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Disorders of the Small and Large Bowel Imaging is recommended with multiphasic CT or MRI of include Campylobacter, hemorrhagic E. coli, Entamoeba the abdomen. Endoscopic ultrasonography (90% sensitive), histolytica, Shigella, and Salmonella. Persistent diarrhea octreotide scintigraphy, or somatostatin-based PET may be (14-30 days) is usually caused by a parasite. See MKSAP 19 needed to detect small lesions. For functional pancreatic NETs, Infectious Disease for further discussion of infectious diarrhea. surgery is recommended if more than 90% of the tumor can be resected. For nonfunctional tumors associated with multiple Evaluation endocrine neoplasia type 1 and von Hippel-Lindau syndrome, Acute diarrhea may be accompanied by abdominal cramping, surgery is usually recommended if the tumors exceed 2 to tenesmus, flatulence, fever, nausea, and vomiting. For patients 3 cm. Medical management of gastrinomas includes oral pro- with acute diarrhea, evaluation of hydration status is impor- ton pump inhibitors two or three times daily or somatostatin tant. Stool testing for infectious causes depends on suspicion analogs. High-volume or progressive disease is best managed of disease outbreak, symptom severity, symptom duration in conjunction with a gastroenterologist. See MKSAP 19 (>7 days), and increased risk for infectious diarrhea (e.g., Oncology for further information on staging and treatment. worker in health care or food preparation).

Imaging is recommended with multiphasic CT or MRI of include Campylobacter, hemorrhagic E. coli, Entamoeba the abdomen. Endoscopic ultrasonography (90% sensitive), histolytica, Shigella, and Salmonella. Persistent diarrhea octreotide scintigraphy, or somatostatin-based PET may be (14-30 days) is usually caused by a parasite. See MKSAP 19 needed to detect small lesions. For functional pancreatic NETs, Infectious Disease for further discussion of infectious diarrhea. surgery is recommended if more than 90% of the tumor can be resected. For nonfunctional tumors associated with multiple Evaluation endocrine neoplasia type 1 and von Hippel-Lindau syndrome, Acute diarrhea may be accompanied by abdominal cramping, surgery is usually recommended if the tumors exceed 2 to tenesmus, flatulence, fever, nausea, and vomiting. For patients 3 cm. Medical management of gastrinomas includes oral pro- with acute diarrhea, evaluation of hydration status is impor- ton pump inhibitors two or three times daily or somatostatin tant. Stool testing for infectious causes depends on suspicion analogs. High-volume or progressive disease is best managed of disease outbreak, symptom severity, symptom duration in conjunction with a gastroenterologist. See MKSAP 19 (>7 days), and increased risk for infectious diarrhea (e.g., Oncology for further information on staging and treatment. worker in health care or food preparation). Management Ampullary Adenocarcinoma Fluid therapy is the mainstay of treatment for acute diarrhea. Adenocarcinoma of the ampulla of Vater accounts for 0.2% of Patients with severe diarrhea or travelers with cholera-like gastrointestinal malignancies and usually presents early diarrhea should receive balanced electrolyte rehydration solu- because of obstruction of the biliary system. Endoscopic ultra- tions. Hospitalization is usually unnecessary except for severe sonography with biopsy is the preferred method for staging disease, hemodynamic instability, or multiple medical comor- and tissue diagnosis, with 90% accuracy. At least 50% of bidities. Confirmed C. difficile infection should be treated patients with familial adenomatous polyposis syndrome according to comorbidities and clinical severity (see MKSAP 19 develop adenomatous changes of the periampullary region, Infectious Disease for discussion of C. difficile infection). which may progress to adenocarcinoma. See Colorectal Treatment of diarrhea in travelers includes bismuth and lop- Neoplasia for more information on adenomatous polyposis eramide to relieve symptoms and possibly empiric antibiotics syndromes. Hereditary tumor syndromes can cause ampullary for moderate or severe symptoms. adenocarcinomas; patients should be considered for genetic testing. Chronic Diarrhea Causes e About 10% to 25% of pancreatic neuroendocrine tumors are Chronic diarrhea can be grouped into six categories by disease

