Chapter 29: Small Bowel

Gross Anatomy

The small intestine is the portion of the alimentary tract extending from the pylorus to the ileocecal valve and it consists of three segments—the duodenum, the jejunum (upper two-fifths), and the ileum (lower three-fifths). The anatomy, physiology, and pathology of the duodenum are discussed in Chapter 23.

The jejunum begins at the ligament of Treitz. The jejunum and ileum are suspended on a mobile mesentery covered by a visceral peritoneal lining that extends onto the external surface of the bowel to form the serosa. There is no sharp demarcation between the jejunum and the ileum; as the intestine proceeds distally, the lumen narrows, the mesenteric vascular arcades become more complex, and the circular mucosal folds become shorter and fewer.

The mesentery contains fat, blood vessels, lymphatic channels and nodes, and nerves. The jejunum and ileum are supplied by the superior mesenteric artery (SMA). Branches within the mesentery anastomose to form arcades, and small straight arteries from these arcades enter the mesenteric border of the gut. Venous blood is drained through the superior mesenteric vein (SMV), which then joins the splenic vein behind the pancreas to form the portal vein.

Lymphatic drainage is abundant. Elliptical, lymphoid aggregates (Peyer’s patches) are present in the submucosa on the antimesenteric border along the distal ileum, and smaller follicles are evident throughout the remainder of the small intestine. Regional lymph nodes follow vascular arcades and drain toward the cisterna chyli.

The nerve supply for the small bowel is both sympathetic (fibers from the greater and lesser splanchnic nerves) and parasympathetic (from the right vagus nerve). Although both types of autonomic nerves contain efferent and afferent fibers, only the sympathetic afferents appear to mediate intestinal pain.

Microscopic Anatomy

The wall of the small intestine consists of four layers—mucosa (innermost), submucosa, muscularis, and serosa (outermost).

The mucosa is characterized by circular folds about 10 mm high, named valvulae conniventes, that are taller and more numerous in the proximal jejunum and project into the lumen (Figure 29–1). These folds, combined with the presence of villi on the surface of the valvulae conniventes, increase the absorptive surface area about eight times. There are approximately 20-40 villi/mm². They are about 0.5-1 mm long and their walls are made up of epithelial cells with tiny projections named microvilli. The epithelial cells enclose a central axis that contains an arteriole surrounded by blood and lymphatic capillaries, known as a lacteal, and fibers from the muscularis mucosae. The microvilli (1 μm in height) amplify the potential absorptive surface area up to 200-500 m² (Figure 29–2).

The mucosa is microscopically subdivided into three different layers: (1) the muscularis mucosae, the outermost, consists of a thin sheet of smooth muscle cells; (2) the lamina propria consists of connective tissue that extends from the base of the crypts up into the intestinal villi; and (3) the epithelium which is the innermost layer.

Intestinal epithelium in composed of multiple cell types that rest on a thin basement membrane overlying the lamina propria. There are two major compartments to the intestinal epithelium, the crypt and the villus, each with distinct function and cellular composition. The crypt is populated by cells that are predominantly secretory and which derive from a pluripotent stem cell located above the base of the crypts of Lieberkühn. Paneth cells stay at the base of the crypts; their function is still unknown but may be secretory, as resembling zymogen-secreting cells of the pancreas.

Most of the crypt cells are undifferentiated; some mature into mucus-secreting goblet cells and enteroendocrine cells, but the majority become absorptive enterocytes. Enteroendocrine cells include enterochromaffin cells (the most common), N cells that contain neurotensin, L cells (glucagon), and motilin and cholecystokinin (CCK) containing cells. Finally, M cells and T lymphocites play a major role in mucosal cell-mediated immunity.

The villus compartment is nonproliferative. Factors that affect enterocyte differentiation include growth factors, hormones, matrix proteins, and luminal nutrients. The life span of enterocytes is 3-6 days.

The submucosa is a dense connective tissue layer populated by different cell types, including fibroblasts, mast cells, lymphocytes, macrophages, eosinophils, and plasma cells. It contains blood vessels, lymphatics, and nerves. Meissner’s submucosal neural plexus interconnects with neural elements from Auerbach’s plexus. The submucosa is the strongest layer of small bowel wall. The muscularis consists of two layers of smooth muscle, a thicker inner circular layer and a thinner outer longitudinal layer. Specialized intercellular junctional structures called gap junctions electrically couple adjacent smooth muscle cells and allow efficient propagation of peristalsis. Ganglion cells and nerve fibers of Auerbach’s myenteric plexus interdigitate between layers and communicate with smaller neural elements between cells. The serosa consists of a single layer of flattened mesothelial cells that covers the small bowel.

Motility

Intestinal motility consists of propulsion of luminal contents (peristalsis) combined with mixing action through segmentation. These functions are accomplished by both the outer longitudinal and inner circular muscle layers of the intestinal wall, mainly under the direct control of the myoenteric nervous plexus. The submucosal nervous plexus is primarily involved in the regulation of secretion and absorption. The extrinsic sympathetic input is excitatory and the peptidergic input likely inhibitory. Intestinal motility is also under positive control by local hormones such as motilin and CCK. Smooth muscles of the small intestine undergo spontaneous oscillations of membrane potentials, known as pacesetter potentials, with progressively decreasing frequency from the duodenum to the ileum. The frequency of pacesetter potentials for the entire small intestine is determined by the duodenum, where they originate. A nerve-related cell type known as the interstitial cell of Cajal appears to play a key role in the generation of pacemaker activity. Small bowel motility varies with the fasted and fed state. During the interdigestive or fasting period, a cyclical pattern of motor activity consisting of three phases is observed. Phase I is resting and lasts for about 80% of the cycle. Phase II, about 15%, consists of random contractions of moderate amplitude. Phase III, about 5%, is a series of brief high pressure waves. This three-phase cycle results in a pattern called the migrating motor complex, which is abolished by ingestion of food. In the fed state, the pattern of contraction is more frequent and consistent over time. Rather than beginning from a proximal site and propagating distally, contractions begin at all levels along the small bowel and spread distally.

Barrier Function

The intestinal epithelium selectively limits the permeation of potentially harmful luminal substances. The anatomical barrier is the intercellular junction complex, a three-level structure that forms a circumferential seal between adjacent cells: the tight junction faces the lumen, the intermediate junction lies deep to the tight junction, and the desmosome is the innermost element of this complex. Several pathological conditions can alter the barrier function. Certain bacterial toxins, such as Clostridium difficile, directly perturb the barrier function through disruption of cytoskeletal-junctional interactions, and various cytokines and proinflammatory mediators can also modulate intestinal permeability.

Digestion & Absorption

Digestion begins in the stomach with the action of gastric acid and pepsin. In the proximal duodenum, ingested food is broken down by pancreatic enzymes such as trypsin, elastase, chymotrypsin, and carboxypeptidases. The activity of intestinal hydrolases and olygopeptidases then accomplishes terminal protein and carbohydrate digestion, and the resulting monosaccharides, amino acids, or di- and tripeptides then serve as substrates for Na⁺- or H⁺-coupled transporters in the apical membrane of absorptive enterocytes. Fat digestion and absorption occur in the proximal small bowel, where pancreatic lipase partially hydrolyzes triglycerides into two fatty acids and a monoglyceride. These substances are solubilized by bile salts to form micelles that diffuse into enterocytes releasing fatty acid and monoglyceride. Triglycerides are transported intracellularly and incorporated along with cellular protein, phospholipid, and cholesterol to form chylomicrons. They then exit the cell to be absorbed by the lymphatic system. Bile salts are reabsorbed into the enterohepatic circulation in the distal ileum by an ileal Na⁺-coupled bile acid transporter.

The small bowel receives about 1-1.5 L/day of ingested fluids and about 8 L of salivary, gastric, and pancreatico-biliary secretions. Most of this fluid is reabsorbed before reaching the colon. Water movement is driven by the active transcellular absorption of Na⁺ and Cl⁻ and by absorption of nutrients such as glucose and amino acids. The energy for many of these processes derives from the activity of a Na⁺-K⁺ ATPase, that maintains the low Na⁺ internal environment that drives uptake via coupled ion exchangers (Na⁺/H⁺ and Cl⁻/HCO₃⁻) and Na⁺-coupled nutrient transporters.

Secretion

Intestinal crypt cells secrete an isotonic fluid through the active transcellular transport of Cl⁻. This process lubricates the mucosal surface and facilitates the luminal extrusion of other secrete substances. Diarrhea results when secretion exceeds intestinal absorptive capacity.

Immune Function

The mucosal immune system is extremely important in defense against toxic and pathogenic threats from the luminal environment. The lamina propria contains numerous immune cells including plasma cells, mast cells, and lymphocytes that produce both immunoglobulins and cytokine mediators.

Plasma cells produce IgA in response to food antigens and microbes. IgA and IgM are secreted into the lumen by a mechanism that involves transcytosis through epithelial cells after binding to the polymeric immunoglobulin receptor on the basolateral membrane. Secretory IgA prevents microbial pathogens from penetrating the epithelial layer. IgA-antigen interactions also occur within the intraepithelial and subepithelial compartments. Intestinal epithelial cells themselves may also contribute to the immune function of the bowel. These cells express major histocompatibility class I and class II molecules on their surface and may function as weak antigen-presenting cells. The epithelial cell layer may transmit important immunoregulatory signals to the underlying lymphocytic population.

Specialized cells known as M cells are found overlying Peyer’s patches and act as the major portal of entry for foreign bodies. Specialized membrane invaginations in these cells create a pocket in which lymphocytes and macrophages gather. Luminal substances are immediately delivered to these antigen-presenting cells, and this information is directly conveyed to the underlying follicles. Intraepithelial lymphocytes (IEL) are specialized T cells that reside in the paracellular space between absorptive enterocytes. The precise role of IELs is still uncertain, but they may mediate cross-talk between epithelial cells and the underlying immune and nonimmune cells of the lamina propria. Within the lamina propria and submucosa, mature T cells, B cells, and macrophages carry out traditional cell-mediated immune response including phagocytosis, cell killing, and cytokine secretion. Mucosal and connective tissue mast cells produce numerous mediators that contribute to overall immune response and modulate the many functions of the epithelial cells.

Neuroendocrine Function

The small bowel is a rich source of regulatory peptides that control various aspects of gut function. These substances, released in response to luminal or neural stimuli, exert their biological actions either at distant sites or locally.

Secretin is a 27-amino-acid peptide released by enteroendocrine cells in the proximal small bowel in response to luminal acidification, bile salts, and fat. Its major function is to stimulate pancreatic ductal alkaline secretion. Secretin inhibits gastric acid secretion, and gastrointestinal motility. In addition, it stimulates bile flow by stimulating fluid secretion from cholangiocytes. Other members of the secretin family that share substantial sequence homology and interact with similar receptors include vasoactive intestinal polypeptide (VIP), glucagon, gastric inhibitory polypeptide (GIP), and enteroglucagon. Enteroglucagon and glucagon-like peptides are secreted by neuroendocrine cells in the colon and small bowel and may play an important role in gut adaptation and glucose homeostasis.

CCK is released by specialized enteroendocrine cells in response to luminal amino acids and medium- to long-chain fatty acids. CCK release is inhibited by intraluminal trypsin and bile salts. Two major targets of CCK are the gallbladder and the sphincter of Oddi, where it causes coordinated contraction and relaxation, respectively, to enhance luminal mixing of bile with ingested food. Furthermore, CCK stimulates pancreatic enzyme secretion and cell growth in intestinal mucosa and the pancreas, insulin release and intestinal motility.

Somatostatin is a 14-amino-acid peptide that exerts a wide variety of inhibitory functions in the gastrointestinal tract. It is released from specialized enteroendocrine cells and it acts in paracrine fashion to inhibit intestinal, gastric, and pancreatico-biliary secretion and cell growth. Synthetic forms of somatostatin are used in the clinical practice in patients with enterocutaneous and pancreatico-biliary fistulae.

Peptide YY is a 36-amino-acid peptide secreted by the distal small bowel and it inhibits gastric acid and pancreatic secretion, as well as several intestinal hormones, and decreases intestinal motility.

Motilin is secreted by the duodenum and the proximal jejunum, where it acts to enhance contractility and accelerate gastric emptying.

Neurotensin is produced in the ileum and enteric nerves; it appears to affect a variety of enteric functions including gastric acid secretion, gastric emptying, intestinal motility, and secretion.

Other peptides (VIP, calcitonin-related peptide, galanin, bombesin, neuropeptide Y, gastrin-releasing peptides, and substance P) are released from enteric nerves, but their precise role has not been fully clarified.

General Considerations

Small bowel obstruction (SBO) is one of the most common disorders affecting the small bowel. It is characterized by impairment in the normal flow of intraluminal contents and can be divided into mechanical obstruction and paralytic ileus.

Mechanical obstruction implies an extrinsic or intrinsic obstacle that prevents the aboral progression of intestinal contents and it may be complete or partial. Simple obstruction occludes the lumen only; obstruction with strangulation impairs the blood supply also and leads to necrosis of the intestinal wall. Paralytic (or adynamic) ileus is due to a neurogenic failure of peristalsis to propel intestinal contents with no mechanical obstruction.

A. Etiology

The causes of mechanical obstruction can be divided into three groups according to the relationship to the intestinal wall: (1) intraluminal; (2) intramural; and (3) extrinsic. The three most common etiologies are intra-abdominal adhesions, hernias, and neoplasms (Table 29–1).

1. Adhesions Sixty to 75% of cases of mechanical SBO are secondary to adhesions related to prior abdominal surgery. Lower abdominal and pelvic surgery appears to be associated with a higher incidence of adhesions compared to upper abdominal surgery. Congenital bands are rarely seen in children.

2. Hernia The most common cause of SBO in patients with no history of prior abdominal surgery is a hernia. A careful search for inguinal, femoral, and umbilical hernias must be made during evaluation of every patient presenting with symptoms consistent with obstruction. Internal hernias into the obturator foramen, the foramen of Winslow, or other anatomic defects must also be considered. In patients who have undergone previous surgery, incisional hernias represent another potential cause of SBO especially after laparotomy, in overweight or obese patients, in patients on steroid therapy or with wound infections.

