BACKGROUND

Lymphocytic and collagenous colitis are uncommon disorders characterized by chronic watery diarrhea and histologic evidence of chronic mucosal inflammation in the absence of endoscopic or radiologic abnormalities of the colon. The two disorders are distinct histologically but have been grouped under the term microscopic colitis. They differ principally by the presence or absence of a thickened collagenous band, which is located in the colonic subepithelium in collagenous colitis.

The term collagenous colitis was used first in 1976 by Lindstrom to describe the findings in a middle-aged woman with chronic diarrhea in whom evaluation was normal except for colonic biopsies that showed a thickened band of subepithelial collagen and increased lymphocytes in the lamina propria.¹ Histologically, the subepithelial collagen deposits resembled those in the small intestine of patients with collagenous sprue. The term microscopic colitis was used first in 1980 by Read and associates, who detailed a group of patients with chronic idiopathic diarrhea, a subset of which had a normal-appearing colon at colonoscopy but abnormal histopathology on biopsy.² Subsequent review showed that most of these patients had collagenous colitis, but some had increased lymphocytes in the lamina propria in the absence of a thickened collagen band. The term lymphocytic colitis was proposed in 1989 by Lazenby and associates³ as a more-specific histopathologic diagnosis to distinguish this entity from patterns of microscopic colitis in which other cellular elements such as eosinophils, mast cells, or neutrophils predominate.

Whether collagenous and lymphocytic colitis represent two ends of the spectrum of a single disorder or different entities remains uncertain, but their clinical presentations, evaluations, and treatments are similar.

EPIDEMIOLOGY

Collagenous and lymphocytic colitis occur most commonly between ages 50 and 70 years. Both have a strong female predominance and frequent association with arthritis, celiac disease, and autoimmune disorders. In a large population-based study in Spain, the demographic features of collagenous and lymphocytic colitis were similar: The disorders were found in 9.5 of every 100 patients with chronic watery diarrhea and normal-appearing mucosa on colonoscopy, of whom 61% had lymphocytic colitis; the incidence rates in the general population of lymphocytic colitis and collagenous colitis were 3.1/100,000 and 1.1/100,000, respectively.⁴ This latter observation contrasts strikingly with published reports of more than 400 cases of collagenous colitis compared with more than 60 cases of lymphocytic colitis, a finding that suggests there may be a publication bias to explain the discrepancy. The overall mean annual incidence of both colitides was 4.2 per 100,000 inhabitants in Spain, similar to the rates from an epidemiologic study conducted in Sweden⁵ but lower than the 8.6 cases for 100,000 person years in the United States.⁶ Although the incidence of these microscopic colitides clearly is higher in older age groups, both entities have been reported in children and teenagers, in whom the clinical presentation is similar to that of adults.

PATHOLOGY

In both collagenous and lymphocytic colitis, there is a modest increase of mononuclear cells within the lamina propria and between crypt epithelial cells, consisting mainly of CD8⁺ T lymphocytes, plasma cells, and macrophages.³ There may be flattening of the surface epithelial cells, a mild decrease in the number of goblet cells, hyperplasia of Paneth cells, and an increased number of intraepithelial lymphocytes (Fig. 124-1). Neutrophils are not prominent, and cryptitis and crypt distortion are unusual.

Figure 124-1. Histopathology of lymphocytic colitis. The arrows point to surface epithelial damage with increased numbers of intraepithelial lymphocytes. In addition, there is a superficial plasmacytosis without crypt distortion. Although a few intraepithelial neutrophils may be seen, widespread cryptitis is not a feature of lymphocytic colitis. (Hematoxylin and eosin.)

(Courtesy of Feldman M, Boland CR, editors. Slide Atlas of Gastroenterology and Hepatology. Philadelphia: Current Medicine; 1996.)

In collagenous colitis, there is a thickened subepithelial collagen layer, which may be continuous or patchy (Fig. 124-2). In normal colon, the width of this collagen band is less than 4 to 5 µm and consists predominantly of type IV collagen, whereas in collagenous colitis, it is greater than 10 µm, averages 20 to 60 µm,⁷ and is composed of type VI collagen and tenascin as well as lesser amounts of types I and III collagen. Tenascin is a glycoprotein that is a marker of matrix remodeling and is a product of intestinal subepithelial myofibroblasts.⁸ These changes are absent in lymphocytic colitis and suggest that the two main forms of microscopic colitis should be considered as separate disease entities.

Figure 124-2. Histopathology of collagenous colitis. A thickened irregular subepithelial collagen table (open arrow) with patchy surface epithelial damage is shown. The surface epithelium also contains increased numbers of intraepithelial lymphocytes (closed arrow). In addition, there is a superficial plasmacytosis with prominent numbers of eosinophils. Crypt distortion and crypt abscesses are not usually seen in collagenous colitis. (Hematoxylin and eosin.)

(Courtesy of Feldman M, Boland CR, editors. Slide Atlas of Gastroenterology and Hepatology. Philadelphia: Current Medicine; 1996.)

Although inflammatory changes occur diffusely throughout the colon in collagenous colitis, the characteristic collagen band thickening is highly variable, occurring in the cecum and transverse colon in more than 80% of cases and in the rectum in less than 30% of cases. Although involvement of the left colon appears to be less intense than involvement of the right colon, multiple biopsies of the left colon taken above the rectosigmoid during flexible sigmoidoscopy are sufficient to make the diagnosis in approximately 90% of cases.⁷ The diagnosis of collagenous colitis requires both mucosal inflammation and a thickened collagen band; artifact resulting from poor orientation can give the mistaken appearance of a thickened basement membrane. It has been suggested that tenascin immunohistochemistry be used as a routine test in the diagnosis of microscopic colitis.⁸

ETIOLOGY AND PATHOGENESIS

The cause(s) of collagenous and lymphocytic colitis is (are) unknown. The most widely held hypothesis is that they are inflammatory disorders arising from epithelial immune responses to intraluminal dietary or bacterial contents. This hypothesis is supported by the regression of inflammation following diversion of the fecal stream and recurrence of inflammation following restoration of intestinal continuity in three patients.⁹ The identity of the inciting antigenic factors is uncertain, although medications,^10,11 bile salts, toxins, and infectious agents¹² have been postulated.

The strong association of rheumatologic diseases with microscopic colitis has raised the possibility that nonsteroidal anti-inflammatory drugs (NSAIDs) might play an etiologic role. One well-controlled study¹³ found that chronic NSAID use occurred more frequently in patients with collagenous colitis than in age- and gender-matched controls (61% vs. 13%; P < 0.02), a finding confirmed by a case-control study.¹⁰ One postulated mechanism by which NSAIDs might damage the colon is by increasing colonic permeability to allow luminal antigens to enter the lamina propria and promote inflammation. Other medications implicated include selective serotonin reuptake inhibitors (SSRIs), specifically sertraline, for collagenous colitis; and SSRIs, beta-blockers, statins, and bisphosphonates for lymphocytic colitis.¹⁰ Because many patients with collagenous or lymphocytic colitis have not used these medications, and because use of these drugs in older adults is common but these disorders are uncommon, other causes have been invoked, including genetic susceptibility. Genetic susceptibility is supported by the finding that 12% of patients with microscopic colitis have a family history of inflammatory bowel disease (IBD).¹¹

Approximately 20% to 30% of patients with celiac disease have been reported to have lymphocytic colitis, raising the possibility of similar pathogenetic mechanisms.¹⁴ In one study, 40% of patients with collagenous colitis had small intestinal biopsies that were compatible with celiac disease,¹⁵ although in another study, the frequency of celiac disease was only 2% of 45 patients with collagenous colitis¹⁶ and 9% of 199 patients with lymphocytic colitis.¹¹ Furthermore, patients with microscopic colitis do not respond to a gluten-free diet, and neither collagenous nor lymphocytic colitis is associated with human leukocyte antigens (HLAs) B8 and DR3, as is celiac disease. Finally, CD8⁺ T intraepithelial cells are predominant in both collagenous and lymphocytic colitis, in contrast to celiac disease, in which CD3 and CD8 predominate.