Management Ampullary Adenocarcinoma Fluid therapy is the mainstay of treatment for acute diarrhea. Adenocarcinoma of the ampulla of Vater accounts for 0.2% of Patients with severe diarrhea or travelers with cholera-like gastrointestinal malignancies and usually presents early diarrhea should receive balanced electrolyte rehydration solu- because of obstruction of the biliary system. Endoscopic ultra- tions. Hospitalization is usually unnecessary except for severe sonography with biopsy is the preferred method for staging disease, hemodynamic instability, or multiple medical comor- and tissue diagnosis, with 90% accuracy. At least 50% of bidities. Confirmed C. difficile infection should be treated patients with familial adenomatous polyposis syndrome according to comorbidities and clinical severity (see MKSAP 19 develop adenomatous changes of the periampullary region, Infectious Disease for discussion of C. difficile infection). which may progress to adenocarcinoma. See Colorectal Treatment of diarrhea in travelers includes bismuth and lop- Neoplasia for more information on adenomatous polyposis eramide to relieve symptoms and possibly empiric antibiotics syndromes. Hereditary tumor syndromes can cause ampullary for moderate or severe symptoms. adenocarcinomas; patients should be considered for genetic testing. Chronic Diarrhea Causes e About 10% to 25% of pancreatic neuroendocrine tumors are Chronic diarrhea can be grouped into six categories by disease functional and hypersecrete hormones, most commonly mechanism: (1) osmotic, (2) secretory, (3) steatorrhea, (4) inflam- gastrin or insulin. matory, (5) motility, and (6) miscellaneous (Table 16). These cat- egories may overlap because some diseases have multiple mech- anisms causing diarrhea. The most common causes are irritable bowel syndrome with predominant diarrhea (IBS-D) Disorders of the Small and functional causes. Medications are also an important

functional and hypersecrete hormones, most commonly mechanism: (1) osmotic, (2) secretory, (3) steatorrhea, (4) inflam- gastrin or insulin. matory, (5) motility, and (6) miscellaneous (Table 16). These cat- egories may overlap because some diseases have multiple mech- anisms causing diarrhea. The most common causes are irritable bowel syndrome with predominant diarrhea (IBS-D) Disorders of the Small and functional causes. Medications are also an important and Large Bowel cause (Table 17).

functional and hypersecrete hormones, most commonly mechanism: (1) osmotic, (2) secretory, (3) steatorrhea, (4) inflam- gastrin or insulin. matory, (5) motility, and (6) miscellaneous (Table 16). These cat- egories may overlap because some diseases have multiple mech- anisms causing diarrhea. The most common causes are irritable bowel syndrome with predominant diarrhea (IBS-D) Disorders of the Small and functional causes. Medications are also an important and Large Bowel cause (Table 17). Diarrhea Evaluation Evaluation of chronic diarrhea includes a careful history and Classification physical examination. Because IBS-D and functional causes Diarrhea is marked by passage of a greater number of less- are the most common, further diagnostic studies should be formed stools than normal. Diarrhea is considered acute if reserved for patients whose symptoms or examination find- occurring for fewer than 2 weeks and chronic if occurring for ings suggest another cause. at least 4 weeks. Acute diarrhea is usually infectious, whereas chronic diarrhea is usually noninfectious. History and Physical Examination The diarrhea pattern and stool characteristics can help deter- Acute Diarrhea mine the most likely diagnosis. Steatorrhea is often described Causes as malodorous, greasy, or oily stools that float. The relation of Causes of acute diarrhea include bacteria, viruses, and para- symptoms to eating can also provide clues to the cause. sites. These can be divided into noninvasive and invasive Osmotic diarrhea occurs with eating and subsides with fast- causes. Noninvasive causes, leading to watery diarrhea, ing, whereas secretory diarrhea does not subside with fasting. include Clostridioides difficile, viruses (e.g., norovirus), Nocturnal symptoms are often related to inflammatory condi- Escherichia coli, cholera, cryptosporidia, and Giardia duode- tions, such as inflammatory bowel disease (IBD). Information nalis. Invasive causes lead to dysentery or bloody diarrhea and about specific dietary factors that commonly cause osmotic