3. Neoplasms Intrinsic small bowel neoplasms can progressively occlude the lumen or serve as a leading point in intussusception. Symptoms may be intermittent, onset of obstruction is slow, and signs of chronic anemia may be present. Peritoneal carcinomatosis from several tumors is an extrinsic cause of SBO due to adhesions of small bowel loops to neoplastic nodules.

Other causes of SBO include Crohn disease (CD), intussusception which is most often seen in children without an organic lesion and rarely in adults with a neoplastic intraluminal lesion; volvulus as a consequence of intestinal malrotation in children, or of adhesions in adults; and foreign bodies including bezoars, ingested foreign bodies, and gallstones through a cholecysto-duodenal fistula. Gallstone ileus is discussed in Chapter 25.

B. Pathophysiology

With the onset of obstruction, gas and fluid accumulate and distend the intestinal loops proximal to the site of obstruction. Fluid from the extracellular space also fills the lumen proximal to the obstruction, due to the impaired bidirectional flow of salt and water and fluid secretion enhanced by substances (endotoxins, prostaglandins) released from proliferating bacteria in the intestinal lumen. As a consequence, intraluminal and intramural pressures rise until microvascular perfusion to the intestine is impaired, leading to intestinal wall ischemia, and ultimately necrosis.

Activity of the smooth muscle of the small bowel is increased in an attempt to propel its contents past the obstruction consuming all energy sources. At this point the intestine becomes atonic and enlarges further. Emesis could be feculent due to bacterial overgrowth—particularly with distal obstruction—as the intestinal dilation progresses proximally (Figure 29–3). Bacterial translocation from the lumen to the mesenteric nodes and the bloodstream occurs and abdominal distention elevates the diaphragm and impairs respiration resulting in potential pulmonary complications such as pneumonia, and atelectasis.

When full thickness necrosis of the intestinal wall occurs, luminal content with an elevated bacterial load enters the peritoneal cavity, is absorbed by the peritoneum causing septic shock.

The progression of pathophysiologic events when the bowel is strangulated occurs more rapidly than with simple obstruction and is characterized by an acute impairment of venous return initially followed by arterial flow with subsequent ischemia, necrosis, and perforation of the intestinal wall.

Clinical Findings

Diagnostic evaluation should distinguish mechanical bowel obstruction from ileus, determine the cause of the obstruction, and recognize simple from strangulating obstruction.

Accurate diagnosis requires obtaining a detailed history paying particular attention to medications known to affect intestinal physiology, previous cancer, inflammatory bowel disease, and abdominal surgery and a meticulous physical examination.

A. Signs and Symptoms

Patients usually present with nausea, vomiting, colicky abdominal pain, and obstipation, although residual gas and stool distal to the obstruction may be expelled. With proximal SBO, emesis is usually profuse, containing undigested food in close temporal association with oral intake; abdominal pain is more often described as upper abdominal discomfort associated with epigastric distension. Distal SBO is characterized by diffuse and poorly localized crampy abdominal pain. Feculent vomiting present in cases of longstanding distal SBO is the consequence of bacterial overgrowth and is pathognomonic for a complete mechanical obstruction. In the presence of strangulation, fever often develops, and previously crampy abdominal pain becomes peritonitis.

Initially, vital signs may be normal, but tachycardia and hypotension usually develop as a result of progressive dehydration. Fever is often present with bowel ischemia or perforation. Inspection of the abdomen usually reveals distension that varies based on the site of obstruction and may be absent in cases of proximal obstruction. Peristalsis is usually tremendously increased in the early phases of mechanical SBO, as a result of intensive intestinal muscular contractions. This so-called “peristaltic rush” progressively decreases until it disappears in the late phase of obstruction. The presence of either surgical scars or hernias should be noted, indicating a possible cause of SBO. Rectal examination is essential to detect rectal lesions and to check for the presence of stool.

B. Laboratory Findings

Laboratory findings reflect intravascular volume depletion and dehydration. An elevated hematocrit is indicative of hemoconcentration. Leukocytosis is often the result of dehydration and an acute stress response rather than an underlying infection. Blood chemistries may reveal elevated serum creatinine levels, indicating hypovolemia with prerenal failure.

Features of strangulated obstruction or perforation include marked leukocytosis and metabolic acidosis.

C. Imaging Studies

Plain x-rays of the abdomen with the patient in supine and upright position can confirm the clinical diagnosis of SBO. They reveal dilated small bowel loops with air-fluid levels in a ladder-like appearance, and a paucity of air in the colon. These features may be minimal or absent in early or high grade obstructions.

Computed tomographic (CT) scan of the abdomen and pelvis with both intravenous and oral contrast is widely used. CT scan can visualize the specific location of the obstruction, showing a discrepancy in the caliber between distended proximal bowel loops and collapsed distal intestine. Moreover, CT scan can also reveal the etiology of SBO and demonstrate signs of strangulation including thickening of the bowel wall, air in the bowel wall or portal venous system, and poor uptake of intravenous contrast by the affected bowel wall. Ascites between dilated bowel loops and in the pelvis is often reported in both simple and strangulated obstruction. Intraperitoneal free air indicates perforation.

Differential Diagnosis

Pain in patients with paralytic ileus is usually not severe but is constant and diffuse, and the abdomen is often distended and mildly tender. If ileus has resulted from an acute intraperitoneal inflammatory process, there should be symptoms and signs of the primary disease as well as the ileus. Abdominal x-rays show the presence of gas in both the colon and in the small bowel.

A postoperative ileus may be caused by several factors, including drugs used for anesthesia and analgesia, and intraoperative manipulation of intestinal loops and the mesentery. Usually, it is temporary; but if it persists for more than 3-5 days, diagnostic evaluation to rule out mechanical causes of obstruction is mandatory.

Colonic obstruction is usually diagnosed by abdominal x-rays that show colonic dilation proximal to the obstructing lesion. In the presence of competent ileocecal valve, a closed loop obstruction occurs with an elevated risk of perforation of the colon. If the ileocecal valve is incompetent, the distal small bowel will be dilated, and patients will exhibit abdominal distension, nausea and vomiting.

Acute gastroenteritis, acute appendicitis, and acute pancreatitis can mimic simple intestinal obstruction, while acute mesenteric ischemia (AMI) must be considered in the differential of small bowel strangulation.

Intestinal pseudo-obstruction comprises a spectrum of specific disorders associated with irreversible intestinal dysmotility, in which there are symptoms and signs of intestinal obstruction without evidence for an obstructing lesion. Acute pseudo-obstruction of the colon carries the risk of cecal perforation and is discussed in Chapter 30. Chronic pseudo-obstruction affecting the small bowel with or without colonic involvement can be idiopathic, or secondary to several (sporadic and familial) visceral myopathies and neuropathies that affect intestinal smooth muscle, and the intra- and extraintestinal nervous system. Systemic disorders such as scleroderma, myxedema, lupus erythematosus, amyloidosis, drug abuse (phenothiazine ingestion), radiation injury, or progressive systemic sclerosis can be complicated by chronic intestinal pseudo-obstruction. In addition, cytomegalovirus and Epstein–Barr viral infections can cause chronic intestinal pseudo-obstruction.

The clinical manifestations of chronic intestinal pseudo-obstruction include recurrent episodes of vomiting, crampy abdominal pain, and abdominal distention. The diagnosis is suggested by clinical findings and medical history, and confirmed by radiologic and manometric studies. Diagnostic laparoscopic full-thickness biopsy of the small bowel may be required to establish the specific cause of the disease. Therapy focuses on palliation of symptoms and nutritional issues.

Treatment

SBO is associated with a marked depletion of liquids caused by decreased oral intake, vomiting, and sequestration of fluid in the bowel lumen. Therefore, vigorous fluid resuscitation and correction of electrolyte disorders (hypochloremic, hypokalemic metabolic alkalosis) is mandatory. A urinary catheter should be placed to monitor urinary output. Gastrointestinal decompression with a nasogastric tube provides relief of symptoms, prevents further gas and fluid accumulation proximally, and decreases the risk of aspiration. Obstruction that occurs in the early postoperative period is usually partial and only rarely associated with strangulation. Therefore, a period of prolonged total parenteral nutrition and hydration is warranted. Patients who have undergone numerous abdominal operations should initially be conservatively treated with decompression, bowel rest, and serial abdominal exams in hopes of avoiding reentering a hostile abdomen. Patients with CD rarely present with a complete bowel obstruction and these patients often benefit from steroids or other immunosuppressive therapy. However, if signs suggestive of ischemia are detected surgery should be promptly undertaken.

Finally, management of patients with diffuse carcinomatosis is often challenging and in most of cases limited to conservative and palliative treatment.

A. Surgery

The surgical procedure performed varies according to the etiology of the obstruction. However, regardless of the cause of obstruction all small bowel loops must be examined and nonviable segments resected. Criteria suggesting viability include normal pink color, presence of peristalsis, and arterial pulsation.

Laparoscopic adhesiolysis may be performed in carefully selected patients by surgeons skilled in this procedure. Generally, however, an open procedure is performed through an incision that is partly dictated by the location of scars from previous operations.

If the cause of the obstruction cannot be removed, as in case with infiltration of vital structures by cancer or in the case of diffuse carcinomatosis, an anastomosis between proximal small bowel and small or large bowel distal to the obstruction (bypass) may be the best procedure in these patients. In some cases, a stoma can be the only choice of treatment.

Prognosis

Vast majority (more than 80%) of patients with adhesive SBO do not need an operation, since they improve with medical therapy. Among patients who require surgery, perioperative mortality rate for nonstrangulating obstruction is less than 5%; most of these deaths occur in elderly patients with significant comorbidities. Strangulating obstruction has a mortality rate of approximately 8% if surgery is performed within 36 hours of the onset of symptoms and 25% if operation is delayed beyond 36 hours.

General Considerations

Crohn disease is a chronic inflammatory disease that commonly affects the small bowel, colon, rectum, and anus, but it can also involve the stomach, esophagus, and mouth. CD is a panintestinal condition which may affect any area from the mouth to the anus. The most commonly affected location is the terminal ileum and one-fifth of all patients have more than one intestinal segment affected simultaneously.

The United States, Canada, and Europe have the highest incidence of CD. The current estimated incidence of CD in the United States is approximately four new cases per year for every 100,000 persons, while the prevalence is much higher, between 80 and 150 cases per 100,000.

It is much less common in Asia, South America, and Japan, while accurate data regarding its incidence in Africa are lacking. The peak age for contracting CD is between 15 and 25 years. Familial clusters of disease are not uncommon, with a six- to tenfold increase in the risk of CD in first-degree relatives of those affected by CD or its sister ailment, ulcerative colitis. Although familial aggregations are common, the distribution within families does not indicate a pattern of simple Mendelian inheritance.

A. Etiology

The etiology of CD is not known. CD is an altered immune response that results in inflammation and destruction of intestinal tissues. If this altered immune response is the result of a primary dysfunction in the gut-related immune system or whether an unknown pathological trigger induces an otherwise normal immune system to overreact is still unclear. CD may occur in individuals with a genetic predisposition, while environmental triggers may start the pathological sequence that ultimately manifests as CD.

To date, even though an increase in intestinal permeability in both CD patients and their symptom-free first-degree relatives has been demonstrated no specific primary defect in the systemic or mucosal immune system has been identified. This may lead to an altered mucosal barrier function with abnormal interactions between the multitude of antigenic substrates normally found in the gut lumen and the immunocompetent tissue of the submucosa.

Concerning genetic predisposition, the CARD15/NOD2 gene has been linked to susceptibility to CD. CARD15 is a gene product related to innate immunity and it is preferentially expressed to Paneth cells of the ileum. Nevertheless, the known mutations of CARD15 are neither necessary nor sufficient to contract the disease. Hence, it appears that the genetic relationship of CARD15/NOD2 to CD is complex and still poorly understood.

The hypothesis that infectious agents may play a role, either directly as a primary cause of CD, or indirectly as a trigger to stimulate a defective immune system, has always found strength in the identification of noncaseating granulomas as the characteristic histopathologic lesion found in Crohn specimens, and in the isolation of Mycobacterium paratuberculosis from resected CD specimens. Nevertheless, even sensitive preliminary chain reaction studies have been unable to provide definitive evidence for the presence of Mycobacterium paratuberculosis-specific DNA in CD-affected segments of the bowel. Other infectious agents, including measles virus, non-pylori Helicobacter species, Pseudomonas, and Listeria monocytogenes have been studied, but none of them has been consistently associated with CD.

Although diet modification can ameliorate the symptoms of CD, no dietary factor has been identified as a cause of CD. Smoking, however, has been associated with the development of CD. In addition, smoking is known to exacerbate existing CD and can accelerate the recurrence of disease after resection.

B. Pathology

Histopathologic examination of CD typically demonstrates transmural inflammation characterized by multiple lymphoid aggregates in a thickened and edematous submucosa that can be found within the muscularis propria. Another typical microscopic feature of CD is the noncaseating granuloma. However, it is demonstrated in only 50% of resected specimens and is rarely detected on endoscopic biopsies. Additionally, the presence of granulomas does not correlate with disease activity.

Small mucosal ulcerations, called aphthous ulcers, are the earliest gross manifestations of CD. They appear as red spots or focal mucosal depressions, typically directly over submucosal lymphoid aggregates. As the inflammation progresses, the aphthous ulcers enlarge and become stellate. They then coalesce to form longitudinal mucosal ulcerations always along the mesenteric aspect of the bowel lumen. Further progression leads to a serpiginous network of linear ulcerations that surround islands of edematous mucosa producing the classic “cobblestone” appearance. Mucosal ulcerations may penetrate through the submucosa to form intramural channels that can bore deeply into the bowel wall and create sinuses, abscesses, or fistulas.

The inflammation of CD also involves the mesentery and regional lymph nodes such that the mesentery may become massively thickened. With early acute intestinal inflammation, the bowel wall is hyperemic and boggy. As the inflammation becomes chronic, fibrotic scarring develops and the bowel wall becomes thickened and leathery in texture.

