Chapter 40. The Intestines: II. Infections; Inflammatory Bowel Diseases

Classification

Intestinal infections can be divided into 3 broad groups (Table 40-1):

1. Enterotoxin-mediated, where the disease is caused by a bacterial exotoxin; the organism does not invade the tissues and in some cases does not even enter the body (staphylococcal toxin, botulism), as the exotoxin is preformed in food.

2. Invasive infections, where the organism invades the intestinal mucosa.

3. Noninvasive infections, where the organism exists in the intestinal lumen and does not invade the tissues.

Most intestinal infections are transmitted by fecal contamination of food or drinking water. They are common in parts of the world where public health sanitary measures such as disposal of feces and purification of water supplies are not adequate.

Clinically, infections that involve the small intestine result in profuse watery diarrhea, while those that involve the colon produce dysentery (frequent small-volume diarrhea with blood and mucus). Fever is present in most invasive infections but is often absent in enterotoxin-mediated diseases.

Diagnosis

(Table 40-2)

Diagnosis of intestinal infection is largely by stool culture (eg, Shigella, Salmonella, Campylobacter, Escherichia coli) or by observation of organisms in smear preparations of stool (eg, Entamoeba, Giardia, Cryptosporidium, Isospora). Serologic diagnosis is of value in certain instances (eg, rising titers of antibody to lipopolysaccharide cell wall O antigens in Salmonella infections). In diseases produced by toxins, identification of the toxin is often the only means of diagnosis (eg, Clostridium difficile enterocolitis).

With intestinal worm infections, stool specimens may reveal whole worms, body segments, larvae, or eggs depending upon the species.

Enterotoxin-Mediated Diseases

Cholera

Cholera is caused by Vibrio cholerae. The original classic strain has been supplanted by the El Tor variant, which is presently endemic in several Southeast Asian countries and occurs also in the southeastern United States. Infection occurs when the organism is ingested with fecally contaminated food or water.

The organism multiplies in the intestinal lumen and produces an exotoxin that binds irreversibly to ganglioside receptors on the surface membranes of small intestinal mucosal cells (Figure 40-1). Toxin binding results in activation of adenylyl cyclase and increased cyclic adenosine monophosphate (cAMP) synthesis in the cell. The cAMP is a stimulus for increased secretion of fluid and electrolytes by the cell into the intestinal lumen and causes secretory diarrhea. The toxin acts for about 24 hours but does not permanently damage the cell. Pathologic examination reveals a normal small-intestinal mucosa on gross, light microscopic, and electron microscopic examination—even in fatal cases.

Clinically, there is a severe secretory diarrhea, often without abdominal pain or fever. Patients become rapidly dehydrated, hypovolemic, and electrolyte-depleted. Shock and death may occur within 24 hours. The diagnosis is made by demonstrating the vibrio in a stool sample.

Cholera is theoretically easy to treat. The diarrhea subsides when the organism has been killed (tetracycline is highly effective) and when the cells bearing bound toxin have been replaced by regenerating cells. Correction of dehydration with fluid therapy is vital in the acute phase. Glucose-containing fluids can be administered orally because the mucosal cell retains the ability to absorb fluid and electrolytes in the presence of glucose; this is important in underdeveloped regions of the world, where intravenous fluid therapy may not be available. The mortality rate in epidemics of cholera is high, partly because of the rapidity with which dehydration occurs and partly because epidemics commonly occur in regions where medical facilities are inadequate.

Toxigenic Escherichia Coli Infection

Certain strains of E coli produce a heat-labile enterotoxin similar to cholera toxin in its mode of action. Others produce a heat-stable enterotoxin. The ability to produce toxin is plasmid-induced and may therefore be transferred to other organisms. Toxigenic E coli causes (1) traveler's diarrhea in adults exposed to toxigenic strains of the bacillus against which they have no immunity and (2) diarrhea epidemics in neonatal units.