Because autoimmune disorders such as arthritis and thyroid abnormalities have been described in patients with collagenous and lymphocytic colitis,¹¹ there have been continued efforts to associate microscopic colitis with various autoimmune HLA haplotypes and serum markers. One small study showed that HLA-A1 antigens were expressed with increased frequency in lymphocytic but not collagenous colitis,¹⁷ and another study showed similar abnormal expressions of HLA-DR antigens by mucosal epithelial cells in both conditions.¹⁸ Whether such abnormalities are the cause or the result of these disorders is unknown. Another study found similarities in HLA-DQ loci between patients with celiac disease and patients with either collagenous or lymphocytic colitis.¹⁹ Although gluten is not the inciting antigen in microscopic colitis, similar immune mechanisms may be involved in celiac disease and microscopic colitis.

The pathogenesis of the increased collagen band in collagenous colitis is unclear. Initially, it had been assumed that collagen synthesis is increased,¹ but colonic biopsies from patients with the disease showed decreased levels of interstitial collagenase, suggesting that reduced matrix degradation might contribute to the accumulation of matrix proteins.²⁰

The mechanism of diarrhea in microscopic colitis is related to the severity of inflammation and not the extent or thickness of the collagen band. Perfusion studies have demonstrated defective active and passive absorption of sodium and chloride and reduced chloride-bicarbonate exchange in the colon²¹; two of six subjects had coexisting abnormalities of small intestinal fluid and electrolyte absorption. Other investigations have correlated colonic fluid absorption with the severity of inflammation.²² A potential role for soluble mediators is suggested by a report that diarrhea was resolved by a histamine H₁ antagonist in a patient with microscopic colitis characterized by increased numbers of mast cells.²³ It has been suggested that bile acid malabsorption might contribute to diarrhea in patients with collagenous colitis and that treatment with a bile acid-binding resin such as cholestyramine might lead to a reduction in diarrhea. Bile acids are unlikely to cause the histologic changes observed in collagenous colitis, however, and a reduction in diarrhea with cholestyramine was not associated with a decrease in colitis. Successful treatment of collagenous colitis with budesonide, however, was associated with increased bile acid absorption and normalization of the ⁷⁵SeHCAT (selenium-75–labeled homocholyltaurine) test for bile acid malabsorption.²⁴

CLINICAL AND LABORATORY FEATURES

Patients with collagenous and lymphocytic colitis usually present with chronic watery diarrhea, with an average of eight stools each day ranging in volume from 300 to 1700 g per 24 hours²¹ and associated with occasional fecal incontinence and abdominal cramps. Symptoms decrease with fasting.⁵ Nausea, weight loss, and fecal urgency are variably present. Diarrhea generally is long-standing, lasting from months to years, with a fluctuating course of remissions and exacerbations. In one series of 172 patients, the median time from the onset of symptoms to diagnosis was 11 months,¹⁶ whereas in another smaller series, the median time to diagnosis was 5.4 years.²⁵ Physical examination usually is unremarkable, and blood is not detected in the stool. Routine laboratory studies also are normal.

Examination of fresh stools showed fecal leukocytes in 55% of 116 patients with collagenous colitis.¹⁶ Mild steatorrhea, mild anemia, low serum vitamin B₁₂ levels, and hypoalbuminemia have been reported in varying numbers of patients and are not characteristic. Autoimmune markers that have been identified in patients with collagenous colitis include antinuclear antibodies (in up to 50%), perinuclear antineutrophil cytoplasmic antibodies (pANCAs) (in 14%), rheumatoid factor, and increased C₃ and C₄ complement levels,²² but none of these markers is of diagnostic value.

Colonoscopic examination usually is normal. Nonspecific abnormalities including patchy edema, erythema, friability, and an abnormal vascular pattern were reported in one study,²⁶ whereas mucosal lacerations in the ascending and transverse colons have been reported in a few patients with collagenous colitis.²⁷

DIFFERENTIAL DIAGNOSIS

Infectious agents should be excluded by testing the stool for enteric pathogens, ova and parasites, and Clostridium difficile toxin. In many patients incorrectly diagnosed with irritable bowel syndrome (IBS), IBS can be excluded if colonic biopsies are abnormal and if stool volume is increased—both of which are uncharacteristic of IBS.

Many other diseases can produce colitis, but they should be distinguishable on histologic grounds. Acute infectious colitis is characterized by neutrophilic inflammation and decreased intraepithelial lymphocytes. Eosinophilic enterocolitis of the mucosal type is characterized by eosinophilic infiltration, shortened crypts, inflammation of the deeper parts of the lamina propria, and absence of increased intraepithelial lymphocytes. Amyloidosis has been mistaken for collagenous colitis, but its distribution includes the basement membranes of the crypts and blood vessels as well as the epithelium; confirmation can be made by histochemical staining. Mild cases of ulcerative colitis and Crohn’s disease should present no diagnostic confusion in view of the characteristic endoscopic and histologic findings and absence of increased intra-epithelial lymphocytes. Hormone-producing tumors, surreptitious laxative abuse, and hyperthyroidism can be excluded on clinical and biochemical grounds.

TREATMENT

There have been few controlled trials of treatment for either collagenous or lymphocytic colitis, and therapy is largely empiric. Evaluation of therapy is difficult, because both disorders usually exhibit a relapsing and remitting course over many years. No single agent works in all cases.²⁸

About one third of patients respond to antidiarrheal agents, such as loperamide or diphenoxylate with atropine, as well as bulking agents such as psyllium or methylcellulose; clinical response is not associated with improvement of inflammation or collagen thickness. In an open-label trial of bismuth subsalicylate (eight chewable tablets per day for eight weeks) in 12 patients, diarrhea resolved and stool weight was reduced within two weeks; in nine patients colitis resolved with disappearance of the collagen band thickening.²⁹ Over a seven- to 28-month follow-up, nine patients remained well, two were well but required retreatment, and one had persistent diarrhea. Both collagenous and lymphocytic colitis responded similarly, and there were no side effects of treatment; a subsequent controlled trial by the same investigators published only in abstract form confirmed these findings. Although the basis for its efficacy is unknown, bismuth subsalicylate possesses antidiarrheal, antibacterial, and anti-inflammatory properties; bismuth enemas have been reported to be effective in ulcerative colitis and chronic pouchitis.³⁰

Other treatment trials for collagenous and lymphocytic colitis have studied 5-aminosalicylate (mesalamine) compounds, glucocorticoids, and bile acid resins, alone or in combination; these agents appear to improve diarrhea and inflammation in some, but certainly not all, patients.²⁸ Although glucocorticoids given by either the oral or the rectal route provide symptomatic improvement and decrease inflammation in more than 80% of cases, relapse usually occurs quickly after the drug is stopped.^5,31 Moreover, long-term use of glucocorticoids has undesirable effects, especially in older patients. Other immunosuppressants, such as azathioprine and 6-mercaptopurine, have been reported to be effective, but there are no sizable studies using these agents.^29,32

Budesonide has been reported to be highly effective over a six- to eight-week period in three placebo-controlled trials in patients with collagenous colitis.^33–35 Budesonide is a topically acting synthetic corticosteroid with both a high receptor-binding affinity in the mucosa and a high first-pass effect in the liver. In view of its proven efficacy, budesonide should be considered over 5-aminosalicylates or bile acid resins in patients who do not respond to antidiarrheal agents and bismuth subsalicylate.^36,37

The only report of surgery for collagenous colitis involved nine patients who underwent ileostomy for disabling refractory collagenous colitis, after which all had symptomatic and histologic remission.²⁸ In patients in whom intestinal continuity was restored, the disease recurred, and of three patients who underwent proctocolectomy with ileal pouch-anal anastomosis, problematic diarrhea occurred. Ileostomy should be considered only as a last resort, but it appears to be effective in patients with disabling and refractory symptoms.