Clinical Findings

A. Symptoms and Signs

The clinical presentation and symptoms of CD depend on the involved segment, the pattern and the severity of disease, and the associated complications. The onset of CD is often insidious and many patients will experience some symptoms for months or even years before the diagnosis is made. The most common complaints are intermittent abdominal pain, bloating, diarrhea, nausea, vomiting, weight loss, and fever. Abdominal pain occurs in 90% of cases: when related to partial obstruction it is mostly postprandial and crampy in nature, while when it is from septic complications it is typically steady and associated with fever. Weight loss is usually related to food avoidance, but in severe cases weight loss may be the result of malabsorption. Symptoms can also be related to complications including abdominal mass, pneumaturia, perianal pain and swelling, or skin rash. Rarely some patients can experience a more sudden onset of pain in the right-lower quadrant, mimicking an acute appendicitis.

In patients suspected of having CD, a complete physical exam should include a thorough abdominal evaluation. In cases of ileal CD, tenderness is typically present in the right-lower quadrant and occasionally a palpable mass is present. The oral cavity should be examined for aphthous ulcers, while the presence of fistulas, abscesses, or enlarged skin tags should be assessed in the perianal area. A digital rectal examination should assess for the presence of anal strictures, fissures, and rectal mucosal ulcerations. The skin in the extremities should be examined for the presence of erythema nodosum and pyoderma gangrenosum.

Patterns of Disease

Even though CD can be categorized into three general manifestations, such as stricturing, perforating, and inflammatory disease, these three classes do not represent truly distinct forms of the disease. It is typical that the same patient can present with more than one pattern even in the same segment of bowel. Nevertheless, one pattern tends to be predominant in most cases, determining the clinical presentation and affecting the therapeutic options.

A. Stricturing Pattern

Fibrotic scar tissue is the result of chronic inflammation of CD, and it constricts the intestinal lumen with cicatricial strictures often referred to as “fibrostenotic lesions.” Patients with a stricturing pattern of disease generally develop partial or complete intestinal obstruction, and hence their symptoms are primarily obstructive in nature. Being the result of scar tissue, these strictures are not reversible with medical therapy and surgical intervention is often required.

B. Perforating Pattern

Perforating CD is characterized by the development of sinus tracts, fistulae, and abscesses. The sinus tracts penetrate through the muscularis propria and give rise to abscesses or to fistulas if they penetrate into surrounding structures. Inflammatory response around the advancing sinus tract typically results in adhesion to surrounding structures, therefore, free perforation with spillage of intestinal contents into the abdominal cavity is uncommon. Typically, perforating disease is accompanied by a degree of stricture formation, but the fistula or abscess generated by the perforating component of the disease dominates the clinical picture.

C. Inflammatory Pattern

The inflammatory pattern of CD is characterized by mucosal ulceration and bowel wall thickening. The edema that results from inflammation can lead to an adynamic segment of intestine and luminal narrowing. This pattern often gives rise to obstructive symptoms. Of the three patterns of disease, the inflammatory pattern is much more likely to respond to medical therapy.

Other common symptoms and findings include anorexia and weight loss. Patients may develop a palpable mass, usually located in the right-lower quadrant, related to an abscess or phlegmon in perforating disease or a thickened loop of intestine in obstructive disease. Evidence of fistulization to the skin, urinary bladder, or vagina may also be elicited with an accurate history and physical exam.

Laboratory Findings

There is no specific laboratory test that is diagnostic for CD. The diagnosis is made by a thorough history and physical examination along with intestinal radiography and endoscopy. Advanced imaging studies such as CT scan or magnetic resonance imaging (MRI) can assess or detect some of the complications and manifestations of CD, but they are generally not useful in making the initial diagnosis of CD.

A. Imaging Studies

Small bowel follow-through or enteroclysis are the best means for assessing the small bowel for CD. The radiographic abnormalities are often distinctive. Mucosal granulations with ulceration and nodularity can be identified in the early stages of the disease. Thickening of the mucosal folds and edema of the bowel wall can be demonstrated as the disease progresses. With more advanced disease, cobblestoning becomes radiographically apparent. Small bowel contrast studies can also provide information regarding enlargement of the mesentery, as well as formation of an inflammatory mass or abscess demonstrated by a general mass effect separating and displacing contrast-filled loops of small intestine. Even though small bowel contrast studies can demonstrate some of the complications of CD, including high-grade strictures and fistulas, they may not identify all such lesions, including ileosigmoid and ileovesical fistulas. Additionally, small bowel studies may not demonstrate all the areas of disease with significant strictures. Small bowel radiographs can also help in assessing the extent of the disease by identifying the location and length of involved and uninvolved small bowel, and by recognizing whether the disease is continuous or discontinuous with skip lesions separated by areas of normal intestine. Experienced radiologists can also assess areas of luminal narrowing and determine if they are the result of acute inflammatory swelling or are the result of fibrostenotic scar tissue. Such a distinction provides valuable information regarding the value of medical therapy versus early surgical intervention, as inflammatory stenoses are likely to respond to medical therapy while fibrotic strictures are best treated with surgery.

Computed tomography findings of uncomplicated CD are nonspecific and routine CT is not necessary for the diagnosis of CD. CT, however, is very useful in identifying the complications associated with CD—thickened and dilated intestinal loops, inflammatory masses, abscesses, and hydronephrosis resulting from retroperitoneal fibrosis and ureteral narrowing (Figure 29–4). CT is also the most sensitive indicator of an enterovesical fistula as suggested by the presence of air within the urinary bladder. More recently cross-sectional imaging techniques have assumed an increasing role in the imaging of patients with CD. Computed tomography enterography (CTE) has been shown to have a higher sensitivity than barium small-bowel follow through. Based on these findings, CTE is often used combined with ileocolonoscopy as a first-line test for the diagnosis and staging of CD. CTE has several potential advantages over barium studies in the identification of fistulizing disease. CTE does not suffer from superimposition of bowel loops, and it displays the mesentery, retroperitoneum, and abdominal wall musculature, typically involved by fistulas. CTE can also readily identify sinus tracts and abscesses. However, recent concerns about radiation-induced cancer arising from medically related CT in young CD patients have encouraged the use of magnetic resonance enterography (MRE). MRE has the same advantages of CTE but does not require ionizing radiation.

B. Endoscopy

While upper endoscopy is useful in the diagnosis of mucosal lesions of the esophagus, stomach, and duodenum a colonoscopy often allows the evaluation of the terminal ileum.

C. Capsule Endoscopy

Capsule endoscopy can detect subtle mucosal lesions that may not be apparent on small bowel x-rays. The value of capsule endoscopy in the diagnosis of CD has been recently evaluated: the rate of abnormalities detected on capsule endoscopy is higher than that of CTE only for the subgroup of patients with known CD. The need for a preliminary small bowel contrast study to detect asymptomatic partial small-bowel obstruction before the capsule endoscopy and the lack of a clear advantage over other imaging studies, limits the utility of capsule endoscopy as a first-line test in CD, and perhaps reserve this study for those cases in which there is a substantial diagnostic uncertainty.

Differential Diagnosis

The differential diagnosis includes irritable bowel syndrome, acute appendicitis, intestinal ischemia, pelvic inflammatory disease, endometriosis, and gynecological malignancies. Other disorders are radiation enteritis, Yersinia infections, intestinal injury from nonsteroidal anti-inflammatory agents, intestinal tuberculosis, and small bowel tumors.

When malignancy is suspected, resection should be undertaken to make the diagnosis certain. The exclusion of intestinal tuberculosis can be difficult, as the inflammation and strictures of the terminal ileum can occur very similarly to CD. A previous exposure to tuberculosis should be evaluated and purified protein derivative skin test should be performed, along with chest radiography. Even when the diagnosis of CD is certain, patients who coincidentally are found to also have latent tuberculosis should be treated in accordance with the American Thoracic Society guidelines prior to the initiation of immunosuppressive therapy for management of CD.

Intestinal injury from nonsteroidal anti-inflammatory drugs (NSAIDs) can result in focal enteritis with ulcerations and strictures. These manifestations can be very difficult to distinguish from CD of the small bowel, and often require resection or biopsy to confirm the diagnosis.

Treatment

A. Medical

Long-lasting symptomatic relief while avoiding excessive morbidity is the goal of medical treatment of CD. Even though CD cannot be cured by medical treatment long periods of disease control can be obtained avoiding a surgical intervention. Medical treatment for each individual is based on the course of the disease, the clinical presentation and associated complications.

Corticosteroids are the most effective agents for controlling acute exacerbations of CD, but their use is limited due to the risk of serious side effects, including diabetes, osteoporosis, cataracts, osteonecrosis, myopathy, psychosis, opportunistic infections, and adrenal suppression, that are related to both the dose and the duration of steroid therapy. The majority of patients with active small bowel CD will experience clinical remission with a short course of oral prednisone given in a dose between 0.25 and 0.5 mg/kg/d. For patients unable to take oral medications, methylprednisolone can be administered in the adult at doses of 40-60 mg given as a daily infusion.

The aminosalicylates include sulfasalazine and 5-aminosalicylic acid (5-ASA) derivatives. They inhibit leukotriene production by inhibiting 5-lipooxygenase activity and the production of inter-leukin-1 and tumor necrosis factor (TNF). Aminosalicylates are effective in the treatment of mild to moderate CD. 5-ASA given in a controlled-release preparation is also effective as maintenance therapy to prevent recurrence after a flare of disease has been effectively managed either medically or surgically.

Aminosalicylates come in a variety of preparations, each designed to deliver the drug in a topical fashion to the affected bowel segments. For instance, Asacol is 5-aminosalicylic acid contained within a pH-dependent resin that releases the drug in the terminal ileum and colon where the pH is greater than 7.0. Pentasa is 5-aminosalicylic acid contained within ethylcellulose-coated microgranules that slowly releases the active compound throughout the entire small bowel and colon. Azathioprine and 6-mercaptopurine (6-MP) are immunosuppressive agents that inhibit cytotoxic T-cell and natural killer cell function. These agents are effective in treating mild to moderate CD. Azathioprine given at 2.0-2.5 mg/kg/d or 6-MP in doses of 1.0-1.5 mg/kg/d will result in a 50%-60% response rate in patients with active CD. Both 6-MP and azathioprine are also effective in maintaining remission following surgery or successful medical management.

Infliximab is a chimeric mouse-human monoclonal antibody to TNF that is a proinflammatory cytokine that may be important in the pathophysiology of CD. Infliximab binds to both free and membrane-bound TNF, and prevents TNF from binding to its cell surface receptors. Clinical trials have demonstrated an 80% response rate with a single dose of infliximab. It is important to note that the doses and dosing intervals of infliximab must be individualized, but a typical regimen would include 5 mg/kg of infliximab given IV at weeks 0, 2, and 6, with a dose of 5 mg/kg every 8 weeks thereafter. Because Infliximab is a potent immunosuppressive agent concerns have been raised about the risk for poor wound healing and postoperative septic complications. Nevertheless, current available data on the perioperative risks associated with infliximab does not seem to support this hypothesis.

Other agents that are used with varying success in the treatment of CD include methotrexate, metronidazole, cyclosporine, tacrolimus, and thalidomide.

B. Surgical Therapy

Similarly to medical treatment, the goal of surgical treatment of CD is to provide long-lasting symptomatic relief while avoiding excessive morbidity. Like medical treatment, surgery should be considered palliative. Therefore, treatment of complications and palliation of symptoms while avoiding excessive resection of small bowel should be the main aims of surgical treatment.

To avoid excessive loss of small bowel, nonresectional techniques such as strictureplasty may be required. In addition, optimal surgical therapy should be the resection of the only areas of severe and symptomatic CD, leaving behind segments of small bowel affected by mild but asymptomatic CD based on the high risks of recurrence and repeated operations.

C. Indications for Surgery

1. Failure of medical treatment

The failure to respond to medical treatment, the inability to tolerate effective therapy are the most common indications for surgical treatment of CD, as the occurrence of complications related to the medical treatment or the progression of disease while on maximal medical treatment. Some patients may respond to the initial medical therapy only to rapidly relapse with tapering of the medical treatment. For example, some patients respond well to steroid therapy, but become steroid-dependent as tapering of the steroid dose results in recurrent symptoms. Due to the severe complications that are virtually inevitable with prolonged steroid treatment, surgery is warranted if the patient cannot be weaned from systemic steroids within 3-6 months.

2. Intestinal obstruction

Partial or complete intestinal obstruction is a common indication for operation. The clinical presentation of chronic partial SBO is much more typical than complete obstruction, and postprandial cramps, abdominal distension, borborygmi, and weight loss are common symptoms. To avoid them, many patients restrict the diet to soft foods or even liquids. In case of partial obstruction primarily due to acute inflammation and bowel wall thickening, initial medical therapy is warranted. If, however, the obstructive symptoms are secondary to high-grade fibrostenotic lesions, surgery is indicated because medical treatment will not reverse these lesions.

When complete intestinal obstruction occurs, initial conservative treatment consists of nasogastric decompression and intravenous hydration along with administration of intravenous steroids. This treatment leads to decompression of acutely distended and edematous bowel, and in most cases, to resolution of the complete obstruction. However, even patients with complete resolution of the acute obstruction after the initial conservative treatment are at high risk for recurrent episodes of obstruction and are best managed with elective surgery once adequate decompression and resuscitation is achieved. If the obstruction fails to respond to appropriate conservative treatment, then surgery is required. In these situations, a high index of suspicion for small bowel cancer as the cause of the obstruction is mandatory, as obstructions from cancers do not respond to bowel decompression and steroid treatment.

3. Fistulas

Intestinal fistulas occur in one-third of CD patients. However, the presence of an intestinal fistula is not in and of itself an indication for surgery. In general, it is the primary indication for surgery if the fistula is in connection with the genitourinary tract, or if their drainage causes personal embarrassment and discomfort (enterocutaneous and enterovaginal fistulas), or if a bypass causing intestinal malabsorption is created.

Fistulas can be classified according to anatomic site, characteristics of the tract (simple vs. complex), and volume of output (high vs. low). A low volume output is less than 200 mL/24 h, while a high volume output is more than 500 mL/24 h.