The disease is usually mild, although in neonates diarrhea may result in dangerous fluid and electrolyte depletion. The diagnosis is difficult to establish. E coli is a normal commensal in the colon and is present in normal stools. Although specific serotypes of E coli have been reported as being toxigenic, the correlation between serotypes and toxigenicity is not completely accurate. Techniques using tissue culture systems for identifying the heat-labile toxin of E coli are not widely available.

Staphylococcal Food Poisoning

Staphylococcal food poisoning is a common form of epidemic food poisoning all over the world. It is caused by enterotoxin-producing strains of Staphylococcus aureus (Table 40-3). The organism multiplies in food that has been prepared and kept without refrigeration for several hours before it is eaten, leading to accumulation of the enterotoxin. Heating the food before ingestion destroys staphylococci but not the heat-stable toxin. The toxin causes severe nausea and vomiting of short duration, usually accompanied by abdominal cramps and diarrhea. The disease is self-limited. Death almost never occurs.

Clostridium Difficile Pseudomembranous Enterocolitis

Pseudomembranous enterocolitis complicates treatment with certain antibiotics—most commonly clindamycin, ampicillin, or tetracycline—that alter the intestinal bacterial flora, permitting the overgrowth of C difficile. C difficile produces a powerful exotoxin that binds to and has a cytotoxic effect on mucosal epithelial cells, resulting in superficial necrosis and acute inflammation of the intestinal mucosa. The necrotic mucosa and exudate remain adherent to the mucosal surface as yellow plaques or membranes. The colon is usually most severely involved.

Clinically, there is an acute severe diarrhea with blood and mucus, accompanied by fever and an elevated white blood count. The disease progresses rapidly and is frequently fatal in the absence of prompt treatment. The diagnosis is based on the endoscopic and histologic features (Figure 40-2) and demonstration of C difficile exotoxin in blood and stool. Stool culture shows decreased numbers of commensal organisms; the finding of C difficile is difficult to interpret because the organism is a normal commensal. Vancomycin is effective in treatment; cholestyramine is of immediate value in that it binds with and neutralizes the toxin.

Approximately 90% of cases of pseudomembranous enterocolitis are caused by C difficile. The causes in the other cases are unknown. Very rarely, invasive S aureus infection causes a severe pseudomembranous enterocolitis associated with the presence of large numbers of gram-positive cocci in a gram-stained smear of feces.

Other Enterotoxic Diseases

Clostridium perfringens and Bacillus cereus also produce toxins that give a clinical picture of food poisoning similar to staphylococcal food poisoning (Table 40-3). Vibrio parahaemolyticus, often ingested in uncooked shellfish, multiplies in the intestine much like V cholerae. The mechanism of action of the enterotoxin is not known. The disease is mild and self-limited and is characterized by abdominal pain and diarrhea. In botulism, the toxin of C botulinum is present in inadequately processed food (commonly sausage or home-canned food). The toxin is destroyed by heating for 20 minutes at 100 °C, which is achieved in commercial canning operations. Though classified as a form of “food poisoning,” botulism rarely causes diarrhea and usually presents with neuromuscular paralysis due to the systemic action of the exotoxin (see Chapter 13: Infectious Diseases: I. Mechanisms of Tissue Changes in Infection).

Invasive Viral & Bacterial Infections

Viral Gastroenteritis

Viral gastroenteritis (stomach flu) is one of the most common infections of humans. It is most often caused by rotaviruses and parvoviruses, of which the best known is the Norwalk agent. Numerous other viruses, including adenoviruses, calicivirus and astrovirus, are sometimes implicated.

The viruses infect the small intestinal epithelial cells, causing acute inflammation. The villi become blunted and infiltrated with lymphocytes and plasma cells.

Clinically, patients present with fever, acute diarrhea, vomiting, and abdominal pain. The illness is self-limited and mild, lasting 3–4 days. Diagnosis may be made by demonstrating the virus in stools or detecting a rise in antibody titer.

