The cause and pathogenesis of both these chronic inflammatory bowel diseases (CIBDs) are unknown. Both are characterized by a chronic inflammatory cell infiltrate of the bowel. However, whereas CUC is restricted to the colon, Crohn’s disease can involve the entire alimentary tract from the mouth to the anus, although the distal ileum and colon are the portions most frequently affected. Another distinguishing feature of Crohn’s disease is the involvement of all layers of the bowel, whereas the inflammation seen in CUC is mostly limited to the mucosa. In addition, focal granulomas are common in Crohn’s disease but rare in CUC. However, neither disease has pathognomonic features, and Crohn’s disease of the colon cannot be histologically distinguished from CUC in 15% to 25% of cases of chronic colitis.

Compare and contrast the principal clinical features of CUC and Crohn’s disease.

The severity, clinical course, and prognosis of CUC and Crohn’s disease are widely variable. Onset in both diseases occurs most often in early adulthood. The symptoms of CUC may range from slight rectal bleeding to fulminant diarrhea with colonic hemorrhage and hypotension. Most patients have intermittent attacks, although some can have continuous symptoms without remission. The clinical features of Crohn’s disease depend on the severity and location of the bowel involvement; the principal features are diarrhea, abdominal pain, hematochezia, intestinal obstruction, fissures, and fistulas.

Extraintestinal manifestations are common in both Crohn’s disease and CUC, but more common in CUC. The manifestations include arthritis, arthralgia, iritis, uveitis, liver disease, and skin lesions. The arthritis may present as a migratory arthritis, involving large joints, sacroiliitis, or ankylosing spondylitis. Primary sclerosing cholangitis, which is associated with an increased frequency of cholangiocarcinoma, and chronic hepatitis are common hepatobiliary abnormalities.

The principal features that differentiate Crohn’s disease from CUC are listed in Table 4.1.

The frequency of intestinal cancer is increased in Crohn’s disease, but not to the extent in CUC. According to some reports, the frequency of colon cancer in adults who have CUC involving the entire colon is approximately 25 times greater than that in the general population. The risk of colon cancer developing in patients with CUC is positively correlated with the extent and duration of the disease.

The general measures to control the symptoms of both diseases include correction of fluid–electrolyte imbalances; iron, folate, or vitamin B₁₂ supplementation as needed for the treatment of anemia; and dietary adjustments aimed at maintaining adequate nutrition. Total parenteral nutrition may be
required for the short-term treatment of severe acute disease, but “bowel rest” and hyperalimentation are of dubious value in the long term. Antidiarrheal agents such as loperamide are usually contraindicated in patients with CUC because they may contribute to the development of toxic megacolon, but they may help alleviate the diarrhea and abdominal cramps in the setting of stable Crohn’s disease.

In CUC, corticosteroids are useful for inducing remissions or improvement in an acute attack, and they may be required for long-term management. However, the possible benefits of corticosteroids in the long term are offset by their many adverse side effects. The rectal administration of steroids or mesalamine can be beneficial, especially when rectal involvement (proctitis) is severe. However, significant absorption of rectal steroids can occur, so systemic effects of the agents (both beneficial and undesirable) may arise when they are given by this route. Sulfasalazine is metabolized by colonic bacteria, releasing sulfapyridine and 5-aminosalicylate (5-ASA); the latter is believed to be the
active compound. Sulfapyridine is absorbed systemically, which accounts for the side effects of sulfasalazine (e.g., headache, occasional megaloblastic anemia, skin rash). The greatest utility of sulfasalazine in patients with CUC is in long-term management, where it has been proved to reduce the frequency of relapses. 5-ASA, given rectally by enema or suppository, is well tolerated and effective. Given orally, 5-ASA is rapidly denatured by gastric acid, so alternatives to plain 5-ASA, such as microencapsulated (Pentasa; Hoechst Marion Roussel, Kansas City, MO) or acrylic-based resin-coated (Asacol; Procter & Gamble Pharmaceutical, Norwich, NY) forms of 5-ASA, may be used. Because the relative risk for development of CUC is greater in nonsmokers than in smokers (the opposite is true in Crohn’s disease), nicotine is being tried in the treatment of CUC; some benefit has been reported, but additional research is needed.