Based on available data, the treatment algorithm shown in Figure 124-3 is proposed.

Figure 124-3. Algorithm for the treatment of collagenous or lymphocytic colitis.

BACKGROUND AND EPIDEMIOLOGY

Diversion colitis is an inflammatory process that occurs in the diverted segment of colon and rectum after surgical diversion of the fecal stream. The entity was first reported in 1981 by Glotzer and colleagues in 10 patients who had undergone ileostomy or colostomy for various indications other than IBD.³⁸ Since then, diversion colitis has been found in patients who have undergone surgical diversion for many indications, although it has been reported to occur more commonly in patients with IBD (87%) than in those with noninflammatory conditions (28%).^39,40 The prevalence of diversion colitis has been underestimated because many patients are asymptomatic, even though histologic changes are likely to occur in diverted segments of the colon within months of surgical diversion.

PATHOLOGY

A spectrum of histologic changes has been described in diversion colitis, ranging from lymphoid follicular hyperplasia and mixed mononuclear and neutrophilic infiltration to severe inflammation with crypt abscesses, mucin granulomas, and Paneth cell metaplasia^41,42; however, large ulcers and transmural changes are absent and crypt architecture generally is preserved. Endoscopic findings include erythema, friability, nodularity, edema, aphthous ulcerations, exudates, and frank bleeding, as in idiopathic IBD. After extended periods following diversion, inflammatory pseudopolyps and strictures can develop.

PATHOGENESIS

Diversion colitis appears to be caused largely by luminal nutrient deficiency of the colonic epithelium. The principal nutrient substrates of the colonocytes are luminal short-chain fatty acids (SCFAs), which are metabolic products of carbohydrate and peptide fermentation by anaerobic bacteria.^43,44 Roediger demonstrated that SCFAs are the major and preferred energy source for colonic epithelium and that the distal colon is more dependent on SCFAs for its metabolic needs than is the proximal colon.⁴⁵ Butyrate supplies the bulk of oxidative energy to the distal colon, and acetate, glutamine, and ketones provide alternative sources of energy. Harig and associates demonstrated that the excluded segments of colon contain negligible amounts of SCFAs and that infusion of glucose results in no appreciable anaerobic fermentation.⁴⁶ The number of obligate anaerobes is reduced in the excluded colon, consistent with reduced production of SCFAs.⁴⁷ Further support for the SCFA nutrient deficiency hypothesis is from the report that instillation of enemas containing SCFAs resulted in disappearance of endoscopic changes within four to six weeks in four patients with diversion colitis, although resolution of histologic abnormalities was slower and incomplete.⁴⁶

Although SCFA deficiency has been widely accepted as the cause of diversion colitis, other observations suggest that this might not be the entire etiologic explanation. First, studies in children indicate that SCFA enemas are not universally successful in treating diversion colitis.⁴⁸ Second, in germ-free rodents with surgical diversion and in patients receiving long-term parenteral nutrition or elimination diets (circumstances in which luminal SCFA concentrations are low), mucosal atrophy occurs rather than inflammation.⁴⁹ Third, inflammation does not occur in urinary colon conduits from which the fecal stream has been diverted, and urine does not contain measurable SCFAs.⁵⁰ Finally, in a prospective, randomized, double-blind study of 13 patients with diversion colitis, butyrate enemas given for 14 days provided no improvement in either endoscopic or histologic parameters.⁵¹ In a subsequent study by the same group, administration of SCFAs did not affect the bacterial population in the excluded colon.⁵² Other luminal elements besides SCFA deficiency are likely to play a role, but the nature of such factors is unknown.

DIAGNOSIS

The diagnosis of diversion colitis is based on the clinical picture, endoscopic findings, and histology. Diagnosis is relatively straightforward in a patient without preexisting IBD, and stool specimens for C. difficile toxin,⁵³ ova and parasites, and cultures usually are adequate to exclude other etiologies.

In patients with a preoperative diagnosis of Crohn’s disease, diversion colitis must be distinguished from recurrent IBD. Colonoscopic findings such as linear ulcers and possibly strictures are said to favor Crohn’s disease, as do transmural inflammation, marked crypt architectural abnormalities, and epithelioid granulomas.³⁹ Lymphoid hyperplasia occurs in both disorders but tends to be more prominent in diversion colitis.⁵⁴ If rectal involvement with Crohn’s disease is absent before diversion, rectal inflammation is more likely to be caused by diversion than Crohn’s disease.^2,39,55

TREATMENT

The preferred treatment of diversion colitis is surgical restoration of colonic continuity, which rapidly reverses symptoms and histologic changes. If symptoms are moderate to severe and reanastomosis is not feasible, SCFA enemas in a volume of 60 mL and containing a mixture of 60 mmol/L of acetate, 30 mmol/L of propionate, and 40 mmol/L of butyrate with 22 mmol/L of sodium chloride per liter are administered through the anus or mucous fistula twice daily for four weeks and then decreased to once or twice weekly.⁴⁶ Such preparations are not commercially available and must be formulated by compounding pharmacies, making it the most expensive of the nonsurgical options.⁵⁶ There are anecdotal reports that 5-aminosalicylate and hydrocortisone retention enemas are effective as well.⁵⁷ Because they are available commercially, these agents are considered first-line therapies for most patients. One report suggested that intraluminal irrigation with soluble and insoluble fiber solutions improved endoscopic and histologic abnormalities and might be useful to reduce inflammation before surgical restoration of bowel continuity.⁵⁸

PATHOGENESIS

The causes of nonspecific colonic ulcers are unknown. Potential etiologies that have been suggested, albeit with little or no supporting evidence, include ischemia and cecal diverticulosis. Correlations with the use of drugs such as glucocorticoids, NSAIDs,^61,62 oral contraceptives, and oxyphenbutazone have been suggested, but cause has not been established and these drugs have not been implicated in most of the ulcer cases reported. It is likely that no single causative agent explains all cases. There have been reports of associations of nonspecific colon ulcers with chronic renal failure and renal transplantation,⁶³ Churg-Strauss syndrome,⁶⁴ Wegener’s granulomatosis,⁶⁵ Behçet’s disease, essential mixed cryoglobulinemia,⁶⁶ and systemic lupus erythematosus. Perhaps a mechanism common to all exists, but none has yet been identified.

CLINICAL FEATURES

The most common presenting symptoms are abdominal pain and bleeding. More than half of patients with nonspecific colon ulcers present with acute or chronic abdominal pain, often in the right lower abdomen and mimicking appendicitis.⁵⁹ One third have lower gastrointestinal bleeding with hematochezia, and 16% present with an abdominal mass, most often when the ulcer is located in the left or sigmoid colon. A cecal ulcer should be suspected in a patient with gastrointestinal bleeding when the clinical picture is otherwise consistent with appendicitis or in a patient with symptoms suggesting pelvic inflammatory disease, ovarian disease, or Crohn’s disease in the absence of these diseases.

DIAGNOSIS

Historically, nonspecific colonic ulcers usually were diagnosed at laparotomy after complications occurred. With the advent of endoscopy, many colonic ulcers are now diagnosed preoperatively and, in many cases, are managed conservatively.

Colonoscopy currently is the diagnostic test of choice.⁵⁴ Flexible sigmoidoscopy is inadequate because most colonic ulcers are beyond the reach of the instrument. Abnormalities have been described in up to 75% of air-contrast barium enemas⁵⁹ and include mucosal irregularities, intraluminal filling defects or narrowing, a mass effect, or localized colonic spasm (Fig. 124-5). Roentgen findings are nonspecific, however, and are diagnostically inferior to direct inspection by colonoscopy. Computed tomographic (CT) scans are most helpful in the presence of perforation or associated abscess formation.

Figure 124-5. Nonspecific ulcer of the colon. Film from a barium enema examination showing the lesion in Figure 124-4 (arrow). The initial interpretation was carcinoma of the ascending colon.