Cytomegalovirus Enterocolitis

Cytomegalovirus is an important cause of intestinal infection in immunocompromised patients and is common in persons with acquire immunodeficiency disease (AIDS). The virus infects the entire intestinal tract, producing a severe chronic diarrhea that may cause death, and it infects mucosal epithelial cells as well as vascular endothelial cells. Cytomegalovirus vasculitis may result in focal ischemic necrosis of the wall; rarely, perforation of the intestine results. The diagnosis is established by demonstrating infected cells—greatly enlarged and containing large intranuclear inclusions and granular cytoplasmic inclusions—in biopsy specimens taken endoscopically.

Salmonella Gastroenteritis

Salmonella species other than Salmonella typhi are a common cause of bacterial “food poisoning” all over the world (Table 40-3). Infection results when food, water, and dairy products are contaminated with infected human or animal feces. Pasteurization of milk has decreased the incidence of this disease.

Infection causes acute inflammation of the small intestine, with diffuse mucosal hyperemia, swelling, focal superficial ulceration, and neutrophil infiltration.

Patients present 1–3 days after infection with an acute onset of fever, abdominal pain, and diarrhea. The disease is usually mild. Rarely, a more severe illness with bacteremia may occur.

Typhoid Fever

Typhoid fever is caused by Salmonella typhi; Salmonella paratyphi may produce a similar illness. The organism infects only humans, and infection results from contamination of food and water with feces from a symptomatic case or asymptomatic carrier of typhoid. Typhoid is uncommon in the United States but is still prevalent in Third World countries.

Pathology & Clinical Features

The ingested bacillus invades the small intestinal mucosa, where it is taken up by macrophages and transported to regional lymph nodes. S typhi is a facultative intracellular organism and multiplies in the intestinal lymphoid tissue during the 1- to 3-week incubation period (Figure 40-3).

At the end of the incubation period, the bacilli enter the bloodstream (bacteremic phase), resulting in fever, headache, and muscle aches. Many tissues, including liver, heart, kidney, lungs, meninges, and bone, may be infected during this phase.

The diagnosis of typhoid fever is suggested by the following in a patient with continued fever: (1) splenomegaly; (2) a petechial skin rash (rose spots); (3) bradycardia, which is unusual in other febrile illnesses; and (4) peripheral blood neutropenia. All of these findings are present toward the end of the first week of clinical illness. The diagnosis is established at this time by blood culture, which is positive in 95% of cases.

In the second week of illness, S typhi reenters the intestinal lumen by way of biliary excretion (intestinal phase). The organism reinfects lymphoid tissue in the small intestine and colon in large numbers, causing acute inflammation, necrosis, and ulceration. Necrosis is the result of direct invasion plus endotoxin released by the bacillus, together with delayed hypersensitivity, which has developed by this time. The mucosal ulcers tend to take the shape of the underlying lymphoid follicles and typically occur as longitudinal ulcers overlying the Peyer patches in the ileum (Figure 40-4).

Microscopic examination shows edema and acute inflammation. The cellular infiltrate in typhoid is deficient in neutrophils and composed of macrophages, lymphocytes, and plasma cells. Necrosis and ulceration follow.

Clinically, the intestinal phase is characterized by diarrhea and continued fever. The diagnosis can be established by stool and urine culture (Figure 40-3), which is positive at this stage. Blood culture is still positive in about 60% of patients.

Complications

Bacteremia is common and often fatal if the patient is not treated. Hemorrhage may occur from the intestinal ulcers, and perforation may lead to peritonitis.

There may be evidence of skin infection (rose spots) or, rarely, of meningitis, endocarditis, chondritis, osteomyelitis, or widespread focal necrosis of muscle (Zenker's degeneration).