There is no uniformly effective treatment available for Crohn’s disease. However, corticosteroids have documented efficacy in diminishing the activity of the disease process. Long-term use of corticosteroids is not recommended because of their many side effects, such as osteoporosis, diabetes, and cataracts. Sulfasalazine has some effectiveness, especially in colonic Crohn’s disease, but is less effective than corticosteroids. Pentasa, in doses of more than 3 mg per day may be efficacious in mild to moderate Crohn’s disease, particularly in ileal disease. Metronidazole may be at least as effective as sulfasalazine. When Crohn’s disease cannot be controlled by these medications, the immunosuppressive agent azathioprine and its metabolite 6-mercaptopurine are often used. These drugs are effective in both inducing and maintaining remission in inflammatory-type and fistulizing-type Crohn’s disease. Their use can result in a reduction in the corticosteroid dose needed, but this advantage may be offset by their toxic effects (e.g., pancreatitis, allergic reactions, and leucopenia). More recently, infliximab, a chimeric monoclonal antitumor necrosis factor antibody, has been shown to be effective in Crohn’s disease, both in the inflammatory and the fistulizing types. The role of immunodulator drugs in CUC is less clear than in Crohn’s disease.

Chronic liver disease may be the sequela of several kinds of toxic, metabolic, infectious, immunologic, or hereditary conditions. Table 4-2 contains a partial list.

The clinically available liver function tests include those that assess, at least in part, liver synthetic function (serum albumin and bilirubin concentrations, and prothrombin time) and those that mostly evaluate the hepatocellular release of enzymes (aminotransferases and alkaline phosphatase). Often, the levels of aminotransferase [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase] are not markedly elevated in patients with chronic liver disease, and consequently do not accurately predict prognosis. The serum albumin and bilirubin concentrations and the prothrombin time are more likely to be distinctly abnormal, and more accurately reflect the true status of the liver’s functional capacity.

Categories of these diseases, constructed by international committees, consist of three components: the etiology of the diseases, grading of disease activity (i.e., the severity of the necroinflammatory process), and staging of the disease (i.e., the degree of fibrosis subsequent to necroinflammatory insults). The grading and staging are usually given a semiquantitative score (0 to 4) or a descriptive characterization (e.g., minimal to severe inflammation, or no fibrosis to cirrhosis).

Nocturnal diarrhea suggests an organic cause of the diarrhea. Patients with irritable bowel syndrome or other “functional” diarrheas rarely have diarrhea that awakens them from sleep.

Secretory diarrhea is due to the active secretion of water and electrolytes into the intestinal lumen. The mechanism of action responsible for the release of the secretagogues is variable. For instance, the diarrhea of cholera, the classic example of a secretory diarrhea, is caused by the stimulation of adenylate cyclase activity by cholera toxin; this, in turn, causes an increase in the intracellular concentration of cyclic adenosine monophosphate, which stimulates electrogenic chloride secretion and inhibits electroneutral sodium chloride absorption. Increases in intracellular concentrations of Ca²⁺ as well as cyclic guanosine monophosphate have been proposed as the abnormalities at work in various other forms of secretory diarrhea.

In osmotic diarrhea, an unabsorbable solute (often a carbohydrate or divalent mineral) increases the osmolality of the intestinal contents. This increased osmolality passively “drags” water into the intestinal lumen. Patients with osmotic diarrhea usually have a stool osmolality measure that is much greater than that yielded by the formula: 2 × serum Na⁺ + serum K⁺; this condition constitutes an osmotic gap. A common osmotic diarrhea is that which occurs after the ingestion of milk or milk products in people who are deficient in the intestinal enzyme lactase, or those who ingest magnesium-containing antacids or laxatives.

