Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition

Section V LARGE INTESTINE

CHAPTER 27. Large Intestinal Miscellaneous Inflammatory Diseases

Reena Khanna, MD, FRCPC and John K. Marshall, MD, MSc, FRCPC, AGAF

Image True/False: Lymphocytic and collagenous colitis are distinct clinical entities.

This question continues to be debated. Although they differ slightly in the histologic criteria for diagnosis, growing evidence suggests that lymphocytic and collagenous colitis are two manifestations of the same disorder, with similar presentation, response to treatment and prognosis. Approximately half of the cases fulfill histologic criteria for both lymphocytic and collagenous colitis, representing a mixed disease variant.

Image How does microscopic colitis typically present?

Patients with microscopic colitis are typically middle-aged or elderly females (female to male ratio 4:1 for lymphocytic colitis and 1:1 for collagenous colitis) with large-volume, nonbloody, watery diarrhea. A prior history of nonsteroidal anti-inflammatory drug ingestion is common and was suggested to be a risk factor in a published case-control study. Clinical severity correlates with the degree of inflammation seen in histological samples.

Image Which medications are associated with the development of microscopic colitis?

The most consistent association has been with nonsteroidal anti-inflammatory drugs. Other medications linked to microscopic colitis include acarbose, aspirin, carbamazepine, flutamide, gold salts, proton pump inhibitors, paroxetine, sertraline, ranitidine, simvastatin, and ticlopidine.

Image True/False: Rectal biopsy is highly sensitive for detecting collagenous colitis.

False. Only 27% of cases of collagenous colitis are detected on rectal biopsy. To exclude the diagnosis, full colonoscopy is usually required. Histologic changes are seen in the cecum in 82% of patients and the transverse colon in 83%.

Image True/False: Microscopic colitis can cause histologic changes in the small bowel.

True. Increased intraepithelial lymphocytes have been seen in terminal ileal biopsies from patients with microscopic colitis. More than five intraepithelial lymphocytes per 100 epithelial cells in the terminal ileum has been suggested to have high predictive value for the diagnosis of microscopic colitis when compared with healthy controls or patients with inflammatory bowel disease (IBD).

Image What are the classic histological features of lymphocytic and collagenous colitis?

Image

Figure 27-1A See also color plate. (Figure used with permission of Dr J. Radhi, McMaster University, Hamilton, ON, Canada.)

Image

Figure 27-1B See also color plate. (Figure used with permission of Dr J. Radhi, McMaster University, Hamilton, ON, Canada.)

Lymphocytic colitis is defined as the presence of more than 15–20 intraepithelial lymphocytes per 100 epithelial cells (normal 3–5 intraepithelial lymphocytes per 100 epithelial cells), as shown in Figure 27-1A. Collagenous colitis is characterized by a thickening of the subepithelial collagen band to greater than 10 µm (normal 1–7 µm), which can be seen in Figure 27-1B. Although thickening of the collagen band is a hallmark feature of collagenous colitis, it is not pathognomic. Thickening of this band can also be seen with ischemia, trauma, or neoplasia. (See also color plate.)

Image What are some proposed theories for the pathogenesis of collagenous colitis?

Proposed mechanisms include abnormalities in collagen metabolism, effects of bacterial toxins, altered expression of transforming growth factor 1, and drug effects.

Image What are six conditions associated with microscopic colitis?

Celiac disease, irritable bowel syndrome, thyroid disease, diabetes mellitus, rheumatoid arthritis, and asthma/allergy.

Image True/False: Approximately 5% of patients with celiac disease have features of lymphocytic colitis on colonic biopsies.

False. Features consistent with lymphocytic colitis are seen in 20%–30% of patients with celiac disease undergoing colonoscopy with biopsy. The relative risk of microscopic colitis among patients with celiac disease is approximately 70.

Image True/False: Lymphocytic colitis usually responds to a gluten-free diet.

False.

Image What laboratory abnormalities are associated with microscopic colitis?

Laboratory abnormalities that have been associated with microscopic colitis include anemia, elevated inflammatory markers, and presence of autoantibodies (rheumatoid factor, antimitochondrial antibody, and antineutrophilic cytoplasmic antibodies [ANCA]).

Image Characterize the natural history of lymphocytic/collagenous colitis.

Lymphocytic and collagenous colitis usually enter remission spontaneously in the short term but may ultimately follow a chronic relapsing course. Between one-quarter and two-thirds of patients will require long-term medication for chronic intermittent diarrhea.