After clinical recovery, 5% of patients continue to excrete bacilli in urine or feces; this carrier state is believed to be due to persistent low-grade infection in the kidney and gallbladder. Carriers represent a public health hazard, particularly if they are involved in handling food.

Shigella Colitis (Bacillary Dysentery)

Bacillary dysentery is caused by Shigella species. Shigella sonnei and Shigella flexneri are the common species and cause a relatively mild illness. Shigella boydii is uncommon. Shigella dysenteriae type I (Shiga's bacillus) produces a severe illness and is endemic in Central America and parts of Asia. Shigella dysentery is common in the United States.

Shigella species affect the colon, producing an acute inflammation with diffuse hyperemia, edema, and multiple superficial ulcers. Neutrophils are the dominant cells. Bacteremia is rare, occurring only in severe cases, particularly with S dysenteriae type 1.

Clinically, bacillary dysentery is an acute illness characterized by high fever, severe diarrhea with blood and mucus in the stool, and neutrophilic leukocytosis. Passage of 10–40 stools per day is usual; individual stools are of small volume and often composed entirely of blood, mucus, and the inflammatory exudate. Diagnosis is made by stool culture.

Enteroinvasive Escherichia Coli Infection

Some strains of Escherichia coli have the ability to invade the intestinal mucosa and cause epidemics of necrotizing enterocolitis in neonates or invasive intestinal infections in older children and adults. Extensive necrosis of the mucosa often causes death in neonates. The disease in children and adults simulates either salmonellosis, when the small intestine is maximally involved, or Shigella dysentery when colitis predominates. Children who recover may develop fibrous strictures. The identification of serotypes of E coli that are invasive is very difficult.

Campylobacter Fetus Infection

Campylobacter fetus is a curved bacterium recognized recently as being a common cause of enterocolitis and responsible for about 10% of cases of bacterial diarrhea in children. The disease is acquired from infected humans and animals.

Both small intestine and colon are affected, causing diarrhea and dysentery. The disease is usually mild. Diagnosis is by stool culture. Treatment with antibiotics is effective.

Yersinia Enterocolitica & Yersinia Pseudotuberculosis Infection

These two Yersinia species cause fever, diarrhea, and marked painful enlargement of mesenteric lymph nodes (mesenteric adenitis), with right lower quadrant abdominal pain. Differentiation from acute appendicitis can be difficult.

Diagnosis is made by stool culture.

Intestinal Tuberculosis

Primary Intestinal Tuberculosis

Primary tuberculous infection of the intestine has become rare as a result of pasteurization of milk and eradication of bovine tuberculosis in dairy herds. It is characterized by a small focus in the intestine and large mesenteric lymph nodes, analogous to the primary complex in the lung.

Secondary Intestinal Tuberculosis

This form of tuberculosis still occurs as a result of swallowing of infected sputum by patients with active pulmonary disease or reactivation of a dormant intestinal focus, usually in the terminal ileum or cecum.

Typical caseous granulomas form. The organisms spread locally in the intestinal lymphatics, resulting in ulcers that are transverse because the intestinal lymphatics pass circumferentially. Fibrosis leads to strictures (Figure 40-5). Involvement of the serosa results in fibrous adhesions between loops of intestine. Fistula formation may occur.

Clinically, intestinal tuberculosis is a chronic illness characterized by low-grade fever and diarrhea, which may be tinged with blood. A mass may be palpable in a few cases (hyperplastic cecal tuberculosis). The diagnosis is made by culturing tubercle bacilli from the stools.

Complications of intestinal tuberculosis include intestinal obstruction, caused by strictures, fistulas, and tuberculous peritonitis.

Atypical Mycobacteriosis

Intestinal infection with Mycobacterium avium-intracellulare occurs in elderly or immunocompromised patients. M avium-intracellulare enteritis is one cause of severe chronic diarrhea in patients with AIDS. The organisms accumulate in large numbers in macrophages in the mucosa, and there is little or no inflammation. Spread to lymph nodes is common. The diagnosis may be established by biopsy or identification of the organism in stools by direct examination (using acid-fast stain) or culture.