4. Ileosigmoid fistulas

Ileosigmoid fistula is a common complication of perforating CD of the terminal ileum. Typically, the inflamed terminal ileum adheres to the sigmoid colon that is otherwise healthy. Most ileosigmoid fistulas are small and asymptomatic. These ileosigmoid fistulas do not in and of themselves require operative management. On the other hand, large ileosigmoid fistulas can result in bypass of the intestinal contents from the terminal ileum to the distal colon and thus give rise to debilitating diarrhea. Such symptomatic fistulas should be managed surgically, as they often fail to respond to medical therapy.

More than half of the ileosigmoid fistulas from CD are recognized intraoperatively. Ileosigmoid fistulas can be managed by simple division of the fistulous adhesion and resection of the ileal disease. The defect in the sigmoid colon is then debrided and simple closure is undertaken. In about 25% of cases, resection of the sigmoid colon is needed, particularly when primary closure of the fistula is at risk for poor healing. This is the case when either the sigmoid is also involved in CD, when the fistulous opening is particularly large, or when there is extensive fibrosis extending along the sigmoid colon. Also, fistulous tracts that enter the sigmoid colon in proximity to the mesentery can be difficult to close and often require resection and primary anastomosis.

5. Ileovesical fistula

Ileovesical fistulae occur in approximately 5% of CD patients. Although hematuria and fecaluria are virtually diagnostic of ileovesical fistula, these symptoms are absent in almost 30% of cases. Air within the bladder, as noted on CT scan, is often the best indirect evidence for the presence of an enterovesical fistula, while small bowel x-rays, cystogram, and cystoscopy often do not detect the fistula. An ileovesical fistula is an indicator of complex fistulizing disease, as most ileovesical fistulas occur along with other enteric fistulae.

The necessity for surgery for ileovesical fistula is controversial. While it is not mandatory to operate on all cases of enterovesical fistulas, surgery is warranted to avoid deterioration of renal function with recurrent infections or if symptoms persist in spite of appropriate medical therapy.

Surgical treatment of ileovesical fistulae requires resection of the ileal disease with closure of the bladder defect. Most ileovesical fistulas involve the dome of the bladder, and thus debridement and primary closure can be accomplished without risk of injury to the trigone. Decompression of the bladder with an indwelling Foley catheter should be continued postoperatively until the bladder is confidently healed without leaks. A cystogram taken postoperatively is useful to confirm the seal of the bladder repair, before removing the Foley catheter.

6. Enterovaginal and enterocutaneous fistulas

These are rare fistulas caused by perforating small bowel disease draining through the vaginal stump in a female who has previously undergone a hysterectomy or through the abdominal wall, usually at the site of a previous scar. These fistulas often require surgical intervention because they cause physical discomfort and personal embarrassment. Surgical treatment requires resection of the small bowel disease. The vaginal cuff does not need to be closed; the chronic infection along the abdominal wall fistulous tract requires debridement and wide drainage to allow healing by secondary intention.

7. Abscess

Intra-abdominal CD abscesses tend to have an indolent course with modest fever, abdominal pain, and leukocytosis. In up to 30% of cases preoperative clinical signs of localized infection are absent and the abscesses are discovered only at the time of operation. When an abscess is suspected or an abdominal mass is palpated, a CT scan should be obtained, as 50% of tender intra-abdominal masses will harbor an abscess collection within. The CT scan can detect most chronic abscesses and can also delineate the size and location of the abscess as well as the relationship of the abscess to critical structures such as the ureters, duodenum, and the inferior vena cava.

In the majority of cases, abscesses are very small collections contained within the area of diseased small bowel and its mesentery. In the case of small intraloop or intramesenteric abscesses, resection of the involved bowel segment and its mesentery often extirpates the abscess such that drains are not necessary and primary anastomosis can be performed without risk.

Large abscesses are best managed with CT-guided percutaneous drainage. However, abscess drained percutaneously is very likely to recur or result in an enterocutaneous fistula, and surgical resection is often advised even after successful drainage. Such a fistula may spontaneously close or it may persist and the intestine may continue to be a source of sepsis. With successful drainage of the abscess, the sepsis often clears well enough that it can be tempting to try to manage the disease without subsequent surgery. In the absence of symptoms, initial non-operative management after successful percutaneous drainage can be undertaken in carefully selected patients. If drainage through the fistula continues, surgical resection of the affected segment of intestine becomes necessary.

8. Perforation

Free perforation is a rare complication of CD occurring in less than 1% of patients because the chronic progressive inflammation of CD usually leads to adhesions with adjacent structures, and it is an obvious indication for urgent operation with resection of the diseased segment and exteriorization of the proximal bowel as an end ileostomy. The diagnosis of free perforation is made by detecting a sudden change in the patient’s symptoms along with the development of the physical findings of peritonitis or the identification of free intraperitoneal air as demonstrated on plain x-rays or CT scan. The use of immunosuppressants and glucocorticosteroids can blunt many of the physical findings of acute perforation; therefore the index of suspicion for perforation must be higher in immunocompromised patients.

Creation of a primary anastomosis even with a proximal protecting loop ileostomy carries a high risk of anastomotic breakdown and should be avoided. Primary closure of the perforation should never be attempted, as sutures will not be able to approximate the edges of the perforated, edematous, and diseased bowel in a satisfactory and tension-free way and the presence of a distal intestinal stenosis or partial obstruction will cause an increase in the intraluminal pressure at the level of the local repair with subsequent dehiscence.

9. Hemorrhage

Hemorrhage is an uncommon complication from small bowel CD. Angiography in the presence of brisk bleeding leads to localization of the site of bleeding. Bleeding from small bowel tends to be indolent with episodic or chronic bleeding requiring intermittent transfusions, but rarely requires emergent surgery. However, because the risk of recurrent bleeding is high, elective resection of the areas of CD is recommended. Finally, risk for bleeding from peptic ulcer disease is increased in patients, particularly in those receiving corticosteroids.

10. Cancer or suspicion of cancer

The presence of CD increases the risk of adenocarcinoma of the small bowel. The diagnosis of adenocarcinoma of the small bowel is difficult because symptoms and radiographic findings can be similar to those of the underlying CD. Male patients, patients with long-standing disease and patients with defunctionalized segments of bowel appear to be at increased risk for small bowel adenocarcinoma. For this reason, bypass surgery should be avoided for CD of the small intestine and defunctionalized rectal stumps should either be restored to their function or excised.

Adenocarcinoma of the small intestine should be suspected in any patient with long-standing disease whose symptoms of obstruction progress after a lengthy quiescent period.

11. Growth retardation

Growth retardation occurs in a quarter of children affected by CD. Although steroid treatment may delay growth in children, the major cause of growth retardation in CD patients is due to the malnutrition associated with active intestinal disease.

D. Surgical Options

1. Intestinal resection

Intestinal resection with anastomosis is the most common surgical procedure performed for the treatment of small bowel CD. In most cases of CD only limited resections are required with no risk for short bowel syndrome. Only grossly apparent disease should be resected, as wider resections do not improve the surgical outcomes. Grossly normal resection margins with microscopic evidence for CD activity are not associated with early recurrence or other complications. Therefore, intraoperative frozen section of the resection margins is not necessary.

The extent of mesenteric dissection does not affect the long-term results. Division of the thickened mesentery of small bowel CD can be the most challenging aspect of the procedure, as identification and dissection of individual mesenteric vessels is often not feasible. A common technique consists of the application of overlapping clamps on either side of the intended line of transection. The mesentery is then divided between the clamps and the tissue contained within the clamps is suture ligated. In severe cases, a vascular clamp may be used at the root of the small bowel mesentery to obtain proximal control: mattress sutures may then be need to be applied to the cut edge of the mesentery to control bleeding. Even when tissue welding devices such as the LigaSure device are used, mattress sutures in the mesentery are commonly needed for complete hemostasis.

2. Anastomosis

There is no consensus regarding the optimal technique for intestinal anastomosis in CD. Recurrent CD after resection of terminal ileum is most likely to occur at the ileocolonic anastomosis or at the pre-anastomotic ileum. It has been proposed that large caliber anastomoses require a longer period to stricture down to a critical diameter that becomes symptomatic. The argument is made that a longer side-to-side anastomosis may be beneficial over an end-to-end or end-to-side anastomosis. To date, however, clinical data do not indicate a benefit for one particular intestinal configuration over another. Intestinal anastomosis for CD cases can be fashioned with a stapling device or may be hand sutured. Under selective conditions, small bowel anastomotic dehiscence rates is under 1%. In the presence of sepsis, severe scarring, malnutrition, or recent treatment with methotrexate or infliximab, it may be wise to protect the anastomosis with a proximal loop stoma or to forego the anastomosis altogether and bring out an end stoma at the point of resection.

3. Bypass Procedures

Initially conceived to bypass an area of stricture or obstruction, the use of bypass procedures was eventually extended to CD complicated by septic complications. Increased experience with bypass procedures revealed that patients with persistent disease are at higher risk of persistent sepsis, and eventually neoplastic transformation. Therefore, bypass procedures were supplanted by limited intestinal resection as the main surgical option in the late 1960s in all intestinal districts except the duodenum, where a simple side-to-side retrocolic gastrojejunostomy adequately relieves the obstructive symptoms. With increased experience in the performance of strictureplasty, duodenal disease is nowadays more and more commonly handled with strictureplasties.

4. Strictureplasty

Strictureplasties are best performed when resection would otherwise result in loss of a long segment of bowel with an increased risk for short bowel syndrome, including cases of stricturing disease involving long segments of bowel and patients with multiple prior resections. They are also indicated as a simpler alternative to resection in case of short recurrent disease at a previous ileocolic or enteroenteric anastomosis.

There is increased evidence that the acuity of the disease decreases at the site of the strictureplasty and the disease becomes quiescent, maybe in correlation with a simultaneous restoration of absorptive function.

The most commonly performed strictureplasty is the Heinecke–Mikulicz strictureplasty, that is appropriate for short segment strictures of 2-5 cm in length. A longitudinal incision is made along the antimesenteric border of the stricture extending for 1-2 cm into the normal elastic bowel on either side of the stricture. Once the enterotomy is made, the area of the stricture should be closely examined to rule out a malignancy. The longitudinal enterotomy of the Heinecke-Mikulicz strictureplasty is then closed in a transverse fashion with either single- or double-layered sutures.

The Finney strictureplasty can be used for strictures up to 15 cm in length. The strictured segment is folded onto itself in a U-shape, and a row of seromuscular sutures is placed between the two arms of the U. A longitudinal U-shaped enterotomy is then made paralleling the row of sutures. The mucosal surface is examined and biopsies are taken as necessary. In essence, the Finney is a short side-to-side functional anastomosis. A very long Finney strictureplasty may result in a functional bypass with a large lateral diverticulum that, in theory, could be at risk for bacterial overgrowth and the blind loop syndrome. However, this theoretical concern has not been observed in clinical practice.

Repeated Heinecke–Mikulicz or Finney strictureplasties to manage multiple strictures should be separated from each other by at least 5 cm, in order to avoid excessive tension on each suture line.

Patients with long segment stricturing disease and multiple strictures grouped close together are best managed with a side-to-side isoperistaltic strictureplasty, also called Michelassi strictureplasty. The segment of stricturing disease is divided at its midpoint. The proximal and distal ends are then drawn onto each other in a side-to-side fashion. Division of some of the mesenteric vascular arcades facilitates the positioning of the two limbs over each other. The proximal and distal loops are then sutured together with a layer of interrupted seromuscular sutures. A longitudinal enterotomy is then made along both of the loops. The intestinal ends are spatulated to provide a smoothly tailored fit to the ultimate closure of the strictureplasty. The outer suture line is reinforced with an interior row of either interrupted or running full-thickness sutures. This inner suture line is continued anteriorly. The anterior closure is then reinforced with an outer layer of interrupted seromuscular sutures to complete the strictureplasty. In appropriately selected patients, perioperative morbidity from strictureplasty appears to be similar to that of resection and primary anastomosis. Specifically, intestinal suture line dehiscence appears to be uncommon with any of the described strictureplasty techniques. The most common postoperative complication directly related to strictureplasty is hemorrhage from the strictureplasty site, in up to 9% of cases. Usually, the gastrointestinal hemorrhage following strictureplasty is minor and can be managed conservatively with transfusions alone. Rarely, a reoperation to control hemorrhage after strictureplasty is necessary. It is by now also well established that strictureplasty techniques provide excellent long-term symptomatic relief which is comparable to resections with anastomosis.

5. Laparoscopy

Most CD patients are well suited for laparoscopy. They are usually young, otherwise healthy, and interested in undergoing an operation that involves minimal scarring, since they are facing the risk of multiple major abdominal operations in their lifetime.

The indications for laparoscopic surgery for CD should not differ from conventional open surgery as described before. Contraindications to a laparoscopic approach include patients who are critically ill and unable to tolerate the pneumoperitoneum due to hypotension or hypercarbia, patients with extensive intra-abdominal sepsis (abscess, free perforation, or complex fistula), and difficulty in identifying the anatomy (previous surgery, obesity, or adhesions). The same variety of surgical procedures described earlier can be performed laparoscopically.

Primary CD of the duodenum almost always manifests with stricturing disease that can be managed by strictureplasty or with bypass procedures, while resection of the duodenum for CD is almost never required. When CD fistulas involve the duodenum, it is always the result of disease within a distal segment of the small bowel that fistulizes into an otherwise normal duodenum. Heinecke–Mikulicz strictureplasties can be safely performed in the first, second, and proximal third portion of the duodenum, while strictures of the last portion of the duodenum are better handled with a Finney strictureplasty constructed by creating an enteroenterostomy between the fourth portion of the duodenum and the first loop of the jejunum.

If the duodenal stricture is lengthy or the tissues around the stricture are too rigid or unyielding, then a strictureplasty should not be performed and an intestinal bypass procedure should be undertaken. The most common bypass procedure performed for duodenal CD is a side-to-side retrocolic gastrojejunostomy. This procedure effectively relieves the symptoms of duodenal obstruction related to CD strictures, but carries a high risk for stomal ulcerations. To lessen the likelihood of ulcerations forming at the anastomosis, it has been recommended that a selective vagotomy be performed along with the gastrojejunostomy in order to reduce the risk of vagotomy-related diarrhea. If only the third or fourth portions of the duodenum are involved by the structuring CD, a Roux-en-Y duodenojejunostomy to the proximal duodenum is preferred over a gastrojejunostomy, having the Roux-en-Y duodenojejunostomy the advantage of bypassing strictures and eliminating the risk of acid-induced marginal ulceration and the need for vagotomy.