Image What treatments may be prescribed for lymphocytic/collagenous colitis?

Patients should be advised to avoid secretagogues such as caffeine and lactose. Medical treatment options include budesonide, bismuth subsalicylate, 5-aminosalicylate derivatives, cholestyramine, and systemic corticosteroids. Antidiarrheal agents such as diphenoxylate and loperamide are often ineffective. Refractory cases have required surgical diversion of the fecal stream.

Image Which of the above treatment options is/are supported by evidence from controlled clinical trials?

For induction of remission, a meta-analysis of randomized controlled trials found clinical response to occur in 100% of patients taking bismuth compared to 0% on placebo (p = 0.03). In three trials of budesonide, clinical response was seen in 81% of patients in the treatment arm compared to 17% in the placebo group (p < 0.00001), with an odds ratio of 12.32 (95% CI 5.53 to 27.46) and a number need to treat of 2. Clinical response to budesonide was associated with a significant histologic response. Small trials have failed to show the superiority of prednisolone, probiotics, or mesalamine with or without cholestyramine over placebo in the treatment of microscopic colitis (p = 0.15, p = 0.38, and p = 0.14, respectively).

For maintenance of remission, budesonide given at a dose of 6 mg daily for 6 months maintained clinical response in 83% of patients compared to 28% receiving placebo (p = 0.0002), with an odds ratio of 7.17 (95% CI 3.00 to 17.12) and a number needed to treat of 2. Similarly, histologic response occurred in 48% in the treatment arm and 15% among those receiving placebo (p = 0.0002).

Image True/False: Collagenous/lymphocytic colitis is associated with an increased risk of IBD.

False.

Image True/False: Collagenous/lymphocytic colitis increases the risk of developing colorectal carcinoma.

False.

Image True/False: Diversion colitis occurs more commonly after colectomy for IBD than for cancer.

True. Diversion colitis develops more frequently among patients who undergo surgery for IBD (89%) than for cancer (23%).

Image How does the endoscopic appearance of diversion colitis differ from that of ulcerative proctitis?

Diversion colitis cannot be differentiated endoscopically from ulcerative proctitis. Endoscopy typically reveals an erythematous and friable rectal mucosa with superficial ulceration.

Image What causes diversion colitis?

Diversion colitis occurs when a segment of bowel is excluded from the fecal stream. Current evidence implicates deficiency of luminal short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. Butyrate normally provides 70% of the oxidative energy for colonocytes. SCFAs also regulate colonic motility, fluid and electrolyte balance, and blood flow. The absence of SCFAs is believed to alter colonic bacterial flora in the excluded segment resulting in fewer anaerobic and more nitrate-producing bacteria.

Image How does diversion colitis present?

Up to 40% of patients develop symptoms from diversion colitis, including tenesmus, rectal discharge (blood and mucous), abdominal pain, and diarrhea. Rarely, sepsis or rectal abscesses have been described.

Image How is diversion colitis treated?

The best treatment for diversion colitis is to restore the fecal stream. SCFA enemas induce remission in many patients but are not commercially available. A suggested formulation contains 60 mmol/L acetate, 30 mmol/L propionate, and 40 mmol/L butyrate. Hydrocortisone enemas are ineffective and there is little evidence to support the use of aminosalicylate preparations.

Image What histologic feature, as shown in Figure 27-2, is the hallmark of diversion colitis?

Image

Figure 27-2 See also color plate. (Figure used with permission of Dr J. Radhi, McMaster University, Hamilton, ON, Canada.)

Lymphoid follicular hyperplasia with germinal centers is found in almost all cases. Cryptitis and neutrophil infiltration develop in at least 60% after 3 months.

Image How does acute radiation proctosigmoiditis present?

Acute injury presents with diarrhea and tenesmus during radiation treatment or within 6 weeks of exposure. The endoscopic appearance of the rectum is normal.

Image What are the clinical manifestations of chronic radiation proctitis?

The typical symptoms of chronic injury are rectal bleeding, diarrhea, and tenesmus. Rectal strictures may develop as can fistulae to the vagina, bladder, or uterus.

Image True/False: Rectal biopsies may lead to fistula formation in chronic radiation proctitis.

True, theoretically. Although evidence for a clear link between fistula formation and biopsy is lacking, a theoretical risk exists. A fistula is thought to develop from a site of necrosis. It is recommended to avoid taking biopsies from the rectal wall with greatest radiation exposure. For example, biopsies should be avoided from the anterior rectal wall in patients receiving radiation therapy for prostate cancer.