VIP is produced by the intestinal mucosa in increased amounts in the WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome. VIP causes diarrhea by stimulating mucosal adenylate cyclase activity, and therefore would be expected to cause a secretory diarrhea. In such a condition, fasting would not decrease the stool volume until the patient becomes severely dehydrated.

Typically, travelers’ diarrhea is watery and occurs within 3 to 6 days of arriving in another country, or on return. Symptoms usually last for 2 to 3 days and resolve spontaneously. The most common pathogens responsible are the enterotoxigenic strains of Escherichia coli, which can elaborate heat-labile and heat-stable enterotoxins. The heat-labile toxin acts similarly to cholera toxin, whereas the heat-stable toxin stimulates mucosal guanylate cyclase activity. Other types of diarrhea-producing E. coli and their associated symptoms are the enteropathogenic type, which causes watery diarrhea, predominantly in children and newborns; the enteroinvasive type, which causes bloody diarrhea (dysentery) in children and adults, usually after the ingestion of contaminated food and water; and the enterohemorrhagic type, which causes bloody diarrhea in people of all ages and is transmitted through contaminated food (often poorly cooked hamburger). Serotype 0157:H7 of the enterohemorrhagic type has been identified in several outbreaks of infection characterized by particularly severe disease (hemolytic uremic syndrome).

Other pathogens associated with travelers’ diarrhea include Shigella and Salmonella species, C. jejuni, and Vibrio parahaemolyticus. Because of the numerous causes of traveler’s diarrhea, the effect of fasting is usually unpredictable.

The osmotic diarrhea that occurs only after drinking large amounts of carbonated beverages is due to the ingestion of large amounts of fructose, which is the sugar used to sweeten these beverages (although not diet drinks) and comes in the form of corn syrup. Fructose is poorly absorbed by the proximal small intestinal mucosa. Cessation of fructose intake should stop the diarrhea.

Pseudomembranous colitis (PMC) caused by Clostridium difficile is a likely diagnosis in this instance, given the patient’s recent antibiotic use. The disease is usually self-limited, with the diarrhea dissipating 5 to 10 days after discontinuation of the offending antibiotic. Clindamycin was the first drug proved to cause PMC; later, ampicillin, because of its widespread use, was the drug most commonly implicated, but virtually any antibiotic can be responsible. In healthy adults, C. difficile colonization rates of 2% to 3% have been reported, whereas the rates in adults receiving antimicrobials but without diarrheal symptoms are as high as 10% to 15%.

The most commonly used method for diagnosing PMC is the cytotoxicity assay, which involves observation of the cytopathic effect produced by the toxin on a cell culture; the assay has a sensitivity of 95% to 97%. Although the latex agglutination test for the presence of toxin is both cheaper and faster to perform, it has a sensitivity of only approximately 85%. Gross colonic abnormalities in patients with PMC, which can be seen endoscopically, typically occur in the descending and sigmoid colon, making flexible sigmoidoscopy an adequate examination in most cases; however, cases with only right-sided involvement have been reported. The endoscopic findings in patients with PMC include erythematous, friable mucosa with characteristic pseudomembranes. Care must be taken to rule out bacterial or parasitic infections (especially C. jejuni and Entamoeba histolytica) and inflammatory bowel disease.

The recommended treatment for less severe cases of PMC consists of either oral metronidazole (250 mg four times a day) or vancomycin (125 to 500 mg four times a day). Parenteral doses of metronidazole [500 mg intravenously (IV) every 6 hours] should be given only when oral medication cannot be tolerated. The IV administration of vancomycin is not effective. The rates of relapse are similar for both metronidazole and vancomycin and range from 10% to 15%. Cholestyramine has been reported to be effective in the treatment of mild PMC or as an adjunctive measure, presumably by binding the toxin intraluminally. Cholestyramine may be used in conjunction with metronidazole but not with vancomycin, because it can bind and inactivate vancomycin. Recently, the oral administration of the nonabsorbed antibiotic rifaximin and probiotics (preparations of viable bacteria with therapeutic physiologic effects) has been reported effective in the treatment of recurrent PMC.