Protozoal Infections

Amebiasis

Entamoeba histolytica is a common pathogen of the colon in underdeveloped countries. In the United States it occurs mainly in cities with high immigrant populations.

Infection occurs by ingestion of cysts in food and water contaminated with feces. Ingested cysts release active amebas (trophozoites) that invade the large intestinal mucosa and enter the submucosa, which is the site of maximal involvement. The amebas cause multiple areas of enzymatic necrosis of tissue and acute inflammation, leading to flask-shaped submucosal abscesses throughout the colon (Figure 40-6). The mucosal surface—as seen at colonoscopy—shows multiple ulcers separated by healthy-appearing mucosa which is, however, undermined by the submucosal abscesses. Confluence of mucosal ulcers results in large areas of denuded mucosa covered by a necrotic base. Amebas are found in the walls of the ulcers (Figure 40-7). The trophozoites typically contain phagocytosed erythrocytes in their cytoplasm.

Infection is usually localized to the submucosa and mucosa. Rarely, necrosis involves the muscle, leading to intestinal perforation. Hemorrhage and toxic megacolon may also occur with severe infection, and venous spread to the liver may occur (Chapter 42: The Liver: I. Structure & Function; Infections).

Clinically, patients with amebic colitis present with bloody and mucous diarrhea accompanied by low-grade fever. The diagnosis is made by the finding of trophozoites of E histolytica in the stools or in a biopsy specimen. Amebicidal drugs such as metronidazole are highly effective in treatment.

Giardiasis

Giardiasis is a common infection caused by the protozoan flagellate Giardia lamblia. Infection is by ingestion of cysts in food and water contaminated with feces. After ingestion, excystment and release of trophozoites occurs in the duodenum.

Giardia attaches itself to the surface of the small intestinal mucosal cells by its ventral sucker. The duodenum is involved most heavily. In heavy infections, a large part of the mucosal surface area may be occupied by parasites, causing mechanical interference with absorption. Giardiasis also causes partial villous atrophy, which contributes to malabsorption. The organism does not invade tissues.

Clinically, infected individuals develop cramping abdominal pain, with diarrhea and steatorrhea due to malabsorption. The diagnosis is made by identifying the organism in stools, duodenal aspirates (Figure 40-8), or duodenal biopsies.

Intestinal Cryptosporidiosis, Microsporidiosis, & Isosporiasis in Aids

Cryptosporidium, Isospora, and Microsporidium species have been identified as common causes of chronic watery diarrhea in patients with AIDS.

Cryptosporidium and Isospora species may rarely infect healthy individuals, causing a mild self-limited acute diarrhea. In AIDS, multiplication proceeds unimpeded, leading to massive infection of the small intestine and colon, and severe diarrhea. Cryptosporidium is present in large numbers, usually attached to the surface of the epithelial cell. The diagnosis is established by identifying the organism in stool smears stained with acid-fast stains. Cryptosporidium is 2–4 μm in diameter, round, and seen only in acid-fast stained smears. Isospora is larger and may be seen in both unstained wet mounts and acid-fast stained smears. Microsporidium infects duodenal epithelial cells. They are minute organisms that are best seen by electron microscopy and silver-stained sections.

Intestinal Helminthiasis

Intestinal helminthiasis is extremely common in underdeveloped countries and has been estimated as afflicting about 25% of the world population. In many of these diseases, the worm lives in the lumen without causing major symptoms; in others, significant clinical manifestations occur (Table 40-4).

The term idiopathic inflammatory bowel disease is used for two diseases—Crohn's disease and ulcerative colitis. Although their causes are still not clear, the two diseases probably have an immunologic hypersensitivity basis. They are recognized as distinct entities with distinct clinical and pathologic features (Table 40-5).