Most of these duodenal fistulas are small in caliber and asymptomatic, but larger fistulas may shunt the duodenal contents to the distal small bowel resulting in malabsorption and diarrhea. In most cases, duodenoenteric fistulas are identified with preoperative small bowel radiography; however, many are discovered only intraoperatively. Most duodenal fistulas are located away from the pancreatico-duodenal margin, and thus these fistulas can be managed by resection of the primary CD with primary closure of the duodenal defect. In case of larger fistulas or fistulas that are involved with a large degree of inflammation closure with a Roux-en-Y duodenojejunostomy or with a jejunal serosal patch may be required.

Prognosis

The risk for recurrence after surgery is high in CD patients. Most cases of histological or endoscopically detected recurrences, however, do not produce symptoms of CD. For this reason, histological or endoscopic evidence of recurrent disease are not typically used as a guide for clinical management.

The development of symptoms related to recurrent CD activity is the most commonly applied definition of disease recurrence, as it is the recurrence of symptoms that has the most relevance to the patient. The onset of symptoms of recurrent CD is often insidious and the severity of symptoms varies greatly. A CD Activity Index (CDAI) greater than 150 is generally accepted as defining clinical recurrence. Once symptoms suggestive of recurrent disease occur, it is necessary to carry out radiological and endoscopic tests to confirm that the symptoms are in fact related to CD.

The clearest end point as a definition of recurrence is the need for reoperation. While reoperation is the most precise definition of recurrence, even this standard does not allow for accurate and reproducible comparisons between series, as some centers may submit patients to surgery earlier than other centers.

Reported crude and cumulative recurrence rates vary greatly. Symptomatic recurrence occurs in about 60% of patients at 5 years and recurrences increase with time such that at 20 years clinical recurrence can occur in between 75% and 95% of cases. Reports of surgical recurrence rates range from 10% to 30% at 5 years, from 20% to 45% at 10 years, and from 50% to 70% at 20 years. Recurrent CD is most likely to occur in proximity to the location of the previously resected intestinal segment, typically at the anastomosis and preanastomotic bowel, in particular in case of terminal ileal disease. Additionally, the length of small bowel involved with recurrent disease parallels the length of disease originally resected. Also, to a lesser degree of concordance, stenotic disease tends to recur as stenotic disease and perforating disease tends to recur as perforating disease.

While many factors that may influence the risk of recurrence have been studied, the cumulative literature has validated very few as true risk factors. Cigarette smoking has a significant effect on the clinical course of CD. Smoking not only exacerbates existing CD, but also has been identified as a risk factor for the development of CD, and for endoscopic, symptomatic, and surgical recurrence. While the mechanism by which smoking results in exacerbation of CD is not known, the risk from smoking appeared to be dose-related with heavy smokers being at higher risk, and reversible. There is concern that NSAIDs may exacerbate the activity of both ulcerative colitis and CD, but there are not conclusive data.

The risk for recurrent disease can be reduced with postoperative maintenance therapy. The most common agents are controlled-release 5-aminosalicylic acid and 6-­mercaptopurine. Maintenance with 5-ASA is associated with few side effects, but up to sixteen pills have to be taken daily. 6-Mercaptopurine is less expensive and is taken on a once-daily basis. Additionally, 6-MP may be more effective in diminishing the risk of recurrence. 6-MP, however, is associated with potential bone marrow suppression, so that patients on 6-MP maintenance must be followed with periodic blood cell counts.

General Considerations

Fistulas are an abnormal connection between two epithelial lined organs and while enterocutaneous fistulas (ECF) may form spontaneously as a result of disease, about 80% are complications of surgical procedures (anastomotic dehiscence or injury to bowel during dissection). Fistulas are particularly prone to develop when the surgeon encounters extensive adhesions, inflamed intestine, radiation enteritis, a malnourished patient, or emergency procedures.

Clinical Findings

A. Symptoms and Signs

Postoperative fistula formation is heralded by fever, abdominal pain, and distention. Frequently a wound infection is recognized and drained 7-10 days postoperatively with subsequent discharge of enteric contents through the abdominal incision. Spontaneous fistulas from neoplasms or inflammatory disease usually develop in a more indolent manner. ECF are often associated with abscesses, which often drain incompletely with fistulization, so that persistent sepsis is a common feature. Intestinal fluid escaping through the fistula may severely excoriate the skin and abdominal wall tissues. Persistent sepsis and difficulty in nourishing the patient contribute to rapid weight loss.

B. Laboratory Findings

Routine laboratory tests reflect the severity of deficits in red cell mass, plasma volume, and electrolytes. Hypokalemia is the most common electrolyte abnormality. Ongoing losses may be significant especially with high output fistulas necessitating serial measurement of serum electrolytes. Leukocytosis due to sepsis and hemo-concentration is common.

C. Imaging Studies

The goals of imaging are to detect concurrent abdominal pathology and to characterize the fistula. Contrast studies with contrast medium administered orally, per rectum, or through the fistula (fistulogram) delineates the abnormal anatomy, including intrinsic bowel disease, and demonstrates the location and number of fistulas, the length and course of fistula tracts, associated abscess cavities, and the presence of distal obstruction. Radiologists can manipulate catheters into tracts and provide detailed diagnostic information; this procedure may also be therapeutic (see later). CT scans, endoscopy, and other special studies may be indicated in certain individuals.

Complications

Fluid and electrolyte losses, malnutrition, and sepsis contribute to multiple-organ failure and death unless effective therapy is instituted promptly.

Treatment

The initial management of an ECF involves recognition of the fistula, control of sepsis, resuscitation, local wound care, and nutritional optimization. A systematic approach combining diagnostic, supportive, and operative procedures is essential in the management of patients with fistulas (Table 29–2). The proper timing of intervention is as critical in few other conditions.

A. Fluid and Electrolyte Resuscitation

Many fistula patients are profoundly depleted of intravascular and interstitial volume especially if the fistula is large, if it is proximal, or if there is partial or complete intestinal obstruction distal to the fistula and correction of hypovolemia and electrolyte imbalances are the first priority. Central venous pressure, urine output, and skin turgor are guides to the progress of volume resuscitation. Fluid and electrolyte resuscitation can usually be accomplished within the first day or two. Subsequent maintenance of homeostasis depends on accurately measuring losses and replacing them.

B. Control of Fistula

Fistulous effluent must be collected to avoid excoriation of skin and abdominal wall tissues and to record volume losses. An ostomy appliance or pouch should be placed around the fistula and needs to be tailored based on the characteristics of the fistula. Alternatively, a catheter inserted by a radiologist under x-ray guidance may work best. In selected cases, a vacuum-assisted wound management device can be used to control fistula drainage and accelerate closure of the fistula. The assistance of a skilled and experienced wound care and/or enterostomal nurse is indispensable.

C. Control of Sepsis

Abscesses should be drained as soon as they are diagnosed. While therapy with broad-spectrum antibiotics may be necessary to control infection, is not a substitute for proper management of abscesses. Most contained abscesses can be drained percutaneously with CT or ultrasound guidance. Drainage catheters should be left in place until the abscess cavity has resolved which can be confirmed with a drain study once drainage has ceased. A drain study can also demonstrate the presence of persistent communication between the small bowel and the fistula. Free drainage of enteral contents into the abdominal cavity will likely cause peritonitis necessitating an emergent laparotomy.

D. Delineation of Fistula

Radiographic contrast studies (mentioned previously) should be obtained as soon as feasible.

E. Nutrition

Adequate nutrition and control of sepsis make the difference between survival and death for these patients. A useful general rule is to avoid oral intact during the initial stage of treatment. Nasogastric suction may be necessary temporarily. As soon as fluid, electrolytes, and vitamin abnormalities are corrected, parenteral nutrition should be instituted via a central intravenous catheter.

For many patients, total parenteral nutrition is the principal exogenous source of calories and nitrogen until the fistula heals or is closed surgically. For patients with low-output or distal fistulas, the enteral route for nutrition is preferred, and elemental or polymeric diets can be delivered into the distal gut in some patients with proximal fistulas.

F. Other Measures

H2 receptor antagonists and proton pump inhibitors are useful adjuncts in patients with proximal fistulas. By reducing gastric acid secretion, fistula output is decreased and fluid and electrolyte management is simplified. Somatostatin analogs decrease fistula output and may accelerate fistula closure.

G. Operation

About 30% of fistulas close spontaneously with proper medical management. CD, irradiated bowel, cancer, foreign body, distal obstruction, extensive disruption of intestinal continuity, and a short (< 2 cm) fistula tract are associated with failure of fistulas to heal. Fibrin glue has been effective in some small bowel fistulas; in particular, it may be considered in complicated patients with a history of a hostile abdomen. Treatment may be successful if the fistula is long and the output is low. If they are going to heal spontaneously, fistulas usually close within 5-6 weeks after eradication of infection and institution of adequate nutritional support. Patients who fail 6 weeks of nonoperative management will often require surgical intervention. Serum levels of short-turnover proteins, particularly transferrin, might be useful in predicting which patients are unlikely to close their fistulas. The operation should be postponed, however, until one can predict that the phase of dense adhesions associated with ECFs has resolved and nutrition is optimized typically at least 3 months after the last operation. The fistulous segment should be resected, associated obstruction relieved, and continuity reestablished by a functional end-to-end anastomosis.

Prognosis

The plan of management outlined earlier results in survival rates of 80%-95% in patients with external fistulas. Uncontrolled sepsis is the chief cause of death.

The normal concentration of bacteria in the small intestine is about 105/mL. Mechanisms that limit bacterial populations include the continual flow of luminal contents, gastric ­acidity, local effects of immunoglobulins, and the prevention of reflux of colonic contents by the ileocecal valve. Disturbance of any of these mechanisms can lead to bacterial overgrowth and blind loop syndrome. Strictures, diverticula, fistulas, and defunctionalized segments of bowel allow bacterial proliferation.

This entity is rare and clinical manifestations include steatorrhea, diarrhea, abdominal pain, vitamin deficiency, neurologic symptoms, anemia, and weight loss. Steatorrhea is the consequence of bacterial deconjugation and dehydroxylation of bile salts in the proximal small bowel. Deconjugated bile salts have a higher critical micellar concentration, and micelle formation is inadequate to solubilize ingested fat in preparation for absorption. The presence of partially digested triglycerides in the distal ileum inhibits jejunal motility; nevertheless, the unabsorbed fatty acids enter the colon, where they increase net secretion of water and electrolytes, and diarrhea results. Hypocalcemia occurs because calcium is bound to unabsorbed fatty acids in the intestinal lumen. Macrocytic anemia is secondary to malabsorption of vitamin B₁₂, largely because it is consumed by anaerobic bacteria. Vitamin B₁₂ deficiency also causes neurologic symptoms due to demyelination of the posterior and lateral spinal columns. Malabsorption of carbohydrate and protein is due partly to bacterial catabolism and partly to impaired absorption of these nutrients because of direct damage to the small intestinal mucosa. All of these mechanisms contribute to malnutrition.

Quantitative culture of upper intestinal aspirates is valuable if properly performed; bacterial counts of more than 10⁵/mL are generally abnormal. Endoscopic biopsies of the duodenum can be helpful in patients with suspected small intestinal malabsorption. Laboratory studies reveal impaired absorption of orally administered vitamin B₁₂ (Schilling test), D-xylose, and ¹⁴C triolein.

Surgical treatment of the underlying disease is carried out whenever possible. If there is no a surgical cause of blind loop syndrome, treatment consists of broad-spectrum antibiotics and medications to control diarrhea. It may be necessary to use different antibiotics in sequence, guided by culture results and response to therapy. Damage to enterocytes appears to be reversible with treatment. Octreotide (somatostatin analog) may reduce bacterial overgrowth and improve abdominal symptoms in patients with scleroderma, according to a recent report.

General Considerations

Acute mesenteric ischemia (AMI) is a life-threatening clinical condition if not diagnosed promptly and treated adequately. Despite diagnostic and therapeutic advances, morbidity and mortality associated with AMI remains high. A high index of suspicion for this disease is essential since the clinical presentation is often nonspecific. AMI results from four main processes: (1) arterial embolism (50%) most commonly in patients with previous myocardial infarction or atrial fibrillation; (2) acute arterial thrombosis (25%) in patients with diffuse atherosclerosis or less frequently with connective tissue disorders; (3) nonocclusive mesenteric ischemia (20%); and (4) venous thrombosis (5%) associated with portal hypertension, abdominal sepsis, hypercoagulable states, or trauma.

The clinical consequences of acute arterial or venous mesenteric ischemia depend on several factors, including the vessel involved, the level of occlusion, the development of collaterals, and reperfusion. Tissue injury caused by the ischemic event compromises the immune and barrier functions of the small bowel, allowing bacterial translocation, cellular degradation, reactive oxygen species formation in case of reperfusion and intravascular thrombosis. The release of these products into the portal system and the systemic circulation initiates a cascade of events leading to damage of targets organs such as the lungs and kidneys.

A. Symptoms and Signs

The clinical presentation is nonspecific.

Patients with arterial embolism initially present with sudden-onset diffuse abdominal pain that is out of proportion to the clinical examination and often unresponsive to narcotics. The lack of well-developed collaterals causes ischemia which eventually becomes transmural. As ischemia worsens, patients develop nausea and vomiting, bloody diarrhea, and eventually peritonitis.

Patients with acute thrombotic mesenteric occlusion also present with severe abdominal pain, but it is usually chronic postprandial abdominal pain (intestinal angina) accompanied by weight loss.

With cardiogenic or hypovolemic shock, blood is shunted away from the mesenteric circulation and this process is exacerbated by the following local vasoconstriction. Pain in patients with nonocclusive mesenteric ischemia is usually not as sudden as that with embolic or thrombotic occlusion. Moreover, pain is more difficult to assess because many of these patients are hospitalized in intensive care units for life-threatening conditions.

Patients with venous thrombosis commonly complain of nausea, vomiting, diarrhea, and non-localized abdominal pain.