Diarrhea Evaluation Evaluation of chronic diarrhea includes a careful history and Classification physical examination. Because IBS-D and functional causes Diarrhea is marked by passage of a greater number of less- are the most common, further diagnostic studies should be formed stools than normal. Diarrhea is considered acute if reserved for patients whose symptoms or examination find- occurring for fewer than 2 weeks and chronic if occurring for ings suggest another cause. at least 4 weeks. Acute diarrhea is usually infectious, whereas chronic diarrhea is usually noninfectious. History and Physical Examination The diarrhea pattern and stool characteristics can help deter- Acute Diarrhea mine the most likely diagnosis. Steatorrhea is often described Causes as malodorous, greasy, or oily stools that float. The relation of Causes of acute diarrhea include bacteria, viruses, and para- symptoms to eating can also provide clues to the cause. sites. These can be divided into noninvasive and invasive Osmotic diarrhea occurs with eating and subsides with fast- causes. Noninvasive causes, leading to watery diarrhea, ing, whereas secretory diarrhea does not subside with fasting. include Clostridioides difficile, viruses (e.g., norovirus), Nocturnal symptoms are often related to inflammatory condi- Escherichia coli, cholera, cryptosporidia, and Giardia duode- tions, such as inflammatory bowel disease (IBD). Information nalis. Invasive causes lead to dysentery or bloody diarrhea and about specific dietary factors that commonly cause osmotic 26

Disorders of the Small and Large Bowel TABLE 16. Types of Chronic Diarrhea TABLE 17. Medications That Cause Diarrhea Diarrhea Type Causes (examples) Cc ommon | Osmotic Medications (laxatives) Antacids, proton pump inhibitors Undigested sugars (lactose, fructose, Chemotherapy sorbitol, mannitol) ecw betes Secretory Medications (nonosmotic laxatives, Bus ee Colchicine antibiotics) ; . Metformin Endocrine (neuroendocrine tumors, adrenal | insufficiency, hyperthyroidism) NSAIDs, mesalamine Bile salt malabsorption (ileal resection, Cholesterol-lowering drugs cholecystectomy) . 7 F Riek Rarer Noninvasive infections (giardiasis, cryptosporidiosis) ACE inhibitors |

Bile salt malabsorption (ileal resection, Cholesterol-lowering drugs cholecystectomy) . 7 F Riek Rarer Noninvasive infections (giardiasis, cryptosporidiosis) ACE inhibitors | | Small intestinal bacterial overgrowth Angiotensin receptor blockers Steatorrhea Maldigestion (decreased bile salts, B-adrenergic receptor antagonists pancreatic dysfunction) Carbamazepine Malabsorption (celiac disease, tropical Lipase inhibitors sprue, giardiasis, Whipple disease, chronic mesenteric ischemia, short bowel syndrome, Lithium small intestinal bacterial overgrowth, Prostaglandin lymphatic obstruction) Vitamin/mineral supplements Inflammatory Inflammatory bowel disease (ulcerative colitis, Crohn disease, microscopic colitis) | Adapted with permission from Schiller LR, Pardi DS, Spiller R, Semrad CE, Surawicz CM, Giannella RA, et al. Gastro 2013 APDW/WCOG Shanghai working party report: | Malignancy (colorectal cancer, lymphoma) | chronic diarrhea: definition, classification, diagnosis. J Gastroenterol Hepatol. | 2014;29:6-25. [PMID: 24117999] doi:10.1111/jgh.12392. © 2013 Journal of Invasive infections (Clostridioides difficile, Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd. | cytomegalovirus, Entamoeba histolytica, tuberculosis)

| Small intestinal bacterial overgrowth Angiotensin receptor blockers Steatorrhea Maldigestion (decreased bile salts, B-adrenergic receptor antagonists pancreatic dysfunction) Carbamazepine Malabsorption (celiac disease, tropical Lipase inhibitors sprue, giardiasis, Whipple disease, chronic mesenteric ischemia, short bowel syndrome, Lithium small intestinal bacterial overgrowth, Prostaglandin lymphatic obstruction) Vitamin/mineral supplements Inflammatory Inflammatory bowel disease (ulcerative colitis, Crohn disease, microscopic colitis) | Adapted with permission from Schiller LR, Pardi DS, Spiller R, Semrad CE, Surawicz CM, Giannella RA, et al. Gastro 2013 APDW/WCOG Shanghai working party report: | Malignancy (colorectal cancer, lymphoma) | chronic diarrhea: definition, classification, diagnosis. J Gastroenterol Hepatol. | 2014;29:6-25. [PMID: 24117999] doi:10.1111/jgh.12392. © 2013 Journal of Invasive infections (Clostridioides difficile, Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd. | cytomegalovirus, Entamoeba histolytica, tuberculosis) Ischemia Epidemiologic factors may also be helpful. Conditions Radiation colitis/enteritis such as IBS and microscopic colitis are more common in Motility Postsurgical (vagotomy, dumping) women than men. IBS onset is most common in the third and