In about 10% of patients with idiopathic inflammatory bowel disease affecting the colon, it is difficult to differentiate between Crohn's disease and ulcerative colitis because features of both are present. These cases are characterized as indeterminate idiopathic inflammatory bowel disease. Because such “mixed” cases occur and because both Crohn's disease and ulcerative colitis have similar geographic distributions and occur in similar ethnic and age groups—or even in single families—it has been suggested that both may represent one disease process. However, there are so many differences that it is probably best to regard them as two diseases until their cause (or causes) is determined.

The diagnosis of idiopathic inflammatory bowel disease is suspected clinically (chronic or recurrent diarrhea) and confirmed by colonoscopy and biopsy. The mucosal features of idiopathic inflammatory bowel disease on histology include distortion of crypt architecture, crypt destruction and loss, and a marked increase in lymphocytes and plasma cells in the lamina propria. These changes distinguish idiopathic inflammatory bowel disease from acute infectious colitides and from other causes of chronic colitis such as collagenous disease (where the crypts are normal and there is a layer of collagen under the epithelial basement membrane), ischemia, and radiation injury.

The differentiation between Crohn's colitis and ulcerative colitis is possible in mucosal biopsies only in those rare cases (10–20%) where the mucosal biopsy contains epithelioid cell granulomas. In other cases, the differentiation is made on clinical and radiologic grounds (see Table 40-5).

Crohn's Disease

Crohn's disease is a chronic inflammatory disorder that most commonly affects the ileum and colon but has the potential to involve any part of the gastrointestinal tract from the mouth to the anus. It is characterized by involvement of discontinuous segments of intestine (skip areas), noncaseating epithelioid cell granulomas, and transmural (full-thickness) inflammation of the affected parts (Figure 40-9).

Incidence

Crohn's disease occurs mainly in Western Europe and the United States and is uncommon in Asia and South America. The incidence appears to be increasing. In the United States, Crohn's disease affects chiefly whites; blacks, Native Americans, and Hispanics are less frequently affected. The highest incidence is in Jews.

Both sexes are affected equally. The disease can occur at any age but has its highest incidence in young adults. It is uncommon in young children. Crohn's disease has a familial tendency, with 20–30% of patients giving a positive family history. There is no inheritance pattern, and the familial tendency is likely to be the result of a shared, common environment.

Etiology

The cause of Crohn's disease is unknown. Despite extensive search, no infectious agent has been found.

There is strong but not conclusive evidence that Crohn's disease is the result of some immunologic injury. Antibodies with activity against intestinal epithelial cells have been identified in the serum and lymphocytes of patients with Crohn's disease. These antibodies may be autoantibodies (making Crohn's disease an autoimmune disease), or they may represent an immune response to an intestinal epithelial injury due to other causes. Patients with active Crohn's disease frequently have T cell dysfunction (anergy to tuberculin and mumps antigen, low peripheral blood T cell count).

Pathology

(Figure 40-9)

Sites of Involvement

Combined ileal (most commonly terminal ileum) and colonic disease is most common (50%). The ileum alone is involved in 30% of patients and the colon alone in 20%. Crohn's disease of the colon is also called granulomatous colitis. Involvement of the oral cavity, larynx, esophagus, stomach, and perineum are rare.

Patients with Crohn's disease commonly (in 75% of cases) have perianal lesions such as abscesses, fistulas, and skin tags. Perianal disease occurs in both ileal and colonic disease and is not dependent on the presence of rectal involvement.

Gross Appearance

Involvement is typically segmental, with skip areas of normal intestine between areas of involved bowel. Normal and affected intestine are sharply demarcated from one another.