B. Laboratory Findings

There are no laboratory tests that are diagnostic for AMI. In most cases, the white blood cell count is elevated, as are lactic acid, amylase (50% of patients), and creatine kinase (BB isoenzyme) levels correlating with intestinal infarction. Significant metabolic acidosis is usually present.

C. Imaging Studies

Abdominal radiographs are not diagnostic, but can reveal late signs consistent with bowel ischemia, such as gas in the bowel wall or the portal venous system, and free air in the peritoneum.

Duplex ultrasonography plays a limited role in the diagnosis of AMI, given accompanying ileus with air and gas-filled loops of bowel. Moreover, it cannot assess distal mesenteric blood vessel flow and nonocclusive etiology of ischemia.

Angiography is considered the gold standard for diagnosis for acute embolic and acute thrombotic arterial mesenteric ischemia. Angiography should include both AP and lateral views of the celiac artery, the SMA and the inferior mesenteric artery. By selective injection of contrast into the SMA, emboli and thrombi can be identified, whereas patients with nonocclusive mesenteric ischemia typically exhibit evidence of SMA vasospasm. During the same procedure, catheters can be positioned selectively for treatment. Angiography is significantly less useful for the diagnosis of mesenteric venous thrombosis compared to CT scan.

Both CT and magnetic resonance angiography (MRA) have undergone significant advances over the past 10 years. Multislice helical CT scan with three-dimensional spatial resolution of the vascular anatomy allows rapid evaluation of atherosclerosis of the aorta and mesenteric vessels, the status of the small bowel wall, and identifies other causes of abdominal pain, such as pancreatitis, bowel perforation, bowel obstruction, and rupture of abdominal aortic aneurism. Nevertheless, it still has some limitations: while the origins of the main abdominal vessels are well-visualized, secondary, tertiary, and smaller branches are less well defined compared to angiography. On the contrary, CT is diagnostic for venous thrombosis and is the preferred diagnostic imaging modality in patients with a suspected mesenteric venous thrombosis.

One of the main advantages of MRA has is the use of gadolinium which is significantly less nephrotoxic than the contrast utilized for CT scan. However, this diagnostic imaging modality is not widely used due to the lack of access in many institutions.

Differential Diagnosis

Acute pancreatitis, intestinal obstruction, aortic dissection, and cholecystitis are the most frequent pathologies that mimic the clinical presentation of AMI.

Treatment

Once the diagnosis is made, fluid resuscitation, antibiotics, and anticoagulants or drugs that inhibit platelet aggregation should be started.

The treatment consists of nonsurgical and surgical options depending on the underlying cause.

The goals of surgery are to restore blood flow when feasible and resect the segments of bowel that are no longer viable. Because the appearance of ischemic bowel may improve dramatically after restoring blood flow, the small bowel should be observed for at least 30 minutes after reperfusion before any decision for resection is undertaken.

For acute SMA embolism, the standard treatment is a laparotomy and embolectomy, with a catheter passed under direct vision into the arterial segment in order to dislodge and retrieve the embolus. Nonsurgical treatments include catheter-directed thrombolytic therapy to treat early acute embolic occlusion in selected patients who present with a partially occluding embolus in the SMA and do not exhibit peritoneal signs on physical examination.

Surgical treatment of acute thrombotic mesenteric occlusion consists of an antegrade or retrograde bypass because a simple thrombectomy usually leads to reocclusion, Revascularization with saphenous vein or prosthetic graft (in the absence of peritonitis) is the most common procedure. Angioplasty can be performed during diagnostic angiography to dilate stenotic lesions; however, clinical findings suspicious for peritonitis frequently make a laparotomy necessary.

In case of nonocclusive mesenteric ischemia, the treatment requires reversal of the underlying causes of the hypoperfusion. Local infusion of vasodilators using selective catheterization of the SMA may also play a role.

Treatment of mesenteric venous thrombosis is nonsurgical and relies on anticoagulation to reverse the hypercoagulable state. Full anticoagulation with heparin is needed with careful monitoring for gastrointestinal bleeding. Long-term oral or subcutaneous anticoagulation therapy is then begun. Exploratory laparotomy is mandatory when clinical conditions worsen and bowel infarction is suspected.

Finally, second-look laparotomy within 24-48 hours is a key point in the management of patients with AMI who require extensive bowel resection during the first operation or have areas of marginally viable bowel after revascularization.

Prognosis

The prognosis of AMI is poor because diagnosis and treatment are often delayed, infarction is extensive, and arterial reconstruction is difficult. Perioperative mortality rates range from 32% to 69%, and 5-year survival ranges from 18% to 50%. Mortality varies substantially according to the cause of AMI, being lower in cases of venous thrombosis than in cases of arterial origin. The only way to reduce the morbidity and mortality associated with this disease is early diagnosis and treatment, before bowel necrosis develops.

General Considerations

Maintenance of adequate nutrition is dependent on the normal digestive and absorptive function of small bowel mucosa. A normal, healthy adult possesses an excess of gut mucosa such that limited resection is well tolerated. However, this depends on the amount of bowel removed and the specific level of resection, the presence or absence of the colon, the absorptive function of the intestinal remnant, adaptation of the remaining bowel, and the nature of the underlying disease process and its complications (Figure 29–5). Symptoms can ensue following surgery, in some cases leading to a condition known as “short bowel syndrome.” Because of the important functional capacities of the duodenum in iron and calcium absorption, and of the distal ileum in regard to vitamin B₁₂ and bile salts, resections of these specific regions tend to be poorly tolerated. In contrast, up to 40% of the mid-small bowel can be removed with only moderate clinical sequelae. As a general rule, resection of 50% of the small bowel produces significant malabsorption, and if 70% or more of the bowel is resected, survival is threatened. Clinical results in treating short bowel syndrome have improved in recent decades due to recognition of its pathophysiology, improved surgical techniques, and better enteral and parenteral nutritional support.

The most common etiology of short bowel syndrome is a massive resection occurring in the setting of AMI. In children, volvulus of the intestine caused by congenital malrotation can also result in the need for a large resection. Less commonly, patients with neoplasms, trauma, or recurrent Crohn disease develop short bowel syndrome.

The minimal amount of small bowel required to sustain life is variable, but in general survival is threatened in patients with less than 60 cm of intestine beyond the duodenum. Patients with short bowel syndrome have impairment in the absorption of water and electrolytes as well as that of all nutrients (fat, protein, carbohydrates, and vitamins). The colon is vitally important for preventing water loss. In addition, the colon plays an important role in nutrient assimilation by absorbing short-chain fatty acids. The ileocecal valve delays transit of enteric content from the small bowel into the colon, thereby prolonging the contact time between nutrients and the small bowel absorptive mucosa.

Important adaptive changes occur in the remaining intestine following massive resection. In addition to mucosal hyperplasia, there is generally seen to be an increase in the caliber of the remaining small bowel, perhaps adding to the absorptive area. From a functional point of view, the amount of fluid and electrolytes losses following massive resection decrease over time, whereas glucose absorption increases.

Short bowel syndrome is associated with gastric hypersecretion that persists for 1-2 years postoperatively, likely related to loss of the “ileal brake,” a mechanism by which luminal fat within the distal small bowel inhibits gastric secretion. The increased acid load delivered to the ­duodenum inhibits absorption by a variety of mechanisms, including the inhibition of digestive enzymes, most of which function optimally under alkaline conditions. Loss of the terminal ileum also results in impairment in the absorption of conjugated bile salts and fat. With limited ileal resections, an increase in the bile salt load to the colon can cause direct injury to the mucosa and resultant diarrhea. With an ileal resection greater than 100 cm, there is a gradual loss in the total bile salt pool, eventually leading to impairment in fat absorption and the onset of steatorrhea. Ileal resections are also associated with lithogenic bile, such that gallstone formation is seen in approximately 30% of patients who have undergone such surgery. Calcium oxalate urinary tract calculi form in 7%-10% of patients who have extensive ileal resection and an intact colon, due to excessive absorption of oxalate from the colon.

Treatment

Initial therapy involves maintenance of fluid and electrolyte balance. Total parental nutrition is often indicated and, depending on the extent of resection, may be required throughout the lifetime of the patient. It is likely that even small amounts of enteral nutrition are beneficial; however, because the luminal nutrients appear to enhance the adaptive response of the remaining gut. Various antidiarrheal and stool-bulking agents have also been used with some benefits. Gastric hypersecretion should be treated with either H2-blockers or proton pump inhibitors. Cholestyramine may be beneficial in patients with limited ileal resections, but if the bile salt pool has been depleted, then cholestyramine is contraindicated. The efficacy of intensive medical management, including maintenance of oral hydration, along with a combination of a high-fiber diet, growth hormone and glutamine is controversial.

The surgical treatment of patients with short bowel syndrome has been disappointing. Various procedures including intestinal lengthening, reversal of short segments, and placation of excessively dilated bowel have been attempted. Although some improvement has been seen in isolated cases, such operations are not widely performed. The results of small bowel transplantation have also been disappointing because of the high rate of rejection. However, more recent experience with small bowel transplantation suggests that this may become a viable surgical alternative in patients with short bowel syndrome.

General Considerations

Small bowel diverticular disease is an uncommon clinical entity. However, with progressive aging of the general population, small bowel diverticulosis is encountered more often. Overall, the frequency reported in the literature of small bowel diverticula varies with the anatomic location of the disease and the type of investigation used for diagnosis. Clearly, autopsy series report a higher incidence, since small bowel diverticulosis is usually asymptomatic and is found often upon post mortem examination only.

A. Etiology

Diverticular disease of the small bowel is generally classified into two groups: the more common, acquired form and the congenital form which is somewhat rare, other than Meckel’s diverticulum in the distal ileum. Primary acquired small bowel diverticula result from the herniation of the mucosa and submucosa through the muscular layer of the bowel wall. These lesions are considered to be false diverticula, with no muscular wall covering. Patients with small bowel diverticula frequently have associated diverticular disease of the colon, diverticula of the esophagus (2%), stomach (2%), or urinary bladder (12%).

In the pathogenesis of small bowel diverticulosis, abnormalities of the myenteric plexus with consequent motor dysfunctions of the small intestine are thought to play a major role. These motility disorders vary in severity and magnitude from localized dysmotility to universal jejunoileal dyskinesia that result in increased intraluminal pressure and ultimately herniation of the mucosa and submucosa through the muscular wall of the small bowel. Usually, diverticula occur where the paired blood vessels penetrate the small bowel wall at the mesenteric site.

In contrast, congenital diverticula are usually considered true diverticula involving the full thickness of the small intestine. Congenital diverticula are often limited to the duodenum (wind-sock diverticulum) and ileum (Meckel diverticulum). Both acquired and congenital diverticula are usually asymptomatic, however, symptoms can originate from small bowel diverticula owing to diverticulitis, perforation, obstruction, or hemorrhage.

B. Duodenal Diverticula

Acquired diverticula are extra-luminal and are a fairly common incidental finding usually visualized either upon esophagogastroduodenoscopy (EGD), endoscopic retrograde cholangiopancreatography (ERCP), or by barium swallow and small bowel follow through. Incidences vary significantly in the literature depending on the diagnostic modality used. In the ERCP literature, incidences up to 23% have been reported, usually increasing with advancing age.

In terms of location, these diverticula are generally located within 2 cm of the ampulla. This is an area of weakening of the duodenal wall mucosa, especially around the papilla of Vater, due to the configuration and orientation of the smooth muscle fiber and the sphincter mechanism of Oddi. If the papilla is involved or included in these diverticula, sphincter dysfunction may lead to biliary dyskinesia, formation of biliary stones, cholangitis, and even pancreatitis. Acquired diverticula are also present in the third and fourth portion of the duodenum with decreasing frequency.

Usually, these diverticula are asymptomatic. Symptoms, when present, often are caused by either dysfunction of the sphincter of Oddi or, when the diverticula are significantly large, by obstruction of the biliary and pancreatic ducts due to external compression. Recurrent episodes of pancreatitis potentially evolving into chronic pancreatitis and formation of biliary stones have been reported in patients with large duodenal diverticula. Furthermore, large diverticula can cause bacterial overgrowth resulting in malabsorption and anemia. Diverticulitis with potential perforation and bleeding from duodenal diverticula has been reported.

Diagnosis is often obtained by EGD or ERCP. An upper GI with a small bowel follow through is also very helpful in localizing the diverticula and in defining the size of it. When a perforation is suspected, CT scan of the abdomen with oral and IV contrast can accurately define the location of the diverticula and the extent of the inflammatory reaction to the diverticular perforation.

Surgical treatment of duodenal diverticula is complicated by significant morbidity and mortality, therefore a prophylactic resection of an asymptomatic duodenal diverticulum is not routinely recommended. In the presence of perforation or bleeding, a generous Kocher maneuver should be performed in order to identify the posterior aspect of the duodenum. It is very important at this stage of the procedure to have a clear idea of the relationship of the biliary and pancreatic ducts with the ampulla in order to avoid an injury that will be extremely difficult to repair in this setting and location. If the pancreatic and biliary structures are not involved with the diverticulum, in the absence of significant retroperitoneal contamination, a primary excision of the diverticulum is indicated. The resulting defect should be closed in two layers using absorbable suture for the inner layer and non-absorbable suture for the outer layer. With a large duodenal defect, a serosal patch technique using a defunctionalized loop of jejunum is a useful alternative. However, in the presence of significant edema and contamination, primary closure around a T-tube with drainage of the surrounding area may be the only solution. In extreme cases, duodenal diverticulization by gastrojejunostomy with a stapled closure of the pylorus may be necessary. A large diverticulum in the third or fourth portion of the duodenum requires mobilization of the distal duodenum with excision and primary closure. In this area, the relationship with the biliary and pancreatic duct is not obviously as crucial and therefore, a more aggressive approach can be undertaken.

C. Jejunoileal Diverticula

The acquired forms of jejunoileal diverticula are usually more common in the proximal jejunum decreasing in frequency throughout the small bowel. Extreme forms of diffuse diverticulosis of the small bowel have been reported. It is a disease of advanced age and is prevalent during the seventh decade of life. These diverticula are located on the anti-mesenteric border of the small bowel. Due to primary motility disturbances of the small intestine, these patients usually present with chronic abdominal pain, early satiety, and different gastrointestinal conditions, such as diarrhea, malabsorption, steatorrhea, Vitamin B₁₂ deficiency, and anemia. These patients can present with an acute abdomen in the presence of a free perforation secondary to diverticulitis. Bleeding is also one of the possible complications and localization of the bleeding diverticulum, in the presence of diffuse diverticulosis may present a significant diagnostic challenge to the clinician.