The key to the diagnosis of these ulcers is the exclusion of diseases that are associated with ulceration, including Crohn’s disease; infections such as tuberculosis, Entamoeba histolytica, cytomegalovirus, and Salmonella typhi; stercoral ulcers; and solitary rectal ulcer syndrome. Amyloidosis and neoplastic causes such as carcinoma and lymphoma are distinguished on histologic grounds but might not be distinguishable from nonspecific colonic ulcers on the basis of endoscopic appearance alone.

TREATMENT

Surgery is recommended for patients with ulcers complicated by perforation or by significant gastrointestinal bleeding and for those with persistent symptoms and failure of the ulcer to heal. In uncomplicated cases, however, an expectant approach has been advocated, with colonoscopy every six weeks to monitor healing. The most common surgical procedures are local excision of the ulcer, oversewing of the ulcer if there is significant bleeding, and occasionally, segmental colectomy.^54,67

PATHOGENESIS

The pathogenesis of these uncommon lesions is unknown but is thought to involve direct contact of the NSAID with colonic mucosa. The vast majority of cases involve oral intake of NSAIDs, and most of the patients in one study were known to have taken extended-release formulations.⁶⁸ Half had used diclofenac, and most patients had lesions in the proximal colon. The injury is presumed to involve a high local concentration of active NSAID, which increases intestinal permeability, a prerequisite for NSAID-induced enterocolopathy. This is in contrast to gastroduodenal injury, which is thought to be mediated more often by systemic effects. Postulated mechanisms of injury include prostaglandin inhibition alterations in mucosal blood flow and increased permeability to injurious luminal substances. The risk of lower gastrointestinal toxicity is reduced by the use of selective COX-2 inhibitors.⁷⁰

CLINICAL FEATURES

The most common clinical presentations include occult blood in the stool, iron-deficiency anemia or frank bleeding, abdominal pain, or change in bowel habits. Other findings can include intermittent bowel obstruction, diarrhea, or colonic perforation with an acute abdomen. Many patients have an underlying rheumatologic disorder and have been using NSAIDs chronically, although lesions have been reported after using NSAIDs for only a few days.⁷¹

DIAGNOSIS

As with nonspecific colonic ulcers, colonoscopy is currently the diagnostic test of choice; flexible sigmoidoscopy is inadequate because most diaphragm disease colon ulcers are proximal to the descending colon (Fig. 124-6). Whereas the differential diagnosis of nonspecific colonic ulcers and NSAID-associated colitis and erosions is broad, the presence of characteristic diaphragmatic webs with normal intervening mucosa in a setting of NSAID use is virtually pathognomonic.

Figure 124-6. A, Colonoscopic photograph showing a diaphragmatic stricture (arrow) associated with chronic use of nonsteroidal anti-inflammatory drugs. B, After balloon dilation there is no residual stricture.

(Courtesy of Deepak Gopal, MD, Madison, Wisc.)

TREATMENT

For nonstricturing NSAID lesions, discontinuing the NSAID often is curative and is essential to management; obstructive symptoms associated with strictures, however, require more-aggressive management. For strictures that are easily accessible, endoscopic dilation with a through-the-scope (TTS) balloon has been reported to be safe and effective.⁷² If endoscopic dilation is not possible, the area should be marked endoscopically to guide the surgeon, because there may be no serosal abnormalities or palpable areas of transition to guide resection. Surgery also is indicated for significant bleeding or perforation and when carcinoma cannot be excluded with confidence.

RADIOLOGIC AND PATHOLOGIC FEATURES

Heilbrun originally described the following characteristics in his original case report: loss of haustrations, pseudostrictures, dilated colon and terminal ileum, and gaping of the ileocecal valve⁷⁸; similarity to the radiologic appearance of chronic ulcerative colitis was noted in this and subsequent studies. Characteristic changes are not always found throughout the colon, and there is a predilection for involvement of the ascending colon. Pathologic changes in resected specimens of cathartic colon have included mucosal atrophy, chronic inflammation with thickening of the muscularis mucosae, submucosal fatty infiltration, and mild fibrosis. Irreversible strictures and degenerative changes in intestinal neurons are absent. Neuronal changes have been found in patients with chronic laxative abuse, but these patients did not exhibit cathartic colon as defined here.⁸¹

CHANGING ROLE OF LAXATIVES IN COLON DAMAGE

The original suggestion that irritant laxatives, predominantly anthraquinones, damage the colon was based on studies in laboratory animals and in colons resected from laxative abusers.⁸² Although mucosal atrophy and abnormalities of the enteric nervous system were described, the identities of the laxatives were not documented, nor was there information concerning preexisting conditions that might have prompted chronic use of laxatives.

Subsequent studies have reported changes in colonic epithelial cells and the submucosa in patients with long-term laxative abuse, and both anthraquinones and bisacodyl have been implicated.⁸¹ The unclear nature and duration of laxative use and the inability to exclude preexisting conditions, however, make the significance of these observations uncertain. Studies in rodents and in chronically constipated women do not support the deleterious effect of anthraquinones on the ultrastructure of colonic nerves,^83,84 nor is there evidence to suggest that sennosides, bisacodyl, or related substances cause significant morphologic damage to the colonic enteric nervous system in either experimental animals or humans. Perhaps one or more laxatives that are no longer in use, such as podophyllin, might have accounted for cases of cathartic colon, because no case of cathartic colon has been reported in persons who began to use or abuse irritant laxatives after 1960.⁸⁵

CLINICAL FEATURES

Habitual laxative users and abusers often complain of abdominal discomfort, bloating, fullness, or inability to defecate completely without using laxatives. In the more-severe cases, electrolyte and fluid abnormalities such as hypokalemia and hypovolemia are associated with excessive thirst and weakness; protein-losing enteropathy is uncommon. All symptoms are reversible on withdrawal of laxatives or conversion to a more-appropriate regimen of laxative use, if there is no underlying diagnosis such as IBS.

TREATMENT

Treatment of cathartic colon and symptoms of chronic laxative use is focused on reducing or eliminating irritant laxatives, substituting bulking or osmotic agents, and retraining the bowel. Although cathartic colon is often thought to be irreversible, there is evidence that it can partially or completely reverse after withdrawal of the offending laxatives. In severe or refractory cases, subtotal colectomy or proctocolectomy has been effective.

The cathartic colon is of historic interest and is unlikely to be identified in current clinical practice. There is no evidence that currently used laxatives can produce this entity. The term cathartic colon should not be confused with “chronic laxative abuse syndrome,” nor should the term imply that current laxatives are dangerous if used chronically but appropriately.

ETIOLOGY AND PATHOGENESIS

Damage to the colon has been reported after exposure to a number of rectally administered agents (Table 124-1), the better known of which are soaps and detergents used as “cleansing” enemas.^96,97 Other offending substances include hydrogen peroxide,⁹⁸ water-soluble contrast agents such as sodium diatrizoate (Hypaque, Gastrografin),⁹⁹ vinegar, potassium permanganate, herbal medications,¹⁰⁰ glutaraldehyde,^101,102 formalin,¹⁰³ and alcohol.¹⁰⁴ Milder damage to the mucosa occurs after use of monobasic or dibasic sodium phosphate enemas,¹⁰⁵ bisacodyl suppositories, and oral henna.¹⁰⁶ Colonic damage presumably occurs from a detergent, hypertonic, or direct toxic effect on the mucosa. The severity of the reaction depends on the type and concentration of the substance, the duration and extent of its contact with the mucosa, and perhaps the presence of underlying colonic disease.¹⁰⁷

Table 124-1 Chemical Agents That Cause Colitis When Given as Enemas

Soaps consist of a number of substances, including strong alkali, potash, phenol, and sodium and potassium salts of long-chain fatty acids. These agents produce liquefaction necrosis with mild to severe inflammation and saponification of the layers of the colon wall. Acute histologic changes include necrosis, which leads, in more severe cases, to ulceration and formation of granulation tissue. Acute colitis can heal without residua or with fibrosis and scarring, or it can progress to transmural necrosis and perforation. Severity of damage probably is related to the concentration of soap and duration of contact with the mucosa. Endoscopic findings have ranged from loss of the normal mucosal vascular pattern to aphthae to mucosal sloughing and ulceration.