Ischemia Epidemiologic factors may also be helpful. Conditions Radiation colitis/enteritis such as IBS and microscopic colitis are more common in Motility Postsurgical (vagotomy, dumping) women than men. IBS onset is most common in the third and Endocrine (diabetes mellitus, fourth decades of life, microscopic colitis is most common in hyperthyroidism) the seventh and eighth decades, and malignancy is suggested Systemic sclerosis by onset at age 50 years and older. Miscellaneous Irritable bowel syndrome Physical examination should assess for hydration and nutrition status, perineal disease suggesting Crohn disease, Functional diarrhea? and sphincter defects suggesting fecal incontinence. Factitious Overflow Additional Testing Fecal incontinence The decision to pursue additional testing, including serologies,

Miscellaneous Irritable bowel syndrome Physical examination should assess for hydration and nutrition status, perineal disease suggesting Crohn disease, Functional diarrhea? and sphincter defects suggesting fecal incontinence. Factitious Overflow Additional Testing Fecal incontinence The decision to pursue additional testing, including serologies, Frequent or loose or watery stools without abdominal discomfort in the absence stool studies, imaging, and endoscopy, depends on the clinical of other identifiable causes. scenario and likelihood of specific diseases. Complete blood Adapted with permission from Schiller LR, Pardi DS, Spiller R, Semrad CE, Surawicz count, iron studies (including ferritin), thyroid-stimulating CM, Giannella RA, et al. Gastro 2013 APDW/WCOG Shanghai working party report: chronic diarrhea: definition, classification, diagnosis. J Gastroenterol hormone level, and testing for celiac disease and C. difficile Hepatol. 2014;29:6-25. [PMID: 24117999] doi:10.1111/jgh.12392. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty infection may be considered. Ltd. For chronic diarrhea without an underlying diagnosis, stool studies can help clarify the cause. Analysis of stool

Frequent or loose or watery stools without abdominal discomfort in the absence stool studies, imaging, and endoscopy, depends on the clinical of other identifiable causes. scenario and likelihood of specific diseases. Complete blood Adapted with permission from Schiller LR, Pardi DS, Spiller R, Semrad CE, Surawicz count, iron studies (including ferritin), thyroid-stimulating CM, Giannella RA, et al. Gastro 2013 APDW/WCOG Shanghai working party report: chronic diarrhea: definition, classification, diagnosis. J Gastroenterol hormone level, and testing for celiac disease and C. difficile Hepatol. 2014;29:6-25. [PMID: 24117999] doi:10.1111/jgh.12392. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty infection may be considered. Ltd. For chronic diarrhea without an underlying diagnosis, stool studies can help clarify the cause. Analysis of stool diarrhea, such as lactose, fructose, or artificial sweeteners includes fecal weight, stool electrolytes, fecal pH, fat content, (sorbitol), should be obtained. The patient should be asked fecal calprotectin, and presence of blood and leukocytes. In about new medications (prescription and nonprescription) watery stools, fecal electrolytes can be used to calculate the and timing of the initiation of medication in relation to diar- fecal osmotic gap:

diarrhea, such as lactose, fructose, or artificial sweeteners includes fecal weight, stool electrolytes, fecal pH, fat content, (sorbitol), should be obtained. The patient should be asked fecal calprotectin, and presence of blood and leukocytes. In about new medications (prescription and nonprescription) watery stools, fecal electrolytes can be used to calculate the and timing of the initiation of medication in relation to diar- fecal osmotic gap: rhea onset. Concomitant symptoms may also suggest a diagno- 290 — (2 x [stool sodium + stool potassium]) sis. Abdominal pain accompanying diarrhea may suggest IBS-D, especially when a bowel movement relieves pain. Rectal An osmotic gap less than 50 mOsm/kg (50 mmol/kg) sug- bleeding and weight loss suggest malignancy in older patients gests secretory diarrhea, and a gap exceeding 100 mOsm/kg or IBD in younger patients. (100 mmol/kg) suggests osmotic diarrhea. 27