Jejunoileal diverticula are usually identified by small bowel follow-through or enteroclysis. CT scan can help in the diagnosis of large diverticula or in the presence of acute diverticulitis or perforation. More recently, the use of capsule or wireless endoscopy has helped the clinician in diagnosing patients with unclear gastrointestinal symptoms and especially patients with recurrent significant GI bleed secondary to diverticular disease. After the initial experimental papers, several human studies, looking at patients with occult gastrointestinal bleeding, have shown capsule endoscopy to be significantly superior to push enteroscopy and preferred by patients undergoing both procedures. Although small bowel diverticular disease is a rare condition, it may be the cause of a lower GI bleed resulting in a diagnostic dilemma. In the presence of acute significant bleeding, angiography should be attempted for localization of the bleeding diverticulum and possible treatment either by vasopressin injection or, in selected cases by super selective embolization. Injection of methylene-blue to help identifying the bleeding diverticulum at the time of exploration is very helpful technique when the bleeding persists despite medical management.

Asymptomatic jejunoileal diverticula are usually treated conservatively. In the presence of localized segments of multiple diverticula, it has been suggested that a resection, even in the absence of symptomatology, might be indicated because the morbidity from a small bowel resection nowadays is much less than the potential complication from acute diverticulitis. This approach has not been validated by any clinical data thus far. In the presence of diverticulitis and perforation, obviously resection and primary anastomosis is indicated. In the presence of bleeding, if the source is localized by either angiography or capsule endoscopy, the bleeding site should be resected with primary anastomosis. Laparoscopy has been extensively used in the management of this unusual problem.

General Considerations

Although the small bowel accounts for 75% of the gastrointestinal length and 90% of its absorptive surface, neoplasms of this organ, both benign and malignant, are relatively rare. They represent less than 10% of all gastrointestinal tumors, 1%-3% of gastrointestinal malignancies and 0.4% of all malignancies.

In recent years, the incidence of two small bowel tumors, lymphomas, and gastrointestinal stromal tumors (GIST), have increased substantially. In the case of primary small bowel lymphoma, the incidence in the United States has nearly doubled in the last two decades, due to the increased numbers of immunocompromised patients and immigrants from developing countries. In the case of GIST, the recognition of the KIT protein (CD117) has changed the way spindle cell tumors of the gastrointestinal tract are classified and has led to an increased awareness and recognition.

Several predisposing conditions associated with small bowel malignancies have been identified: CD, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, blind loop syndrome, Peutz–Jeghers syndrome, celiac sprue, neurofibromatosis, and IgA deficiency.

The disproportion between the low incidence of malignant tumors of the small bowel and the size of its surface area suggests a significant sparing from or resistance to the development of malignancy. Several hypotheses, based on experimental animal models, have postulated that carcinogens in the enteric content may be in contact with small bowel mucosa over a limited time due to the relatively rapid transit time or may be in a diluted and less carcinogenic form. The preponderance of small bowel adenocarcinomas in the duodenum suggests a role for bile or pancreatic secretions either as primary small bowel carcinogens or even as simple vectors for unknown carcinogens.

Other specific characteristics of the small bowel microscopic and chemical environment might be responsible for the observed cancer resistance. The limited and metabolically inactive bacterial flora of the small bowel is likely unable to transform procarcinogens into their active metabolites especially in an alkaline milieu. In addition, the proximal small bowel secretes a number of enzymes that detoxify carcinogens.

Finally the presence of a high concentration of B cells and lymphocytes and high amounts of secretory IgA in the distal small bowel might constitute an effective local immunosurveillance system that prevents carcinogenesis. This theory seems to be supported by the observation that immunocompromised patients have an increased incidence of lymphoma and Kaposi’s sarcoma of the distal small bowel.

Dietary risk factors, such as high caloric dietary intake in general and more specifically consumption of red meat, fat, and salt-cured smoked foods have been shown to increase the incidence of small bowel carcinoma in large population based studies. This similarity in risk factors explains the relatively high risk of synchronous or metachronous colorectal cancer in patients with a known small bowel malignancy.

Pathology

Approximately one-third of primary small bowel neoplasms are benign and two-thirds are malignant. The most common benign tumors are leiomyomas and adenomas; less common lesions include inflammatory polyps, hemangiomas, lipomas, hamartomas (Peutz–Jeghers syndrome), and fibromas. These tumors can occur throughout the small bowel but tend to increase in frequency from proximal to distal, with the exception of adenomas, which occur with the highest frequency in the duodenum.

Adenomas are the most common benign tumors of the small intestine. The duodenum is the most common site of involvement, and the lesion most commonly noted is a villous adenoma. These lesions tend to involve the region of the ampulla of Vater. They may present with obstructive jaundice and are easily diagnosed by upper endoscopy and biopsy. Up to 30 percent of these tumors may have malignant degeneration. The risk of malignant degeneration in a significant proportion of patients poses challenges to treatment planning.

Leiomyomas arise from smooth muscle and can grow both intra- and extraluminally. They can often become very large before causing symptoms. On gross inspection, it is sometimes difficult to distinguish these lesions from their malignant counterparts. This distinction is made histologically with standard criteria including nuclear pleomorphism, increased mitosis and the presence of necrosis although, at times, even histological examination may fail to unequivocally distinguish between benign and malignant histology.

Malignant tumors tend to increase in frequency from proximal to distal, with the exception of adenocarcinomas which are most frequent in the duodenum. Adenocarcinoma is the most common histologic type (45%), followed by carcinoids (30%), lymphomas (15%), sarcomas, and GISTs (10%). Pathologic staging is performed according to the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) system.

Most small bowel adenocarcinomas are solitary, sessile lesions, often appearing in association with adenomas. They are usually moderately to well differentiated and almost always positive for acid mucin. Most arise in the duodenum: within the duodenum, 15% of these tumors are located in the first portion, 40% in the second portion, and 45% in the distal duodenum. Most of these tumors are sporadic with the exception of the ones originating in the context of familial adenomatous polyposis. Presenting symptoms include epigastric and abdominal pain or discomfort, and possibly jaundice and gastric outlet obstruction, depending on the location of the tumor. These symptoms and the accessibility of the duodenum and proximal small bowel to endoscopic modalities allow a relatively high rate of diagnosis and resectability.

Carcinoid tumors are the most common endocrine tumors of the gastrointestinal system.

In the small bowel itself, carcinoids are the most common distal small-bowel neoplasm. These neoplasms arise from enterochromaffin cells and are characterized by the ability to secrete many biologically active substances, including serotonin, bradykinin, dopamine, histamine, and 5-hydroxyindoleacetic acid (5-HIAA). They tend to be small (< 2 cm) and submucosal in location, with a propensity for multicentricity. The most common classification for these tumors is based on embryologic derivation: foregut (stomach and pancreas), midgut (small bowel 90% or more), and hindgut (colon and rectum). Their presentation depends largely on the hormones elaborated and on the site of origin. Up to 40% of small bowel carcinoids are associated with a second gastrointestinal malignancy and 30% present as multiple synchronous lesions.

The gastrointestinal tract is the most frequent site of extra nodal lymphoma: the stomach is the most common site followed by the small bowel and the colon, respectively; within the small bowel, lymphomas parallel the distribution of lymphoid follicles, resulting in the ileum being the most common site of involvement. These tumors may be primary or secondary as a manifestation of generalized involvement of systemic lymphoma. For the diagnosis of primary small bowel lymphomas there must be no peripheral or mediastinal lymphadenopathy, with a normal white cell count and differential, and the tumor must be predominantly in the gastrointestinal tract. When primary, they may be multifocal in as many as 15% of cases. Predisposing conditions include immunodeficiency conditions, CD, and celiac disease.

There are five distinct clinical pathologic subtypes of primary small intestinal lymphoma: the adult Western type, the pediatric type, the immunoproliferative or Mediterranean type, enteropathy associated (celiac sprue) T-cell lymphoma, and Hodgkin’s lymphoma. The most common is the adult Western type, occurring in the sixth and seventh decade of life with a male predominance.

Sarcomas make up only 10% of small-bowel malignancies. Overall these tumors are located in the jejunum and ileum, are relatively slow growing, and are locally invasive. Their growth pattern is most commonly extramural and therefore, they rarely result in obstruction, but sometimes present with free intra-abdominal bleeding. Due to their insidious nature and growth pattern, greater than three-fourths of these tumors exceed 5 cm in diameter at the time diagnosis. The most common histologic subtypes are GISTs, leiomyosarcomas, fibrosarcomas, liposarcomas, and malignant schwannomas and angiosarcomas. Similarly to sarcomas from other anatomic regions, small-bowel sarcomas rarely metastasize to regional lymph nodes. Hematogenous dissemination tends to be the preferred route of distant spread, primarily to the liver, lungs, and bone. Peritoneal sarcomatosis is noted in later stages of the disease.

Malignant GIST is now considered the most common sarcoma of the gastrointestinal tract and accounts for about 5% of all small bowel malignancies. Clinical, histopathological, ultrastructural, and molecular-biological findings have made clear that GIST is a completely separate entity from leiomyoma and leiomyosarcoma. It is currently thought that GISTs originate from stem cells that differentiate towards the interstitial cells of Cajal (ICCs). ICCs arise from precursor mesenchymal cells and are the pacemaker cells of the gastrointestinal tract. Both ICCs and GISTs express KIT protein, have similar ultrastructural features, and express the embryonic form of the heavy chain of smooth muscle myosin.

KIT immunostaining has become the gold standard for the diagnosis of GIST and the term “GIST” should apply only to tumors with KIT immunopositivity. In rare situations a GIST maybe immunohistochemically inert, or, after therapy with imatinib mesylate, KIT immunostaining may become negative. Furthermore a minority of GISTs lacks demonstrable KIT mutations, but KIT is nonetheless strongly activated. Such GISTs might contain KIT mutations, which are not readily detected by conventional screening methods, or alternately, KIT might be activated by non-mutational mechanisms. To better characterize these tumors, other markers have been studied: about 60%-70% of GISTs show immunopositivity for CD34, 30%-40 % for smooth-muscle actin (SMA) and around 5% for S-100 protein. None of the latter antigens are therefore specific for GIST, but can help in the differential diagnosis in KIT negative tumors.

Clinical Findings

A. Symptoms and Signs

The vast majority of patients with benign neoplasms are asymptomatic whereas most of those with malignancies are symptomatic prior to diagnosis. The most common presentation of benign tumors is intermittent episodes of acute crampy abdominal pain associated with intussusception, followed by chronic bleeding with iron deficiency anemia in up to 50% of patients.

Malignant lesions are generally associated with weight loss. Symptoms, when they occur, tend to be vague and nonspecific. In general, most symptoms can be attributed to the location of the tumor, its rate of growth, and its size. For example, tumors in the duodenum tend to be symptomatic at an earlier stage, presenting with pain, gastric outlet obstruction, or obstructive jaundice, whereas those in the jejunum or ileum may present at a later stage with obstructive symptoms. Obstruction in this setting tends to be progressive, compared to benign lesions, whose obstructive symptoms tend to be intermittent as they relate to episodes of intussusception. Bleeding and perforation (in up to 10%) may also occur, predominantly in lymphomatous lesions, but this can also be a feature of any malignant tumor because of ulceration or necrosis.

Carcinoid tumors produce symptoms secondary to hormone production, including hot flashes, bronchospasms, and arrhythmias. This constellation of symptoms, called carcinoid syndrome, occurs when the liver is not able to metabolize the active substances produced by the carcinoid tumor. This is usually the case when tumors are either bulky or metastatic or their venous drainage bypasses the liver.

B. Laboratory Findings

A high index of suspicion is required due to the lack of specificity of these tumor’s signs and symptoms. A correct preoperative diagnosis is made in up to only 50% of patients. Biochemical and hematologic studies are often not helpful. Iron deficiency anemia may be detected with chronic blood loss; elevated liver enzymes may be noted with periampullary lesions or hepatic metastases; elevated 24-hour urinary 5-hydroxyindoleacetic acid can be detected in more than 50% of patients with carcinoid tumors.

C. Imaging Studies

Radiographic-contrast imaging modalities tend to be the most useful in the establishment of the diagnosis. Plain films of the abdomen are generally not helpful and at best may demonstrate nonspecific signs of obstruction or a mass effect. Except for the duodenum and the very proximal jejunum, which can often be evaluated by endoscopy, the diagnosis of small intestinal neoplasms depends on contrast studies such as a small-bowel follow-through or preferably enteroclysis. Small bowel follow-through is still the most commonly used method in the evaluation of small bowel pathology although enteroclysis may be a superior imaging modality.

Computed tomography, ultrasonography, and MRI are complementary to barium studies in the detection of small bowel neoplasms. Abdominal CT has a sensitivity of 50%-80% in detecting the primary small bowel tumors and occasionally plays an important role in differentiating benign from malignant tumors. Additionally CT is valuable in staging malignant tumors (presence or absence of hepatic metastases) and in providing important information related to local extent (presence or absence of local invasion, mesenteric implants, and metastatic lymph nodes). More recently, the association of multi-detector CT and MRI with small bowel lumen distension (CTE and MRE) has led to a considerable improvement in the diagnosis of small bowel neoplasms. On CTE, small bowel adenocarcinomas may manifest as a discrete tumor mass, a circumferential narrowing with abrupt concentric or irregular edges, or as an ulcerative lesion with adjacent enlarged lymph nodes. Mucosal ulceration is a suggestive feature, which is well depicted by CTE. Jejunal lesions have a tendency for being annular. Usually, only a short segment of the small bowel is involved. The mass itself usually shows moderate and heterogeneous enhancement after intravenous administration of iodinated contrast material. Rarely, adenocarcinoma may present as an aneurismal dilatation of a small bowel segment, similar to that observed in case of lymphoma. On MR imaging, small bowel adenocarcinomas have morphological features similar to those observed on CT.