Hydrogen peroxide enemas no longer are commonly used, but at one time they were employed to relieve meconium ileus and to remove fecal impactions. There are reports of severe damage associated with use of hydrogen peroxide, including severe colitis, pneumatosis coli, perforation, sepsis, and death.⁹⁸ Within minutes of contact, diffuse mucosal emphysema occurs, and after about an hour, the colon can become ischemic and eventually ulcerate (Fig. 124-9). Acute colitis also has been reported after using a colonoscope that had been disinfected with glutaraldehyde (Fig. 124-10).^101,102

Figure 124-9. Colonoscopic photographs of chemical colitis in a patient to whom hydrogen peroxide was given to help remove a fecal impaction. Both panels show the snow-white sign, referring to the appearance of the stark white necrotic mucosa.

(Courtesy of Lawrence J. Brandt, MD, Bronx, NY.)

Figure 124-10. Colonoscopic photograph of chemical colitis in a young man who had had a normal colonoscopy three hours before this photograph was taken. Colitis was caused by glutaraldehyde that had been used to disinfect the flexible sigmoidoscope after its previous use but that had not been sufficiently cleansed from the instrument. He complained of “agonizing” pain during the sigmoidoscopic examination and began to pass bright red blood two hours later.

(Courtesy of Lawrence J. Brandt, MD, Bronx, NY.)

Colitis also has followed the use of several hyperosmolar water-soluble contrast materials that often are employed to opacify the colon in cases of partial obstruction and to treat fecal impactions in adults.⁹⁹ Damage is believed to occur because of the hypertonicity of these agents, but the addition of Tween 80 to hyperosmolar agents to improve mucosal contrast might have contributed to the mucosal damage because of its detergent properties. Most reports of injury have occurred in the colon proximal to an obstruction and mainly in the right colon, suggesting that prolonged contact with these agents predisposes to mucosal injury.

PREVENTION AND TREATMENT

Proper cleaning and rinsing of endoscopes are required to minimize exposure of the patient to injurious disinfecting chemicals. Protocols require strict adherence to proper maintenance and adjustments in the rinse cycle of disinfecting machines.¹⁰² Forced-air drying and rinsing of endoscope channels and the exterior of the instrument should ensure a chemical-free procedure.

Rectal instillation of substances other than commercially available enemas for medicinal purposes should be discouraged. Patients and health care professionals should be cautioned that soapsuds enemas should not be used.

Treatment of chemical colitis is largely supportive, with intravenous fluids and broad-spectrum antibiotics. Surgery is indicated in severe cases of bowel necrosis leading to gangrene or perforation. Most patients recover completely four to six weeks after injury.

ETIOLOGY

Several theories have been suggested to explain the large and varied number of conditions associated with pneumatosis cystoides intestinalis. The most plausible theories are the mechanical theory and the bacterial theory.

According to the mechanical theory, intraluminal gas enters the bowel wall under pressure through a defect or potential defect in the intestinal mucosa. The mucosal defect can result from direct trauma or increased intraluminal pressure. This hypothesis could account for reports of pneumatosis after sigmoidoscopy without biopsy; in cases of colitis, perforated duodenal ulcers, and jejunal diverticula; and after intestinal anastomoses. The plausibility of this theory is diminished by the absence of a connection between the mucosa and the cysts and the presence of elevated levels of hydrogen gas in the cysts.¹¹⁴

The bacterial theory suggests that the cystic gas collections are the by-products of bacteria, specifically those that produce hydrogen. This theory has been supported by clinical observations and laboratory experiments. In laboratory animals, pneumatosis coli can be induced by injecting gas-forming bacteria into the bowel wall. In addition to local invasion of the intestinal wall, bacteria can produce gas cysts by manufacturing large amounts of hydrogen gas as a result of the fermentation of carbohydrates. Levitt and Olsson theorized that the high hydrogen tension in the colonic lumen leads to rapid diffusion of this gas into an intramural gas bubble and can cause N₂, O₂, and CO₂ to diffuse from the circulation into the bubble.¹¹⁵ According to their theory, the gas bubble enlarges if there is continued diffusion of hydrogen into it. Indeed, high hydrogen content in the cysts has been documented,¹¹⁶ and cysts regress in patients fed an elemental diet to decrease carbohydrate substrate for colonic bacteria. Two major observations argue against the bacterial theory of pneumatosis: bacteria are not cultured from cysts, and with cyst rupture and pneumoperitoneum, peritonitis is not seen.

It has been hypothesized that gas cysts can form by counterperfusion supersaturation of H₂ gas in which super H₂ production by colonic bacteria provides the condition for H₂ tension in the colonic lumen to approach the level of N₂ tension in the blood.¹¹⁷ One such mechanism is by exposure to certain drugs, such as chloral hydrate, that inhibit the growth of H₂-consuming methanogenic bacteria in the colon and thereby increase net H₂ production.¹¹⁷ Another possible etiologic setting is the administration of a nonabsorbable carbohydrate such as lactulose, thereby increasing colonic hydrogen production, in a setting where bacteria metabolizing H₂ are deficient.¹¹⁸

Successful treatment with antibiotics^116,118 and colonic washouts also supports a bacterial etiology for pneumatosis coli.¹¹⁹ In one study, stools from patients with pneumatosis coli were demonstrated to lack two major species of hydrogen-consuming bacteria.¹¹⁴ Because hydrogen normally is produced only in the colon and not in the small intestine, pneumatosis coli may differ from pneumatosis intestinalis with respect to pathogenic mechanisms.

CLINICAL FEATURES AND DIAGNOSIS

The incidence of pneumatosis coli is highest in the sixth decade, with equal frequency in men and women.¹¹³ In most cases, pneumatosis is an unexpected finding on abdominal plain films. The most common symptoms are diarrhea (68%), mucus discharge (68%), rectal bleeding (60%), and constipation (48%).¹¹³ Approximately 3% of patients present with a complication of pneumatosis coli, including pneumoperitoneum, volvulus, intestinal obstruction, intussusception, tension pneumoperitoneum, and intestinal perforation. Physical examination might detect an abdominal mass, and rectal examination might reveal the cystic lesions.

A plain abdominal film can show radiolucent clusters or streaks along the bowel wall with pneumoperitoneum, if a cyst has ruptured. A markedly redundant sigmoid colon as well as the outline of the cysts or linear streaks may be seen on barium enema (Fig. 124-11).¹¹³ Endoscopic examination with biopsy is necessary for definitive diagnosis, to exclude carcinoma and to differentiate pneumatosis from familial adenomatosis polyposis¹²⁰ and from the thumbprinting of colon ischemia. The endoscopic appearance is of multiple cysts, which vary in size from a few millimeters to several centimeters (Fig. 124-12) and which, on puncture with a needle, rapidly deflate. Endoscopic ultrasonography also has been used to establish the diagnosis in pneumatosis.¹²¹

Figure 124-11. Film from a single single-contrast barium enema demonstrating the presence of numerous gas-filled cysts (arrowheads) in the wall of the colon characteristic of pneumatosis coli.

(From Feldman M, Boland CR, editors. Slide Atlas of Gastroenterology and Hepatology. Philadelphia: Current Medicine; 1996.)

Figure 124-12. Resection specimen of pneumatosis coli. Numerous gas-filled cysts are seen in this surface view of the mucosa (arrows).

(Courtesy of Feldman M, Boland CR, editors. Slide Atlas of Gastroenterology and Hepatology. Philadelphia: Current Medicine; 1996.)