Image Describe the typical endoscopic appearance of chronic radiation proctitis.

Endoscopy typically reveals mucosal pallor, with friability and telangiectasia.

Image How long after radiation exposure does chronic radiation proctitis develop?

On average, symptoms develop after 1 year, fistulae after 18 months, and strictures after 3 years.

Image True/False: Patients with IBD are more likely to develop radiation proctitis following radiation therapy.

True.

Image What other risk factors exist for the development of colonic radiation injury?

Risk factors for radiation injury are thought to include previous lower abdominal surgery, diabetes, and concomitant vascular disease.

Image What medical therapies may be helpful in preventing acute radiation colitis?

Routine prophylactic therapy is not advised; however, potential therapies include amifostine, sulfasalazine, balsalazide, and selenium.

Image What is the natural history of radiation colitis?

One-third of patients with mild radiation proctitis will enter a spontaneous remission within 6 months, without requiring therapy.

Image What treatments are effective in controlling hemorrhage from radiation proctitis?

Oral 5-aminosalicylic acid (5-ASA) and corticosteroid enemas do not appear to control bleeding or tenesmus. Local instillation of 4% formalin, sucralfate, or 5-ASA may be effective. Nd:YAG, argon laser ablation or electrocoagulation of the rectal mucosa are useful endoscopic approaches. Hyperbaric oxygen therapy may also be beneficial by attenuating tissue hypoxia from obliterative endarteritis. Proctectomy may be considered for refractory cases but the colo-anal anastomosis is prone to leakage.

Image At what age is the incidence of milk protein allergy highest?

The peak incidence is at 6 weeks. Symptoms may include vomiting, colic, diarrhea, and rectal bleeding from colonic ulcers. Since the allergy is usually IgE-mediated, eczema, urticaria, and angioneurotic edema may also be seen.

Image How is the diagnosis of milk protein allergy made?

Resolution of symptoms with milk withdrawal and recurrence within 48 hours of rechallenge. Rechallenge is often omitted since it may result in anaphylaxis. If performed, rechallenge should be conducted in a hospital setting.

Image At what age can children with milk protein allergy resume drinking cow’s milk?

Allergy to milk protein usually resolves between 9 months and 3 years of age.

Image What is protein-induced proctitis/proctocolitis syndrome?

This syndrome is characterized by erythema and erosion of the distal colon and rectum induced by protein ingested in breast milk or formula. This results in loose stools with blood and mucous presenting by 6 months, without diarrhea or failure to thrive. White cells are seen in stool samples, while biopsies demonstrate an eosinophilic inflammatory infiltrate with lymphoid hyperplasia.

Image How is the protein-induced proctitis/proctocolitis syndrome treated?

Elimination of the offending allergen results in resolution of bloody stools within days. In breast-fed infants this often requires elimination of cow’s milk from the maternal diet.

Image True/False: Patients with the protein-induced proctitis/proctocolitis syndrome are more likely to develop IBD in adolescence?

False.

Image What is food protein-induced enterocolitis syndrome (FPIES)?

This syndrome is characterized by malabsorption and failure to thrive due to small bowel and colonic inflammation induced by food protein. Infants generally present with nausea, vomiting, and bloody diarrhea. Crypt abscesses and a plasma cell predominant inflammatory infiltrate are hallmark features seen in colonic biopsies.

Image How is FPIES treated?

Treatment of this condition involves complete dietary avoidance of the causal protein and administration of formula with hydrolyzed protein.

Image Which laxatives are associated with melanosis coli?

Anthraquinones, including cascara sagrada, aloe, rhubarb, senna, and frangula.

Image How soon does melanosis coli appear and how quickly does it resolve?

Melanosis coli can develop within 4 months of starting a laxative and resolve within approximately 9 months of its discontinuation.

Image Name the pigment that is deposited in the mucosa in melanosis coli.

The true identity of the pigment is unknown. It has been found to bear some biochemical similarity to lipofuscin, melanin, and the hepatic pigment of Dubin–Johnson syndrome.

Image Describe the location and endoscopic appearance of the solitary rectal ulcer syndrome (SRUS).

Endoscopy reveals a lesion on the anterior rectal wall between 6 and 10 cm from the anal verge. The lesion itself is variable and may appear as a single ulcer, a cluster of ulcers, a polypoid lesion, or an area of erythema.

Image What are the typical histologic features of the SRUS?

Fibromuscular obliteration of the lamina propria. As this term suggests, the lamina propria is replaced with fibroblasts, smooth muscle, and collagen. The muscularis mucosa is hypertrophied and disorganized.