Disorders of the Small and Large Bowel Blood or leukocytes in the stool or an elevated fecal cal- Treatment of secretory diarrhea is aimed at identifying the protectin level suggests an inflammatory cause. A positive cause and careful management of hydration. Repletion of fat- 72-hour stool collection for fecal fat confirms steatorrhea; a soluble vitamins is important in cases of fat malabsorption. random fecal fat assessment may be helpful if timed collec- Medication-induced diarrhea necessitates changing med- tion is not possible. A reduced fecal elastase level is useful for ications unless the benefits exceed the potential harms and the evaluating exocrine pancreatic function. When laxative abuse patient considers the diarrhea manageable. is suspected, a stool or urine laxative screen can aid in diagnosis. e Acute diarrhea (less than 2 weeks’ duration) is usually For suspected small-bowel disease, small intestine evalu- caused by infectious agents; chronic diarrhea (more than ation may include small-bowel radiography, CT, or magnetic 4 weeks’ duration) is most commonly noninfectious. resonance enterography to identify conditions that could lead to bacterial overgrowth, such as small intestinal diverticular e Maintaining hydration is the primary goal of treatment disease, inflammation, or strictures. Upper endoscopy is indi- for acute diarrhea.

Blood or leukocytes in the stool or an elevated fecal cal- Treatment of secretory diarrhea is aimed at identifying the protectin level suggests an inflammatory cause. A positive cause and careful management of hydration. Repletion of fat- 72-hour stool collection for fecal fat confirms steatorrhea; a soluble vitamins is important in cases of fat malabsorption. random fecal fat assessment may be helpful if timed collec- Medication-induced diarrhea necessitates changing med- tion is not possible. A reduced fecal elastase level is useful for ications unless the benefits exceed the potential harms and the evaluating exocrine pancreatic function. When laxative abuse patient considers the diarrhea manageable. is suspected, a stool or urine laxative screen can aid in diagnosis. e Acute diarrhea (less than 2 weeks’ duration) is usually For suspected small-bowel disease, small intestine evalu- caused by infectious agents; chronic diarrhea (more than ation may include small-bowel radiography, CT, or magnetic 4 weeks’ duration) is most commonly noninfectious. resonance enterography to identify conditions that could lead to bacterial overgrowth, such as small intestinal diverticular e Maintaining hydration is the primary goal of treatment disease, inflammation, or strictures. Upper endoscopy is indi- for acute diarrhea. cated when small-bowel mucosal disease (e.g., celiac disease ¢ The primary causes of chronic diarrhea are irritable or chronic infection) is suspected. Capsule endoscopy can bowel syndrome with predominant diarrhea, functional visualize the small intestine but does not allow sampling. causes, and medications. Device-assisted enteroscopy can be used in selected patients who require sampling of small intestinal tissue based on Microscopic Colitis abnormalities found on imaging or capsule endoscopy. Microscopic colitis is characterized by normal mucosal appear- Diagnostic yields for capsule endoscopy and device-assisted ance on endoscopy, with inflammatory changes seen on histo- enteroscopy are low in patients with chronic diarrhea and pathology of colon biopsy specimens. Subclassification into normal laboratory or imaging results. lymphocytic colitis and collagenous colitis (Figure 16) is based Colonoscopy is the primary diagnostic tool for evaluating on predominating histologic features. It mostly affects middle- colonic causes of diarrhea, such as IBD, microscopic colitis, aged and older women and is associated with other autoim- chronic colon infections, and malignancy. Colon biopsies of mune conditions, particularly celiac disease. It presents with the right and left colon are required to exclude microscopic abrupt or gradual onset of watery diarrhea that has a relaps- colitis. Colonoscopy is especially important in patients with ing-remitting course over months to years, sometimes accom- rectal bleeding and/or age older than 50 years. panied by mild weight loss and abdominal pain. Additional testing (including HIV testing) may be war- Several medication classes, including NSAIDs, selective ranted in immunocompromised patients and patients with serotonin reuptake inhibitors, and proton pump inhibitors, secretory diarrhea. Patients found to have a small-bowel are associated with microscopic colitis. The first step in man- tumor in the setting of diarrhea should be considered for addi- agement is discontinuing potentially causative medications tional testing, including radioimmunoassays for peptides and/ and symptomatic treatment with antidiarrheal agents, such as or 24-hour urine 5-hydroxyindoleacetic acid measurement for loperamide. First-line treatment is budesonide. Second-line neuroendocrine tumors. Testing for gastrointestinal neuroen- treatments include bismuth subsalicylate, prednisone, or docrine tumors should be limited to patients with chronic mesalamine and are considered when patient preference, side diarrhea and flushing. effects, or cost make budesonide impractical. Patients with