PATHOLOGY

The cysts of pneumatosis cystoids resemble soap bubbles. They usually are thin-walled and unilocular and can occur separately or in clusters. They do not communicate with the intestinal lumen or with each other and have a spongy consistency that pops like a balloon when compressed. On cross section they appear shiny and honeycombed, and they range in size from a few millimeters to several centimeters. Microscopically, the cysts have an endothelial lining that tends to gather and coalesce, forming multinucleate giant cells that increase in number as the cysts collapse, undergo fibrosis (Fig. 124-13), and eventually are sloughed, leaving the cysts without a lining. Progressive fibrosis leads to a decrease in the size of the cysts and ultimately to their obliteration. The connective tissue surrounding the cysts can show a granulomatous inflammatory reaction made up of eosinophils, lymphocytes, macrophages, and plasma cells. Subserosal cysts are surrounded by fibrous connective tissue and can produce adhesion of adjacent bowel loops. The mucosa in pneumatosis may be normal, or it may be thinned and with or without ulcerations and inflammation where it is stretched over a cyst. Mucosal changes vary from mild focal abnormalities to extensive changes including granulomas, abnormal crypts with branching, shortening, cryptitis and abscesses, dilatation, and rupture.

Figure 124-13. Histopathology of a large gas-filled cyst in the colonic submucosa. These cysts are usually lined by histiocytes and multinucleated giant cells. Similar cysts also may be present in the subserosa. (Hematoxylin and eosin.)

(Courtesy of Feldman M, Boland CR, editors. Slide Atlas of Gastroenterology and Hepatology. Philadelphia: Current Medicine; 1996.)

TREATMENT

Because the natural history of pneumatosis is one of spontaneous regression in up to 50% of cases and because cysts can reappear after surgery, specific treatment is not recommended in asymptomatic patients. Symptomatic patients may be treated successfully by breathing high-flow oxygen for several days¹²² or by using hyperbaric oxygen, especially in resistant cases¹²¹; high oxygen levels lead to replacement of hydrogen within the cysts and a corresponding reduction in the size of the cysts. Because cysts can recur after oxygen therapy,¹²² a minimum of 48 hours of oxygen therapy is recommended to maximize the success rate. Metronidazole also has been used to treat pneumatosis coli, an observation that suggests that anaerobic bacteria play a role in the genesis of the disorder. Because cysts have been reported to recur after short courses of metronidazole,¹¹⁹ treatment should continue until complete resolution of the cysts is documented. In general, colonic resection is reserved for patients with complications such as intestinal obstruction and massive bleeding.

ETIOLOGY

The pathogenesis of malakoplakia is unknown. Proposed etiologies are infection, immunosuppression, systemic illness, neoplasia, and a genetic disorder. Evidence for an infectious etiology is based on the finding that some patients with malakoplakia have associated chronic infections. This was first described in the urologic form of malakoplakia in which more than 75% of patients were infected with Escherichia coli. This finding led to the belief that E. coli might be a primary cause of malakoplakia; however, other organisms also have been isolated, including Klebsiella, Proteus, Mycobacterium, Staphylococcus, and fungi,¹²⁷ suggesting that one infection is not the primary cause of the disease.

Other evidence points to a defect in macrophage killing as the cause of malakoplakia. Nondigested microorganisms are found within the lysosomes of macrophages in affected persons. Macrophages from these patients show a decrease in cyclic guanosine monophosphate, resulting in impaired bactericidal activity.¹²⁸ Peripheral blood monocytes also are found to have decreased bactericidal activity in malakoplakia. The defect in macrophage dysfunction may be reversed with the addition of a cholinergic agonist, both in vitro and in vivo.¹²⁹

Malakoplakia has been reported in patients receiving chemotherapy and immunosuppressive therapy for organ transplantation¹³⁰; reversal of macrophage abnormalities and resolution of clinical symptoms has been documented after discontinuation of glucocorticoids and azathioprine.¹³¹ Malakoplakia has been reported in various immune deficiency states such as primary hypogammaglobulinemia and AIDS,^132,133 and it also has been associated with chronic systemic diseases such as systemic lupus erythematosus, ulcerative colitis, and sarcoidosis.¹²⁶

There have been a substantial number of cases associated with colorectal cancer, to perhaps suggest a neoplastic etiology for at least one form of malakoplakia.^134,135 A possible genetic etiology was suggested by one report of colonic malakoplakia that clustered in a family.¹³⁶

CLINICAL FEATURES AND DIAGNOSIS

Patients with malakoplakia usually present with abdominal pain, diarrhea, hematochezia, and fever.¹²⁶ Physical findings may include a rectal mass on digital examination, abdominal mass, and weight loss. Diagnosis is by colonoscopy (and biopsy), which generally reveals one of the following three patterns of disease:

Biopsy is essential to confirm the diagnosis and to exclude an underlying colonic malignancy (Fig. 124-14). Histology reveals the characteristic macrophages with voluminous cytoplasm (von Hansemann cells) containing the classic Michaelis-Gutmann bodies (intracytoplasmic concentric laminated inclusion bodies). The histiocytes (von Hansemann cells) must be distinguished from those found in fungal disease, leprosy, Whipple’s disease, reticulum cell sarcoma, and macrophages harboring Mycobacterium avium complex.

Figure 124-14. Histopathology of malakoplakia. Sheets of large pale macrophages characterize the histologic changes in malakoplakia. One of the macrophages shows the characteristic ring-like Michaelis-Gutmann body (arrow) consisting of a central core of partially digested bacteria coated with iron and calcium phosphate. (Hematoxylin and eosin.)

(Courtesy of Lawrence J. Brandt, MD, Bronx, NY.)

TREATMENT

Patients with newly diagnosed malakoplakia should undergo a thorough medical evaluation to determine if they are taking immunosuppressive medications or have coexisting medical illnesses. Tests of immune function and screening for associated bladder malakoplakia and colorectal cancer are prudent. Patients receiving immunosuppressive medications might improve after these medications are discontinued. Antibiotics such as trimethoprim-sulfamethoxazole and ciprofloxacin have been successful in treating malakoplakia.^137,138 Both antibiotics appear to kill the bacteria associated with malakoplakia and can penetrate the defective host macrophages. Cholinergic agents also may be useful in treating children with malakoplakia.¹²⁹ Surgical resection of the involved colon is recommended for cases associated with carcinoma or severe bleeding.

ETIOLOGY

The etiology of colitis cystica profunda is unknown, but several theories have been proposed. A possible congenital etiology is supported by several findings. In embryologic examinations, submucosal cysts have been found in multiple gastrointestinal locations. The occurrence of colitis cystica profunda in children and its association with other congenital conditions such as Peutz-Jeghers syndrome¹⁴⁰ also support a congenital origin for this disease; the absence of submucosal cysts in large autopsy series of infants and children reduces the plausibility of this etiology.

Colitis cystica profunda has been associated with acquired diseases that predispose to mucosal ulceration and inflammation, including ulcerative colitis,¹⁴¹ Crohn’s disease,¹⁴² and infectious colitis.¹⁴³ Submucosal cysts also have been reported in areas exposed to local trauma, such as an intestinal anastomosis or colostomy.¹⁴⁴ Proctitis cystica profunda developed in rats treated with irradiation¹⁴⁵ and at small bowel stomas also created in rats.¹⁴⁶

Colitis cystica profunda has been found in association with adenocarcinoma of the colon, suggesting a neoplastic etiology. Several cases of adenocarcinoma of the stomach associated with gastritis cystica profunda have been reported.¹⁴⁷ In some reports, there is strong evidence of a causal link between cancer and colitis cystica profunda, because the submucosal cysts are often found adjacent to the adenocarcinoma, whereas adjacent benign mucosa is devoid of submucosal cysts.