Giardia lamblia infection causes a deficiency in the intestinal disaccharidases, including lactase. The disaccharidase deficiency can cause cramping and flatulence after the ingestion of carbohydrates, especially milk products.

The evaluation of a case of acute diarrhea involves routine culture of the stools, examination of the stools for the presence of ova and parasites, and, in some instances, flexible sigmoidoscopy.

One of the viral causes of acute diarrhea is the Norwalk agent that is seen in family and community epidemics, usually in older children and adults. It has an incubation period of 1 to 2 days. Vomiting and low-grade fever are common. Rotavirus infection is seen in infants and young children, primarily in winter; the incubation period is 1 to 3 days. Vomiting (occurring in 80%), upper respiratory symptoms, and fever (found in 30%) are common. Enteric adenovirus is a sporadic disease of infants and young children, and is often associated with fever and upper respiratory symptoms.

There are many bacterial causes of acute diarrhea. In Shigella infection, the major site of mucosal invasion is the colon. Penetration of the mucosa and invasion of the bloodstream are rare. Crampy abdominal pain and tenesmus are hallmarks of the disease. The organism produces an enterotoxin (Shiga toxin) that activates adenylate cyclase and causes a watery diarrhea in the early stages of the disease. Bloody diarrhea soon follows. The mainstay of therapy is supportive, with rehydration most important. Narcotics and anticholinergic medications should be avoided. Antibiotic treatment is reserved for those cases that do not resolve spontaneously in several days; ampicillin (500 mg four times a day, orally, for 5 days) is usually effective, but trimethoprim/sulfamethoxazole (one double-strength tablet twice daily) can be used for resistant strains. Chronic carriers, although uncommon, are prone to intermittent attacks of the disease.

The major site of Salmonella invasion is the ileal and, sometimes, the colonic mucosa. Bacteremia, with or without associated GI symptoms, occurs in approximately 10% of the cases. Carriers are usually asymptomatic, with the organism harbored in the gallbladder. Periumbilical pain and bloody diarrhea last approximately 5 days. Because antimicrobial treatment significantly increases the carrier rate, it is reserved for those cases that do not resolve spontaneously or for those patients who have an underlying predisposing condition.

C. jejuni is a common bacterial pathogen isolated from patients with acute bacillary diarrhea. Invasion of the mucosa occurs predominantly in the colon. Two features that may distinguish C. jejuni infection from other causes of bacterial diarrhea are (a) a prodrome of constitutional symptoms, and (b) a biphasic course, with initial improvement followed by worsening. No antibiotic regimen has been shown to lessen the symptoms or the time course of the disease.

Yersinia enterocolitica can cause enterocolitis, with a clinical picture consisting of fever, abdominal cramping, and bloody diarrhea lasting 1 to 3 weeks. Watery diarrhea is seen, possibly due to enterotoxin production. Invasive ileitis is also a feature of these infections.

Other diarrhea-producing enteric pathogens include E. histolytica, G. lamblia, and Strongyloides stercoralis.

The presence of numerous leukocytes in stool specimens implies the existence of active inflammation of the intestinal mucosa. In cases of acute diarrhea, the presence of pus implies invasion (Shigella, Salmonella, C. jejuni, and E. histolytica). Although Shigella, E. histolytica, and C. jejuni infections are usually associated with most pus, patients with PMC also often have large numbers of fecal leukocytes. In cases of chronic diarrhea, the presence of pus most often implies tuberculosis, amebic colitis, ischemic colitis, or inflammatory bowel disease (ulcerative colitis more so than Crohn’s disease, unless the latter involves the colon).