cated when small-bowel mucosal disease (e.g., celiac disease ¢ The primary causes of chronic diarrhea are irritable or chronic infection) is suspected. Capsule endoscopy can bowel syndrome with predominant diarrhea, functional visualize the small intestine but does not allow sampling. causes, and medications. Device-assisted enteroscopy can be used in selected patients who require sampling of small intestinal tissue based on Microscopic Colitis abnormalities found on imaging or capsule endoscopy. Microscopic colitis is characterized by normal mucosal appear- Diagnostic yields for capsule endoscopy and device-assisted ance on endoscopy, with inflammatory changes seen on histo- enteroscopy are low in patients with chronic diarrhea and pathology of colon biopsy specimens. Subclassification into normal laboratory or imaging results. lymphocytic colitis and collagenous colitis (Figure 16) is based Colonoscopy is the primary diagnostic tool for evaluating on predominating histologic features. It mostly affects middle- colonic causes of diarrhea, such as IBD, microscopic colitis, aged and older women and is associated with other autoim- chronic colon infections, and malignancy. Colon biopsies of mune conditions, particularly celiac disease. It presents with the right and left colon are required to exclude microscopic abrupt or gradual onset of watery diarrhea that has a relaps- colitis. Colonoscopy is especially important in patients with ing-remitting course over months to years, sometimes accom- rectal bleeding and/or age older than 50 years. panied by mild weight loss and abdominal pain. Additional testing (including HIV testing) may be war- Several medication classes, including NSAIDs, selective ranted in immunocompromised patients and patients with serotonin reuptake inhibitors, and proton pump inhibitors, secretory diarrhea. Patients found to have a small-bowel are associated with microscopic colitis. The first step in man- tumor in the setting of diarrhea should be considered for addi- agement is discontinuing potentially causative medications tional testing, including radioimmunoassays for peptides and/ and symptomatic treatment with antidiarrheal agents, such as or 24-hour urine 5-hydroxyindoleacetic acid measurement for loperamide. First-line treatment is budesonide. Second-line neuroendocrine tumors. Testing for gastrointestinal neuroen- treatments include bismuth subsalicylate, prednisone, or docrine tumors should be limited to patients with chronic mesalamine and are considered when patient preference, side diarrhea and flushing. effects, or cost make budesonide impractical. Patients with Management Treatment of IBS-D is discussed in the Irritable Bowel Syndrome section. Treatment of osmotic diarrhea includes following a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) (Table 18) and lactose-free diet.

cated when small-bowel mucosal disease (e.g., celiac disease ¢ The primary causes of chronic diarrhea are irritable or chronic infection) is suspected. Capsule endoscopy can bowel syndrome with predominant diarrhea, functional visualize the small intestine but does not allow sampling. causes, and medications. Device-assisted enteroscopy can be used in selected patients who require sampling of small intestinal tissue based on Microscopic Colitis abnormalities found on imaging or capsule endoscopy. Microscopic colitis is characterized by normal mucosal appear- Diagnostic yields for capsule endoscopy and device-assisted ance on endoscopy, with inflammatory changes seen on histo- enteroscopy are low in patients with chronic diarrhea and pathology of colon biopsy specimens. Subclassification into normal laboratory or imaging results. lymphocytic colitis and collagenous colitis (Figure 16) is based Colonoscopy is the primary diagnostic tool for evaluating on predominating histologic features. It mostly affects middle- colonic causes of diarrhea, such as IBD, microscopic colitis, aged and older women and is associated with other autoim- chronic colon infections, and malignancy. Colon biopsies of mune conditions, particularly celiac disease. It presents with the right and left colon are required to exclude microscopic abrupt or gradual onset of watery diarrhea that has a relaps- colitis. Colonoscopy is especially important in patients with ing-remitting course over months to years, sometimes accom- rectal bleeding and/or age older than 50 years. panied by mild weight loss and abdominal pain. Additional testing (including HIV testing) may be war- Several medication classes, including NSAIDs, selective ranted in immunocompromised patients and patients with serotonin reuptake inhibitors, and proton pump inhibitors, secretory diarrhea. Patients found to have a small-bowel are associated with microscopic colitis. The first step in man- tumor in the setting of diarrhea should be considered for addi- agement is discontinuing potentially causative medications tional testing, including radioimmunoassays for peptides and/ and symptomatic treatment with antidiarrheal agents, such as or 24-hour urine 5-hydroxyindoleacetic acid measurement for loperamide. First-line treatment is budesonide. Second-line neuroendocrine tumors. Testing for gastrointestinal neuroen- treatments include bismuth subsalicylate, prednisone, or docrine tumors should be limited to patients with chronic mesalamine and are considered when patient preference, side diarrhea and flushing. effects, or cost make budesonide impractical. Patients with Management Treatment of IBS-D is discussed in the Irritable Bowel Syndrome section. Treatment of osmotic diarrhea includes following a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) (Table 18) and lactose-free diet. TABLE 18. Sources of FODMAP Carbohydrates