In the acute phase, the intestine is swollen and reddened. The mucosa shows diffuse hyperemia, acute inflammation, and shallow, aphthous ulceration. In the chronic phase, the affected segment is greatly thickened and rigid (lead pipe or garden hose appearance; Figure 40-10). Marked fibrosis causing luminal narrowing with intestinal obstruction is common. The serosa is dull and granular. In involved ileal segments, the mesenteric fat creeps from the mesentery to surround the bowel wall (creeping fat). The mucosal surface shows longitudinal serpiginous ulcers separated by irregular islands of edematous mucosa. This results in the typical cobblestone effect (Figure 40-11). Fissures (deep and narrow ulcers that look like stabs with a knife that penetrate deeply into the wall of the affected intestine) and fistulas (communications with other viscera) may be present.

Microscopic Features

Crohn's disease is characterized by distortion of mucosal crypt architecture, transmural inflammation (Figure 40-12), and the presence of epithelioid granulomas on histologic examination (Figure 40-13); granulomas are present in about 60% of patients. Numerous other histologic changes occur in Crohn's disease, but none are of great diagnostic use. These features include lymphedema of the submucosa, lymphoid follicles at all levels of the bowel wall, and marked fibrosis. Fissure-ulcers and fistulas can be seen microscopically.

The regional mesenteric lymph nodes are frequently enlarged and may contain noncaseating granulomas.

Clinical Features

Presentation is extremely variable. In the acute phase, fever, diarrhea, and right lower quadrant pain may mimic acute appendicitis.

Chronic disease is characterized by remissions and relapses over a long period of time. Asymptomatic periods may last several months. With the passage of time, weight loss and anemia appear. Thickening of the intestine may produce an ill-defined mass in the abdomen.

Diagnosis

Diagnosis is based on a combination of clinical, radiologic, and pathologic findings. In the active phase of the disease, the erythrocyte sedimentation rate and white blood cell count may be elevated, but these are nonspecific findings.

Complications

Crohn's disease may be complicated by intestinal obstruction or by fistula formation between involved loops of bowel and adjacent viscera. Fistulas between the ileum and the colon result in malabsorption as a result of colonization of the ileum with colonic bacteria; those between ileal loops may short-circuit the bowel, again resulting in malabsorption. Enterovesical fistulas lead to urinary infections and passage of gas and feces with urine. Enterovaginal fistulas produce a fecal vaginal discharge.

Malabsorption syndrome may also follow disease in the terminal ileum, in which there may be failure of absorption of vitamin B12 and bile acids, resulting in megaloblastic anemia and fat malabsorption. Iron deficiency anemia may occur as a result of chronic occult bleeding, and protein-losing enteropathy as a result of loss of protein from the inflamed mucosa.

Extraintestinal manifestations are common in Crohn's disease and include arthritis and uveitis. The mechanisms are unknown.

Crohn's disease carries a slightly increased risk of development of carcinoma of the colon—much less than in ulcerative colitis.

Ulcerative Colitis

Ulcerative colitis is an inflammatory disease of uncertain cause. It has a chronic course characterized by remissions and relapses.

Incidence

In the United States, about 400,000 patients suffer from ulcerative colitis, and there are about 25,000 new cases every year. The disease is common in the 20- to 30-year age group but may occur at any age. The incidence is slightly higher in females than in males. In the United States, whites are more often affected than blacks, and Jews more often than non-Jews. Worldwide, the disease is most prevalent in North America and Western Europe and less prevalent in Asia, Africa, and South America.

Etiology

The cause is unknown; no infectious agent has been identified. Antibodies that cross-react with intestinal epithelial cells and certain serotypes of Escherichia coli have been demonstrated in the serum of some patients with ulcerative colitis. Allergy to food proteins has been suggested as a possible cause but without proof.

Psychologic stress frequently precipitates ulcerative colitis, leading to the suggestion that the disease has a psychosomatic basis.

Pathology

(Figure 40-14)

Sites of Involvement

Ulcerative colitis is a disease of the rectum, which is involved in almost all cases and in some patients remains the only site of disease, and the colon. The disease extends proximally from the rectum in a continuous manner without skip areas. Total colonic involvement is not uncommon. The appendix is involved in about 30% of cases. The ileum is not involved as a rule; 10% of cases show mild nonspecific mucosal inflammation for a few centimeters proximal to the ileocecal valve (backwash ileitis).