Image How does the SRUS usually present?

Patients with SRUS most commonly present with rectal bleeding (up to 50%), straining (30%), or the sense of incomplete emptying (25%). Many are asymptomatic.

Image What are the endoscopic and histologic features of melanosis coli?

Image

Figure 27-3 See also color plate. (Figure used with permission of Dr J. Radhi, McMaster University, Hamilton ON, Canada.)

Endoscopically, melanosis coli appears as a dark brown coloration of the colon, particularly affecting the rectosigmoid segment and with pale patches thought to overlie lymphoid follicles. Histologically, brown pigment is seen within macrophages of the lamina propria (see Figure 27-3).

Image Describe hypotheses regarding the pathogenesis of SRUS.

Self-digitation has been suggested as the cause of SRUS and is documented in up to 50% of patients. An alternate hypothesis is that SRUS results from prolapse and ischemia of the rectal mucosa in the setting of a high fecal voiding pressure. The latter may result from inadequate relaxation of the puborectalis during defecation.

Image Which conditions can mimic SRUS?

Diagnoses whose presentations overlap that of SRUS include IBD, ischemic colitis, malignancy, infection (eg, TB, amebiasis, CMV, lymphogranuloma venereum), autoimmune disorders (eg, Behcet’s syndrome), nonsteroidal anti-inflammatory drug (NSAID) colopathy, and trauma.

Image How is SRUS treated?

Initial conservative therapy with bulk laxatives, avoidance of straining, and reassurance is recommended. Pelvic floor retraining (ie, biofeedback therapy) may be helpful in those with pelvic floor dyssynergia. Topical anti-inflammatory medication is generally ineffective. For refractory cases, the surgical procedure of choice is an abdominal rectopexy.

Image What complications of NSAIDs have been described in the colon?

Acute colitis, ischemic colitis, perforation of colonic diverticula, and diaphragmlike strictures have been reported after NSAID ingestion. NSAIDs may also exacerbate or trigger relapse of Crohn’s disease and ulcerative colitis.

Image Which disease-modifying anti-rheumatic drug has been associated with an acute colitis?

Gold salts may induce an acute colitis characterized by ulceration and friability of the rectosigmoid mucosa. Symptoms typically resolve within 2 weeks of drug withdrawal.

Image Name five classes of drugs that have been associated with ischemic injury of the colon.

NSAIDs, oral contraceptives, vasoconstrictors (eg, vasopressin, ergotamine, cocaine, dextroamphetamine), neuroleptics, and digitalis.

Image What are the three forms of colitis associated with cancer chemotherapy?

Neutropenic enterocolitis (aka, typhlitis), ischemic colitis, and Clostridium difficile colitis.

Image What is typhlitis?

The Greek word typhlos refers to a blind sac. Typhlitis is an acute necrotic inflammation of the cecum. It has also been called neutropenic enterocolitis and ileocecal syndrome.

Image In what clinical setting does typhlitis occur?

Typhlitis classically affects leukemic patients with severe neutropenia but has been described in a number of other immunosuppressed states.

Image How does typhlitis present?

Typical symptoms include fever, abdominal pain, distension, vomiting, and bloody diarrhea. An associated mucositis may involve the oropharynx. Plain films may reveal cecal thumbprinting or pneumatosis. Computed tomography and ultrasound demonstrate bowel wall thickening.

Image Which conditions mimic typhlitis?

Typhlitis should be differentiated from acute appendicitis, appendiceal abscess, Clostridium difficile colitis, ischemia, and colonic pseudo-obstruction.

Image How is typhlitis treated?

The primary management is supportive, with hydration, broad-spectrum antibiotics, and nasogastric decompression. Refractory cases may require a right hemicolectomy with mucous fistula.

Image What is the mortality rate from acute typhlitis?

Short-term mortality from acute typhlitis may be as high as 40%–50%.

Image What is topical colitis?

Topical colitis has been reported after glutaraldehyde and hydrogen peroxide contamination of colonoscope channels.

Image Which segments of the colon most frequently develop ischemic colitis?

The splenic flexure and rectosigmoid junction are supplied by terminal branches of the inferior mesenteric artery. These areas are most susceptible to ischemic damage.

Image What are risk factor for the development of ischemic colitis?

Reported risk factors for the development of ischemic colitis include age over 60, hypotension (from dehydration, sepsis, myocardial infarction, or hemorrhage), aortoiliac or cardiopulmonary surgery, cardioembolic disease, hemodialysis, drugs (including cocaine, amphetamine, ergot, vasopressin, alosetron, estrogen, digoxin, diuretics, simvastatin, and sumatriptan), extreme exercise, prothrombotic conditions, and diabetes.