cated when small-bowel mucosal disease (e.g., celiac disease ¢ The primary causes of chronic diarrhea are irritable or chronic infection) is suspected. Capsule endoscopy can bowel syndrome with predominant diarrhea, functional visualize the small intestine but does not allow sampling. causes, and medications. Device-assisted enteroscopy can be used in selected patients who require sampling of small intestinal tissue based on Microscopic Colitis abnormalities found on imaging or capsule endoscopy. Microscopic colitis is characterized by normal mucosal appear- Diagnostic yields for capsule endoscopy and device-assisted ance on endoscopy, with inflammatory changes seen on histo- enteroscopy are low in patients with chronic diarrhea and pathology of colon biopsy specimens. Subclassification into normal laboratory or imaging results. lymphocytic colitis and collagenous colitis (Figure 16) is based Colonoscopy is the primary diagnostic tool for evaluating on predominating histologic features. It mostly affects middle- colonic causes of diarrhea, such as IBD, microscopic colitis, aged and older women and is associated with other autoim- chronic colon infections, and malignancy. Colon biopsies of mune conditions, particularly celiac disease. It presents with the right and left colon are required to exclude microscopic abrupt or gradual onset of watery diarrhea that has a relaps- colitis. Colonoscopy is especially important in patients with ing-remitting course over months to years, sometimes accom- rectal bleeding and/or age older than 50 years. panied by mild weight loss and abdominal pain. Additional testing (including HIV testing) may be war- Several medication classes, including NSAIDs, selective ranted in immunocompromised patients and patients with serotonin reuptake inhibitors, and proton pump inhibitors, secretory diarrhea. Patients found to have a small-bowel are associated with microscopic colitis. The first step in man- tumor in the setting of diarrhea should be considered for addi- agement is discontinuing potentially causative medications tional testing, including radioimmunoassays for peptides and/ and symptomatic treatment with antidiarrheal agents, such as or 24-hour urine 5-hydroxyindoleacetic acid measurement for loperamide. First-line treatment is budesonide. Second-line neuroendocrine tumors. Testing for gastrointestinal neuroen- treatments include bismuth subsalicylate, prednisone, or docrine tumors should be limited to patients with chronic mesalamine and are considered when patient preference, side diarrhea and flushing. effects, or cost make budesonide impractical. Patients with Management Treatment of IBS-D is discussed in the Irritable Bowel Syndrome section. Treatment of osmotic diarrhea includes following a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) (Table 18) and lactose-free diet. TABLE 18. Sources of FODMAP Carbohydrates | Fructose: honey, apples, pears, peaches, mangos, fruit juice, | dried fruit

Management Treatment of IBS-D is discussed in the Irritable Bowel Syndrome section. Treatment of osmotic diarrhea includes following a low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) (Table 18) and lactose-free diet. TABLE 18. Sources of FODMAP Carbohydrates | Fructose: honey, apples, pears, peaches, mangos, fruit juice, | dried fruit Lactose: milk, custard, ice cream, yogurt, soft cheeses Fructans: wheat, rye, onions, leeks, zucchini | Galactans: legumes Sugar alcohols: xylitol, sorbitol, maltitol, mannitol FIGURE 16. Collagenous colitis: colon mucosal biopsy specimen showing a FODMAP = fermentable oligosaccharides, disaccharides, monosaccharides, and pink, abnormal subepithelial collagen band (arrowhead) and lamina propria polyols. expanded by inflammatory cells (arrow). 28