Gross Appearance

Ulcerative colitis involves mainly the mucosa. Even in severe disease, the external appearance of the affected colon shows nothing other than mild hyperemia. There is rarely any thickening of the wall. In very rare cases of severe acute ulcerative colitis, toxic dilation (megacolon) occurs.

The mucosal surface shows diffuse hyperemia with numerous superficial ulcerations in the acute phase. The rough, red, velvety appearance on colonoscopy is characteristic but not specific (Figure 40-15). In the chronic phase of the disease during remission, the mucosa appears flat and atrophic due to reepithelialization of the ulcers. The regenerated or nonulcerated mucosa may appear polypoid (inflammatory pseudopolyps) in contrast with the atrophic areas or ulcers (Figure 40-16).

Microscopic Appearance

In the active phase, the mucosa shows marked inflammation with neutrophils, lymphocytes, and plasma cells. Neutrophils are present in both lamina propria and in glands (crypt abscesses). In the chronic phase, the crypts are decreased in number (crypt atrophy) and show distorted architecture due to abnormal branching (Figure 40-17). There are numerous chronic inflammatory cells in the lamina propria. Active inflammation correlates well with the severity of symptoms. In treated patients, many of the mucosal changes reverse.

The inflammation is usually restricted to the mucosa. In severe cases with extensive ulceration, the superficial part of the submucosa may be involved, but the muscle wall is not affected.

Clinical Features

In the acute phase and during relapse, the patient has fever, leukocytosis, lower abdominal pain, and diarrhea with blood and mucus in the stool. The disease usually has a chronic course, with remissions and exacerbations; in some cases, the patient has chronic continuous disease with mild diarrhea and bleeding.

Diagnosis

The diagnosis of ulcerative colitis is based on a combination of clinical, radiologic, and pathologic findings. The erythrocyte sedimentation rate and white blood count are elevated during the acute phase.

Mucosal biopsies taken at endoscopy are useful in diagnosis. The presence of crypt atrophy, distortion of crypt architecture, and an increased number of lymphocytes and plasma cells in the lamina propria are helpful in differentiating ulcerative colitis from other causes of acute colitis. However, these mucosal changes can be seen in both ulcerative colitis and Crohn's disease (Figure 40-17). The only finding on mucosal biopsy that reliably differentiates ulcerative colitis and Crohn's disease is the presence of noncaseating epithelioid granulomas in the latter (Table 40-5).

Complications

Severe bleeding may occur as a complication in the acute phase. Toxic megacolon in severe acute disease is characterized by dilation of the colon, with functional obstruction and, rarely, perforation. It carries a high mortality rate and requires emergency colectomy.

Extraintestinal manifestations occur more commonly in ulcerative colitis than in Crohn's disease. They include arthritis, uveitis, skin lesions (a necrotic skin lesion in the extremities known as pyoderma gangrenosum is typical), and sclerosing pericholangitis (fibrosis around bile ducts), leading to obstructive jaundice.

Patients with chronic ulcerative colitis have an increased risk of developing colon carcinoma. The overall risk is about 10%. The risk increases progressively with disease duration beyond 7 years, with the length of colon involved—greatest with involvement of the entire colon—and the age at onset of disease—the earlier the onset, the greater the risk. Carcinomas occurring in ulcerative colitis tend to be poorly differentiated, infiltrative, and aggressive neoplasms with a poor prognosis.

Epithelial dysplasia precedes carcinoma in most cases. Regular surveillance by colonoscopy and biopsy is indicated in patients with ulcerative colitis of more than 10 years' duration. The presence of high-grade dysplasia in a mucosal biopsy (Figure 40-18) imposes a high risk of cancer and is an indication for colectomy.