The localized form of colitis cystica profunda is associated with rectal prolapse and solitary rectal ulcer syndrome.¹³⁹ Mucosal prolapse has been found in more than 50% of patients with the localized form of the disease. Trauma or ischemia caused by chronic traction on the mucosa and intramural vessels might play a role in the development of the submucosal cysts. Microscopic features of the localized form of the disease often include fibrosis of the lamina propria and hypertrophic muscle fibers, changes that are characteristic of solitary rectal ulcer syndrome (see Chapter 115).¹⁴⁸

CLINICAL FEATURES AND DIAGNOSIS

Colitis cystica profunda affects men and women equally. The most common symptoms are rectal bleeding, mucus discharge, and diarrhea¹³⁹; less common are tenesmus, abdominal pain, and rectal pain. Rarely, the patient presents with intestinal obstruction caused by the cysts.¹⁴⁹

At endoscopy, most lesions are located on the anterior rectal wall 6 to 7 cm from the anal verge. The lesions appear as polyps with overlying mucosa that may be normal, inflamed, or ulcerated. Endoscopy might disclose an associated rectal prolapse in some cases. The endoscopic appearance of the lesions may be indistinguishable from a variety of lesions, including adenocarcinoma, adenomatous polyps, submucosal lipoma, neurofibroma, inflammatory pseudopolyps, pneumatosis coli, and endometriosis.¹³⁹ Barium enema can reveal radiolucent filling defects. Transrectal ultrasound may be useful in differentiating this disease from cancer and reveals hypoechoic cysts that may be surrounded by intact submucosa, unlike invasive cancer.¹⁵⁰ A characteristic finding consisting of noninfiltrating submucosal cysts also has been described on magnetic resonance imaging (MRI).¹⁵¹

Biopsy is necessary to differentiate this lesion from a variety of inflammatory, neoplastic, and infectious conditions. On biopsy, the submucosa is seen to be thickened by the presence of the mucus-filled cysts (Fig. 124-16). The cysts usually communicate with the lumen through small openings in the mucosa. Although usually confined to the submucosa, cysts involving the muscularis propria and serosa have been reported. The surrounding connective tissue often shows chronic inflammation, and there may be extensive replacement of the lamina propria by fibroblasts.¹⁴⁸ As with solitary rectal ulcer syndrome, misplaced glands can cause confusion with invasive adenocarcinoma (see Fig. 124-16).

Figure 124-16. Histopathology of colitis cystica profunda showing the mucus-filled cysts and misplaced epithelium (arrow). (Hematoxylin and eosin, ×5.)

(From Mitros FA, editor. Atlas of Gastrointestinal Pathology. New York: Gower Medical Publishers; 1988.)

TREATMENT

A high-fiber diet and bowel retraining to avoid straining have led to regression of this disease in a few cases.¹⁵⁰ If fiber is not effective, polyethylene glycol solutions may be tried.¹⁵² Glucocorticoid enemas also have been used with some success.¹³⁹ Most patients have been treated with surgery. In patients with associated rectal prolapse, repair of the prolapse alone may treat the colitis cystica profunda successfully, whereas for disease localized to the rectum and in the absence of procidentia, local excision through a transanal approach is efficacious.¹⁵² When the disease is localized to the rectum but is circumferential, total excision may be accomplished by mucosal sleeve resection and coloanal pull-through.¹⁵² More-diffuse lesions have been removed by segmental resection. Segmental resection also may be necessary for large obstructing lesions and for lesions that cause hypokalemia, hypoalbuminemia, or severe anemia from chronic blood loss. A diverting colostomy can lead to regression of this disease and may be the best option for a patient with significant comorbidities.

ETIOLOGY

The cause of neutropenic enterocolitis may be multifactorial. The initial injury is an ulceration of the bowel mucosa with no associated inflammatory response. Mucosal injury can occur from leukemic infiltration, stasis of bowel contents, or mucosal ischemia from splanchnic vasoconstriction resulting from sepsis.^155,157,158 Certain drugs also can contribute to mucosal damage. Cytosine arabinoside can cause necrosis and delayed regeneration of intestinal glandular epithelium.¹⁶⁰ Vinca alkaloids used to treat leukemia also can contribute to cecal distention by damaging the myenteric plexus of the intestine. With mucosal injury in the setting of impaired host defenses, infectious colitis subsequently occurs. The infection is often polymicrobial; causative bacteria include Escherichia coli and Staphylococcus, Streptococcus, Enterococcus, and Klebsiella species^161–162; fungal organisms such as Aspergillus and Candida also have been isolated.¹⁶¹ In addition to transmural infection of the intestine, the cecum can become gangrenous and perforate as a result of increased distention and ischemia. The process can involve the ileum alone or both the ileum and cecum.¹⁶¹

CLINICAL FEATURES AND DIAGNOSIS

The most common presentation is with fever, diarrhea, nausea, vomiting, and abdominal pain in a patient who is receiving antineoplastic drugs.¹⁶² Abdominal tenderness typically is localized to the right lower quadrant of the abdomen, but it may be absent or masked by drugs such as prednisone; localized tenderness can progress rapidly to diffuse signs of peritonitis as a result of intestinal perforation. Shock can occur as a result of bacteremia or intestinal perforation. On occasion, the sigmoid colon may be affected, further complicating the diagnosis.¹⁶³ Neutropenia is common but was absent in 12% of children in a review of typhlitis in childhood cancer¹⁶²; blood cultures are positive in up to 50% of cases.^155,161 Differential diagnosis includes appendicitis, pseudomembranous colitis, ischemic colitis, volvulus, diverticulitis, and drug-induced diarrhea.

Diagnostic evaluation should include a radiologic evaluation to exclude other diseases, confirm the diagnosis, and determine the severity of illness. Abdominal films can demonstrate dilated loops of small bowel with decreased air in the right lower quadrant and free intraperitoneal air if intestinal perforation has occurred (Fig. 124-17).¹⁵⁵ CT scans are most sensitive for establishing the diagnosis and help to exclude other conditions such as appendicitis and diverticulitis. The CT scan might reveal a thickened bowel wall, pneumatosis intestinalis, ascites, and free air.¹⁶⁴ One study suggested that ultrasonography is superior to CT scan in predicting the outcome of typhlitis.¹⁶² Barium enema should be avoided because of the potential risk of perforation. Stool assay for C. difficile toxin should be performed routinely to exclude pseudomembranous C. difficile colitis.

Figure 124-17. Left lateral decubitus plain film in a patient with neutropenic enterocolitis. The colon is dilated with a prominent intraluminal gas-fluid interface and free peritoneal air (arrowheads) resulting from cecal perforation.

(From Hunger TB, Bjelland UJC. Gastrointestinal complications of leukemia and its treatment. AJR Am J Roentgenol 1984; 142:513.)

TREATMENT

Management of neutropenic enterocolitis has varied and is controversial because there are no prospective or high-quality retrospective studies concerning medical or surgical therapies.¹⁶⁵ Approaches have included supportive measures alone, aggressive initial surgical resection, and combined medical and surgical treatment; successes and failures have been documented with all these approaches. In two studies, all patients treated medically recovered, whereas in another similar series, all patients managed medically died.¹⁶⁶ Clearly, successful management of patients with neutropenic enterocolitis needs to be individualized to optimize outcome.

In general, medical management includes broad-spectrum antibiotics, nasogastric suction, and bowel rest. Fluid resuscitation with isotonic solutions is critical for maintaining renal perfusion in the face of decreased systemic vascular resistance from sepsis and intra-abdominal fluid sequestration. Close observation and serial abdominal and radiologic examinations are necessary to monitor the response to medical treatment. Antibiotics should have activity against enteric Gram-negative organisms, Gram-positive organisms, and anaerobes. Causative microorganisms include Enterococcus species, S. aureus, E. coli, group A Streptococcus, and Klebsiella.^161,162 For patients who do not respond to antibacterial agents, amphotericin should be considered, because fungemia is common.¹⁶¹ Blood transfusions may be necessary because the diarrhea often is bloody. Granulocyte-macrophage colony-stimulating factor to correct the neutropenia may be a useful adjunct to medical therapy.¹⁶⁷

Early surgical intervention has been recommended in persons with a rapidly deteriorating course despite maximal medical therapy. Two series have shown a decreased mortality rate in patients with severe disease who are treated surgically compared with those treated medically.¹⁶⁶ For patients with complications such as frank gangrene, intestinal perforation, and shock despite vasopressor support, surgical intervention is mandatory.