On CTE, small GISTs typically present as regular, round, or lobulated masses with homogeneous and relatively marked enhancement after intravenous administration of contrast material, whereas larger tumors are heterogeneous with central necrosis and more prone to extraluminal growth. Due to excellent spatial resolution with multi-detector CT, the submucosal origin of the tumor may be suspected in case of small tumors. The malignant potential of these lesions cannot be stated with certainty on cross-sectional imaging unless metastases are present. In some instances, GISTs may display an aneurysmal pattern similar to that observed in case of lymphoma, so that differentiation between these two entities is difficult. On MR imaging, mesenteric small bowel tumors are usually hyperintense on T2-weighted MR images, with variable degrees of enhancement after intravenous administration of a gadolinium chelate. Because of the lower spatial resolution obtained with MR by comparison with CT, the submucosal origin of the tumor may be difficult to ascertain.

Angiography is rarely helpful in establishing or refining a diagnosis of small-bowel malignancy. In rare cases angiographic demonstration of tumor neovascularity without contrast agent extravasation may be of diagnostic importance in patients with chronic occult bleeding when other diagnostic studies, such as endoscopy and barium contrast have been negative. By contrast, this study is rarely beneficial in localizing bleeding tumors since the vast majority bleeds at a rate considerably below the limit of detection for this technique. Nuclear medicine scan with technetium-labeled red blood cells may identify bleeding sites with blood loss rates as low as 0.1 mL/min.

Fluorodeoxyglucose (labeled with fluorine-18) positron emission tomography (FDG-PET) has been shown to be highly sensitive to assess disease status in patients with GISTs. FDG-PET is used for preoperative staging, but more importantly to assess response to therapy.

D. Endoscopy

Enteroscopy is now available in a fiber optic form, using conventional endoscopes or in a wireless form. Push enteroscopy is currently the most frequently used endoscopic method for small bowel examination. The endoscope is introduced orally. After traversing the curve of the second part of the duodenum, the enteroscope is straightened to reduce any loops formed in the stomach. The enteroscope is then pushed to the maximum length of insertion. Dedicated push enteroscopes are 2-2.5 m in length and offer the opportunity of taking biopsies when the neoplastic lesion has been identified.

The double balloon (push and pull) enteroscopy system consists of a high-resolution video endoscope with a working length of 200 cm, and a flexible overtube 145 cm long. The inflated balloon on the overtube is used to maintain a stable position while the enteroscope is advanced. The overtube balloon is deflated whilst the enteroscope balloon is inflated, and the overtube is advanced along the distal end of the enteroscope (push procedure). This is followed by the “pull procedure:” Both the enteroscope and the overtube are pulled back under endoscopic guidance, with both balloons inflated. This procedure is repeated multiple times to visualize the entire small bowel. Few complications have been reported: post-procedure abdominal pain in up to 20% of patients, pancreatitis, bleeding and small bowel perforation which is more common after polypectomy of large polyps (> 3 cm).

The capsule endoscope is a capsule containing a battery-powered imager, a transmitter, antenna and four light emitting diodes. The imager takes two images per second through the transparent plastic dome of the capsule. The capsule is swallowed and is propelled through the intestine by peristalsis. Images taken by the capsule are transmitted to a battery-powered data recorder worn on a belt. The equipment is removed after 8 hours by which time the capsule has reached the caecum in most of cases. The data from the recorder is then downloaded onto a computer workstation which allows approximately 50,000 images to be viewed as a video. The average reading time of the video images takes between 40 and 60 minutes depending on the experience of the endoscopist. This technique may be affected by two problems: firstly, the presence of dark intestinal contents in the small bowel which may impair visualization of the mucosa, and secondly the rate of gastric emptying and small bowel transit which could lead to the exhaustion of the capsule batteries before the capsule reaches the ileocecal valve. Incomplete examination occurs in 10%-25% of cases.

The main risk is capsule retention. Therefore, this procedure is contraindicated in patients with known strictures or swallowing disorders.

E. Laparoscopy

Limited information is available regarding the efficacy of diagnostic laparoscopy in the diagnosis and work-up of small-bowel neoplasms. At present, its usefulness may reside in obtaining staging information and determining resectability prior to formal laparotomy in the case of tumors of the duodenum, and in obtaining images and potentially tissue diagnoses when other imaging studies have failed to suggest an etiology. It is clear, however, that despite the currently available technology, the diagnosis of these tumors is difficult to establish preoperatively in a significant group of individuals. Laparotomy is often required for definitive diagnosis.

Staging Classification

Radiological staging is mainly based on the use of CT and MRI. Intraoperative assessment plays a role in clinical staging. Metastatic involvement of the liver may be further evaluated by intraoperative ultrasonography. As far as pathologic staging, the TNM staging system has been recently revised by the AJCC, but no major changes have been implemented for small bowel neoplasms. The primary tumor is staged according to its depth of penetration and the involvement of adjacent structures or distant sites. There is no subdivision within the N category based on the number of nodes involved with tumor. Hematogenous metastases or peritoneal metastases are coded as M1. Cancers of the small intestine can metastasize to most organs, especially the liver, or to the peritoneal surfaces. Involvement of the celiac nodes is considered Ml disease.

For small bowel lymphoma the most commonly used staging system is the Ann Arbor system based on lymphatic and extralymphatic involvement on either side of the diaphragm.

Treatment

Treatment of adenocarcinoma of the small intestine with localized disease is based on oncologic and anatomic principles. For duodenal lesions the availability of endoscopic ultrasound has allowed better preoperative staging and the availability of endoscopic resection techniques has offered additional therapeutic options. Ultrasound proven benign duodenal or ampullary adenomas can be resected endoscopically with excellent results. Invasive lesions of the first and second portion of the duodenum without major vessel involvement and distant spread are best treated by a pancreaticoduodenectomy (Whipple procedure). For tumors in the third or fourth portion of the duodenum segmental resection with regional lymphadenectomy is indicated. Debate persists about the optimal surgical management of early duodenal cancer. Although early reports suggest that an endoscopic approach could be justified in early favorable lesions, ­long-term follow-up is still lacking and surgical resection is to be preferred in the good-risk patients. Palliative options for unresectable or metastatic duodenal carcinoma include gastrojejunostomy and/or biliary enteric bypass or endoscopic/interventional placement of stents to relieve the intestinal and/or biliary obstruction.

Adenocarcinoma of the jejunum and ileum is treated by wide excision, including areas of contiguous spread and the associated mesentery, with negative surgical margins.

Although only small series have been published, these tumors do not seem to respond to the conventional 5-FU based chemotherapy regimens and there is a radiation dose limitation due to small bowel toxicity. However, for palliation of chronic blood loss in patients with locally advanced unresectable duodenal carcinomas radiotherapy may provide short-term benefit.

The mainstay of therapy for carcinoid tumors is radical surgical excision. In preparation for surgery a complete assessment of the entire gastrointestinal tract is warranted since up to 40% of midgut carcinoids are associated with a second gastrointestinal malignancy and 30% present with multiple synchronous lesions. In addition, preemptive treatment with octreotide is indicated to prevent carcinoid crisis at the time of surgery. At surgery, wide en block resection including the draining mesentery is the standard approach. This is particularly true for small bowel carcinoid, because these lesions have the propensity to metastasize even when very small. Large lesions near the ampulla may require a pancreaticoduodenectomy for cure, while smaller lesions may be treated with either local excision or endoscopic resection with close endoscopic follow-up. Likewise lesions of the terminal ileum or carcinoid tumors of the appendix larger than 2 cm require a formal right hemicolectomy for oncologic clearance of disease.

Treatment for advanced locoregional and distant disease includes both medical and surgical modalities. Surgery should be indicated in patients with resectable metastatic disease for potential cure or at least meaningful palliation. Orthotopic liver transplantation has been used in the treatment of metastatic neuroendocrine tumors to the liver, with discouraging results.

The role of multimodality therapy, including alpha2b interferon and octreotide, for metastatic carcinoid remains limited. The addition of liver chemoembolization has not been shown to have a significant effect on survival in patients with metastatic disease to the liver but may have a role in controlling or decreasing the symptoms associated with carcinoid crisis. Octreotide has been effective in the treatment of patients with carcinoid syndrome by improving diarrhea in up to 83% of the patients and abolishing flushing and wheezing, but has no effect on survival. In consideration of the slow growth rate of many carcinoid tumors, patients with distant metastatic disease can also undergo resection for debulking and palliation of symptoms. For those patients with extensive unresectable disease, the indications for surgical intervention are limited to the occurrence of obstruction, perforation and bleeding. Radiation therapy has not been proven to be effective in either the adjuvant or palliative setting.

Treatment of small bowel lymphoma requires conservative resections with para-aortic and mesenteric lymph node sampling, liver biopsy and bone marrow biopsy performed for staging. Low-grade localized lesions are treated with resection alone, while for intermediate and high-grade lesions resection and chemotherapy is recommended. Radiation is used only for palliation in poor performance patients. This modality is associated with significant side effects, such as bowel necrosis, bleeding and perforation, and is offered for palliation only to patients unfit for surgery or chemotherapy.

Surgical treatment for small bowel sarcomas consists of an en block resection with tumor free margins. There is no role for extended lymphadenectomy in these tumors. Hematogenous dissemination is the preferred route of metastatic spread to the liver lungs and bones. Carcinomatosis is noted in later stages of the disease. In the presence of metastatic disease, local excision or palliative bypass procedure might be indicated to prevent or ameliorate bleeding and obstruction. Furthermore there is no clear benefit from chemoradiation therapy in the adjuvant setting, since radiation doses are limited due to small bowel toxicity. In the presence of recurrent or metastatic disease partial response rates after palliative chemoradiation therapy have been reported in the 10%-20% range, with minimal improvement in survival at best.

Treatment of localized GISTs is based on surgical resection: the tumor should be removed en block with its pseudocapsule and margins of normal soft tissue or bowel. In the presence of large lesions involving other organs, where an en block resection may be associated with significant morbidity, preoperative neoadjuvant use of imatinib mesylate may be entertained.

A significant breakthrough in the management of small bowel tumors and specifically GISTs has come from the understanding of the molecular and genetic makeshift of these lesions. After the discovery that GISTs characteristically express the KIT protein, a transmembrane tyrosine kinase receptor for a stem cell factor, a specific tyrosine kinase inhibitor, imatinib mesylate (Gleevec, Novartis), has been introduced in clinical practice with reduced risks of recurrence.

The role of surgery for recurrent or metastatic disease has been questioned since the introduction of imatinib mesylate. Surgery should still be considered in patients with bleeding or obstructive disease and after partial response to imatinib mesylate if the residual disease is deemed to be resectable.

Prognosis

Prognosis for small bowel adenocarcinoma is based on similar variables as for colorectal cancer, including stage, perineural and vascular invasion, grade, resectability, and surgical margins. The majority of tumors have regional spread at time of diagnosis, and up to one-fourth of patients have distant organ disease. Overall, the 5-year survival rate is 20%-30%. For resectable disease of the duodenum, the 5-year survival rate approaches 50%.

The prognosis for carcinoid tumors with localized disease is excellent with 5-years survival rates approaching 100% after resection. More than 90% of the symptomatic patients have metastatic disease at the time of surgical exploration. The likelihood of distant disease correlates closely with both the size of the primary lesion and the depth of invasion. For tumors less than 1 cm in size, the risk of lymph node metastases is on the order of 2%; for 1-2 cm lesions, there is an approximate 50% incidence of lymph node involvement; and 80% of tumors greater than 2 cm have positive nodes. Survival rates of up to 68% at 5 years have been reported when all gross metastatic disease, including hepatic metastases, is resected. For extensive unresectable disease, debulking has proven to be of some benefit in terms of symptomatic palliation. The 5-years survival for unresectable disease is approximately 35%-40%, reflecting the relatively indolent growth of these tumors.

Prognostic factors for primary small bowel lymphomas include higher grade, greater depth of tumor penetration, lymph node involvement, peritoneal disease and distant metastases. Overall 5-year survival rates range from 20% to 40% for all stages. Five-year survivals of up to 60% have been reported for patients with resected localized low-grade tumors.

Sarcomas tend to have an insidious growth pattern and greater than three-fourths of these tumors are larger than 5 cm at the time of diagnosis and up to 50% of them are not resectable for cure when the diagnosis is established. Prognosis correlates most closely with grade, followed by stage. Five-year survival after curative resection ranges from 60% to 80% for low-grade tumors and is no more than 20% for high-grade lesions.

Assessment of the malignant potential of a primary GIST lesion is difficult in many cases unless tumor spread can be documented beyond the organ of origin at the time of diagnosis. Historically, size has been used to assess tumor behavior. While almost all small (< 1 cm) GISTs are clinically benign and tumors larger than 5 cm in diameter are generally malignant, intermediate size GISTs have uncertain malignant potential and no cut-off diameter predicts subsequent malignant behavior with certainty.

Other factors, which have shown prognostic value, include mitotic rate, presence of tumor necrosis, high cellularity, and pronounced pleomorphism; a high S-phase fraction and DNA aneuploidy in flow or image cytometry; a high Ki-67 score; proliferating-cell nuclear-antigen expression; presence of telomerase activity, incomplete surgical resection, tumor rupture at surgery and invasion of adjacent structures.

Recently KIT mutations have been shown to be an independent prognostic factor for patients with GISTs.

The median disease-specific survival is about 5 years for primary disease, and 10-20 months in recurrent or metastatic disease. Most recurrences take place within 5 years of the primary diagnosis, but in the slowly proliferating subset of GISTs and especially after therapy with imatinib mesylate, metastases can appear more than 10 years after the primary diagnosis.

The outcome of patients with metastatic malignancies to the small intestine (more commonly ovarian, colon, lung cancers, renal cell carcinoma, and melanoma) is dismal despite palliative therapeutic intervention.

Follow-up

Routine follow-up for small bowel cancers is accomplished with endoscopy and radiologic imaging. The only exception is GIST. As previously discussed, PET scan is used to follow tumor response to imatinib mesylate; to detect recurrence after either complete response to imatinib mesylate or after curative surgery; to identify secondary resistance to imatinib mesylate before tumor progression on treatment.