Image What is the mechanism of injury in ischemic colitis?

Ischemic colitis most commonly results from nonocclusive ischemia due to decreased blood flow and/or vasospasm.

Image How does ischemic colitis usually present?

Patients often present with left-sided abdominal pain and hematochezia.

Image What are the endoscopic features of ischemic colitis?

Image

Figure 27-4 See also color plate.

Classically, the mucosa is pale with petechial hemorrhage. Submucosal hemorrhage and pseudomembranes may be noted. A single left-sided colonic ulcer, typically longer than 5 cm (the “single stripe sign”), may occur in mild disease states, whereas cyanosis with frank ulceration denotes severe disease (see Figure 27-4). These changes occur segmentally, often with rectal sparing.

Image What are three complications of ischemic colitis?

In the short term, ischemic colitis can progress to frank necrosis and gangrene. Over the longer term, ischemic colitis can lead to a chronic inflammatory state (persistent colitis) or stricture.

Image How is ischemic colitis treated?

Supportive measures including intravenous hydration and withdrawal of offending agents. Empiric antibiotics may be given in severe cases. A nasogastric tube may be placed if an ileus is present.

Image Describe the gastrointestinal manifestations of acute intestinal graft versus host disease (GVHD).

Acute GVHD occurs within 100 days of a stem cell transplant and results in profuse diarrhea and abdominal pain. Nausea, vomiting, and anorexia have also been described. Other systemic manifestations most commonly include skin rash and elevated liver tests.

Image What are the histological features of acute GVHD?

Image

Figure 27-5 See also color plate. (Figure used with permission of Dr J. Radhi, McMaster University, Hamilton ON, Canada.)

Biopsies show a spectrum of findings including apoptosis, crypt necrosis (marked with black arrows in Figure 27-5), and ulceration with denuded epithelium in severe cases.

Image In pneumatosis intestinalis, air-filled cysts are found in which layers of the colonic wall?

The air-filled cavities of pneumatosis intestinalis are pseudocyts and can arise in the mucosa, submucosa, or subserosa. They are most commonly found in the submucosa. These appear endoscopically as blue polypoid lesions.

Image How does pneumatosis intestinalis present?

Most patients are asymptomatic; however, diarrhea, rectal bleeding, abdominal pain, bloating, and constipation have been reported.

Image What are five complications of pneumatosis intestinalis?

Bowel obstruction, hemorrhage, intussusception, volvulus, and pneumoperitoneum.

Image How is symptomatic pneumatosis intestinalis treated?

Mild symptoms have been treated with antibiotics, elemental diets, high-flow oxygen, hyperbaric oxygen, surgery, and endoscopic puncture with sclerotherapy. These treatments have not been validated by large clinical trials. Preliminary data suggest a high rate of recurrence (up to 40% within 18 months) after any therapy.

Image What is diverticular colitis?

Diverticular colitis is a segmental colitis associated with diverticular disease.

Image True/False: Diverticular colitis and diverticulitis are synonymous.

False.

Image What are the endoscopic and histologic features of diverticular colitis?

Mild disease is characterized by minimal inflammation with red spots surrounding diverticula (“Fawaz spots”). These red spots likely represent submucosal hemorrhage. Severe disease may be indistinguishable from IBD.

Image What is the proposed pathogenesis of diverticular colitis?

Proposed mechanisms include fecal stasis, bacterial overgrowth, and local ischemia.

Image How does diverticular colitis usually present?

This condition typically presents in the seventh decade of life with diarrhea, rectal bleeding, and abdominal pain.

Image What is the treatment of diverticular colitis?

A high-fiber diet is generally recommended. Small clinical trials demonstrate some efficacy for antibiotics, aminosalicylates, and probiotics; however, the long-term management remains controversial.

• • • SUGGESTED READINGS • • •

Tursi A. Segmental Colitis Associated with Diverticulosis: Complication of Diverticular Disease or Autonomous Entity? Dig Dis Sci. 2011;56:27-34.

Feuerstadt P, Brandt LJ. Colon Ischemia: Recent Insight and Advances. Curr Gastroenterol Rep. 2010;12:383-390.

Yen EF, Pardi DS. Review article: microscopic colitis—lymphocytic, collagenous and “mast cell” colitis. Aliment Pharmacol Ther. 2011;34:21-32.