Controversy surrounds the choice of operation. Gangrenous or perforated bowel should be resected. When the bowel is edematous with no vascular compromise and no signs of perforation, successful management has included no resection,¹⁶⁸ intestinal diversion with no resection,¹⁶⁶ and resection of the involved bowel. If resection is performed, construction of an ileostomy and mucous fistula may be the safest option, because intestinal anastomoses may be prone to breakdown in patients with neutropenia.¹⁶⁹ Because recurrences of neutropenic enterocolitis are common when chemotherapy is restarted, right hemicolectomy is recommended before chemotherapy is resumed.¹⁵⁷

ETIOLOGY AND PATHOGENESIS

Several hypotheses have been advanced to explain the ectopic location of endometrial tissue.^175–177 The most commonly accepted explanation is that of retrograde passage of endometrial tissue, which then implants and grows on pelvic organs and the peritoneum. From these sites, more distant implants arise via hematogenous or lymphatic dissemination; further dissemination can occur during surgical interventions. A less-accepted hypothesis, with fewer supporting data, is that of endometrial metaplasia, in which multipotential peritoneal mesothelial cells are induced by unknown factors to undergo metaplastic transformation to endometrial tissue.

Once implanted, endometrial tissue appears to be regulated by hormonal influences, so that estrogen promotes and progesterone inhibits its growth. These repetitive cycles of growth and sloughing of tissue can lead to serosal irritation and progressive endometrial invasion of intestinal muscle with resultant fibrosis and muscle hypertrophy. Thus, pain can arise from nerve impingement or serosal inflammation, whereas obstruction can result from narrowing of the lumen or kinking of the intestine.

CLINICAL FEATURES

Endometriosis is found almost exclusively in women of childbearing age, with clinical onset usually between the ages of 20 and 45 years.¹⁷³ Women who experience symptoms or who undergo surgery for endometriosis beyond menopause presumably have chronic fibrosis or exacerbations induced by exogenous estrogen.

Although most women with endometrial implants on intestinal structures have no symptoms, those with serosal implants may complain of localized tenderness, low backache, or abdominal pain. Penetration of endometrial tissue into the bowel wall can produce constipation, diarrhea, and partial obstruction, resulting in intermittent abdominal pain. Contrary to popular thinking, symptoms are not always cyclical and might not fluctuate with hormonal levels; nor are gastrointestinal symptoms necessarily associated with gynecologic symptoms. Rarely, hematochezia occurs when endometrial implants penetrate to the mucosa or when severe colonic fibrosis results in ischemia.¹⁷² Less common presentations occur with involvement of the more proximal colon or small intestine and include acute appendicitis caused by an obstructing endometrioma, small bowel intussusception, and volvulus.^174,178

DIAGNOSIS

The clinical diagnosis of intestinal endometriosis may be difficult because symptoms often are nonspecific and there might not be a close relationship between the symptoms and the menstrual cycle. Endometriosis should always be considered in women with recurrent abdominal pain and bowel symptoms, especially if they are in their reproductive years and have gynecologic complaints. Diagnosis is especially difficult because IBS is so common in women.

An important component of the evaluation is a careful pelvic examination that includes combined rectovaginal palpation. Finding tender nodules or irregularities in the cul-de-sac is highly suggestive of endometriosis. Because findings can vary considerably during the menstrual cycle, the pelvic examination should be performed immediately before and again after menstruation if no abnormalities were found initially.

It is rare to see endometrial implants on the colonic mucosa except when there is hematochezia. Thus, colonoscopy is often normal except for areas of extrinsic compression or strictures with intact mucosa.¹⁷⁹ More helpful is an air-contrast barium enema, which demonstrates submucosal polypoid masses or areas of noncircumferential narrowing of the lumen (Fig. 124-18). Diagnostic yield and accuracy may be enhanced by performing these tests just before the onset of menses. CT scans (Fig. 124-19), ultrasonography, and MRI all have been reported to assist with the diagnosis or assessment of the extent of endometrial involvement. High-resolution transvaginal and transrectal ultrasonography also may be useful in detecting small endometrial implants, particularly in the retroperitoneal pelvis.¹⁸⁰

Figure 124-18. Film from a single-contrast barium enema demonstrating a large, nodular, partially obstructing endometrioma in the rectosigmoid colon (arrow).

(Courtesy of Mark Peterson, MD, Pittsburgh, Pa.)

Figure 124-19. Computed tomography scan in the same patient as in Figure 124-18 showing the endometrial mass in the cul-de-sac (arrow) extending into the colon.

(Courtesy of Mark Peterson, MD, Pittsburgh, Pa.)

Definitive diagnosis of endometriosis often is made by laparoscopy or laparotomy with biopsy and is especially useful in patients with intestinal implants without pelvic involvement. The classic peritoneal implant appears as a bluish-black “powder-burn” lesion with variable degrees of pigmentation and surrounding fibrosis, the dark coloration resulting from hemosiderin deposition. Most peritoneal implants, however, appear as subtle, nonpigmented lesions. The appreciation that endometrial tissue may be nonpigmented has increased the yield of these procedures considerably.¹⁷¹

The differential diagnosis of intestinal endometriosis includes inflammatory disorders such as Crohn’s disease and ulcerative colitis with stricture, diverticulitis, infectious diseases such as ileocolonic tuberculosis and schistosomiasis, benign and malignant neoplastic disorders, and colon ischemia.¹⁷⁴ It is important to emphasize that no radiologic or imaging finding is pathognomonic of endometriosis; mucosal abnormalities that permit positive biopsies are rare; and tissue for a definitive diagnosis usually is obtained only at laparotomy (Fig. 124-20).

Figure 124-20. Histopathology of endometriosis. Endometrial stoma is seen around the glandular structures in the muscularis propria of the colon in a woman presenting with obstructive symptoms. The diagnosis of endometriosis was proved at surgery. (Hematoxylin and eosin, ×10.)

(From Mitros FA, editor. Atlas of Gastrointestinal Pathology. New York: Gower Medical Publishers; 1988.)

TREATMENT

In general, when a diagnosis of serosal intestinal endometriosis is made, hormonal therapy is often the first therapeutic option, similar to the standard approach to pelvic endometriosis.^181,182 Low-dose estrogen-progestin compounds cause a pseudopregnancy state that results in decidualization of endometrial tissue and often relieves dysmenorrhea. Their use in more-severe disease is questionable, however, and they generally are not recommended for symptomatic intestinal disease.

The most effective agents currently available are the synthetic androgen danazol and the gonadotropin-releasing hormone agonists.^183,184 Both act to decrease ovarian steroid synthesis by inhibiting pituitary release of follicle-stimulating hormone and luteinizing hormone. Although both are effective in decreasing pelvic pain associated with endometriosis and appear to decrease the size of endometrial implants, there are no studies of these agents in endometriosis-associated intestinal disease, and there is some concern that treatment can result in increased fibrosis and inadequate resolution of symptoms.¹⁸⁵ Ablation of endometrial implants on surfaces that can be visualized laparoscopically can be accomplished using carbon dioxide laser.¹⁸⁶

For endometriosis that causes partial obstruction of the colon or small intestine, segmental resection of the involved area provides the best results and also serves to exclude an underlying carcinoma.^187–189 Resection can be performed by laparoscopy or by open surgery, according to available expertise.¹⁹⁰ If the patient is postmenopausal or if future pregnancies are not wanted, hysterectomy and bilateral salpingo-oophorectomy can be done at the time of resective surgery to minimize the risk of symptomatic disease in the future. Similar surgery also can be performed in premenopausal women who, despite medical therapy, have intractable symptoms.