary amylase initiates the
process. The terminal products of amylase-mediated starch digestion are oligosaccharides, maltotriose,
maltose, and alpha-limit dextrins (Fig. 28-6). These products, as well as the major disaccharides in the
diet (sucrose and lactose), are unable to undergo absorption in this form. They must first undergo
hydrolytic cleavage into their constituent monosaccharides; these hydrolytic reactions are catalyzed by
specific brush border membrane hydrolases that are expressed most abundantly in the villi of the
duodenum and jejunum. The three major monosaccharides that represent the terminal products of
carbohydrate digestion are glucose, galactose, and fructose.
Under physiologic conditions, most of these sugars are absorbed through the epithelium via the
transcellular route. Glucose and galactose are transported through the enterocyte brush border
membrane via intestinal SGLT1 (Fig. 28-7). Fructose is transported through the brush border membrane
by facilitated diffusion via glucose transporter-5 (GLUT5, a member of the facilitative glucose transporter
family). All three monosaccharides are extruded through the basolateral membrane by facilitated
diffusion. Extruded monosaccharides diffuse into venules and ultimately enter the portal venous system.

There is evidence of overexpression of hexose transporters, specifically SGLT1, in disease states such as
diabetes. Several approaches aimed at down-regulation of these transporters are being investigated as a
novel therapy for disease states such as diabetes and obesity.

PROTEIN DIGESTION AND ABSORPTION

Ten to 15% of energy consumption in the average Western diet consists of proteins. In addition to
dietary proteins, approximately one half of the protein load that enters the small intestine is derived
from endogenous sources including salivary and GI secretions and desquamated intestinal epithelial
cells. Protein digestion begins in the stomach with action of pepsins. This is not, however, an essential
step, because surgical patients who are achlorhydric, or have lost part or all their stomach, are still able
to successfully digest proteins. Digestion continues in the duodenum with the actions of a variety of
pancreatic peptidases. These enzymes are secreted as inactive proenzymes. This is in contrast to
pancreatic amylase and lipase, which are secreted in their active forms. In response to the presence of
bile acids, enterokinase is liberated from the intestinal brush border membrane to catalyze the
conversion of trypsinogen to active trypsin; trypsin, in turn, activates itself and other proteases. The
final products of intraluminal protein digestion consist of neutral and basic amino acids and peptides two
to six amino acids in length (Fig. 28-8). Additional digestion occurs through the actions of peptidases
that exist in the enterocyte brush border and cytoplasm. Epithelial absorption occurs for both single
amino acids and di- or tripeptides via specific membrane-bound transporters. Absorbed amino acids and
peptides then enter the portal venous circulation.
Of all amino acids, glutamine appears to be a unique, major source of energy for enterocytes. Active
glutamine uptake into enterocytes occurs through both apical and basolateral transport mechanisms.