Disorders of the Small and Large Bowel microscopic colitis have no long-term increased risk for colo- serologic tests with results positive for celiac disease necessi- rectal cancer. tate upper endoscopy with biopsies from the duodenum to confirm the disease. If clinical suspicion is high and results of initial testing are negative, upper endoscopy and duodenal

microscopic colitis have no long-term increased risk for colo- serologic tests with results positive for celiac disease necessi- rectal cancer. tate upper endoscopy with biopsies from the duodenum to confirm the disease. If clinical suspicion is high and results of initial testing are negative, upper endoscopy and duodenal Celiac Disease and Nonceliac biopsy can be pursued. There are specific recommendations for the biopsy procedure to minimize false-negative results. Gluten Sensitivity Celiac disease is confirmed by increased intraepithelial lym- Celiac disease is an immune-mediated disease that primarily phocytosis and blunting or atrophy of the duodenal villi. If affects the small intestine in response to dietary gluten. It is a biopsy results suggesting celiac disease are obtained before common cause of malabsorption and affects only genetically serologic testing, confirmatory serologic testing should be predisposed individuals. The immune reaction leads to performed. destruction of the small intestinal villi, starting in the proximal duodenum. Although antibodies are produced as part of the Management and Monitoring immune reaction, their contribution to the pathogenesis of Patients with celiac disease should be educated about the celiac disease is uncertain. gluten-free diet by a knowledgeable registered dietician. Treatment of celiac disease is lifelong avoidance of wheat, rye, Testing and barley, including in patients without symptoms. Patients Testing should be pursued in patients with typical gastrointes- should know hidden sources of gluten, such as soy sauce (which tinal symptoms or extraintestinal manifestations and should may contain wheat). Dietary oats are generally safe in celiac be considered in those with increased risk (type 1 diabetes disease but should be limited to those with a gluten-free label mellitus, autoimmune thyroid disease, or a first-degree family because cross-contact with gluten-containing grains is possible member with celiac disease). Gastrointestinal symptoms of in some processing settings. Monitoring includes clinical assess- celiac disease include chronic diarrhea, bloating, and weight ment of symptoms and signs of celiac disease, assessment of loss as well as constipation and dyspepsia. Other manifesta- dietary adherence, and confirmation of normalized antibody tions include iron deficiency anemia, bone loss, abnormal levels. Antibody testing may be repeated at 6 and 12 months aminotransferase levels, neurologic symptoms, and dermatitis after diagnosis to assess response to the gluten-free diet and herpetiformis. Patients may also be asymptomatic. then annually. Repeat upper endoscopy with biopsies should be The best initial step is to test for IgA tissue transglutami- considered for individuals who have ongoing symptoms while nase antibodies. Because IgA deficiency is more common in adhering to a gluten-free diet. Assessment of bone density at celiac disease, total IgA levels may also need to be measured to diagnosis should be considered to ensure adequate bone health. prevent false-negative results. In patients with IgA deficiency, testing for anti-deamidated gliadin peptide IgG antibodies or tissue transglutaminase IgG antibodies can be used. Anti- Nonresponsive Celiac Disease

Celiac Disease and Nonceliac biopsy can be pursued. There are specific recommendations for the biopsy procedure to minimize false-negative results. Gluten Sensitivity Celiac disease is confirmed by increased intraepithelial lym- Celiac disease is an immune-mediated disease that primarily phocytosis and blunting or atrophy of the duodenal villi. If affects the small intestine in response to dietary gluten. It is a biopsy results suggesting celiac disease are obtained before common cause of malabsorption and affects only genetically serologic testing, confirmatory serologic testing should be predisposed individuals. The immune reaction leads to performed. destruction of the small intestinal villi, starting in the proximal duodenum. Although antibodies are produced as part of the Management and Monitoring immune reaction, their contribution to the pathogenesis of Patients with celiac disease should be educated about the celiac disease is uncertain. gluten-free diet by a knowledgeable registered dietician. Treatment of celiac disease is lifelong avoidance of wheat, rye, Testing and barley, including in patients without symptoms. Patients Testing should be pursued in patients with typical gastrointes- should know hidden sources of gluten, such as soy sauce (which tinal symptoms or extraintestinal manifestations and should may contain wheat). Dietary oats are generally safe in celiac be considered in those with increased risk (type 1 diabetes disease but should be limited to those with a gluten-free label mellitus, autoimmune thyroid disease, or a first-degree family because cross-contact with gluten-containing grains is possible member with celiac disease). Gastrointestinal symptoms of in some processing settings. Monitoring includes clinical assess- celiac disease include chronic diarrhea, bloating, and weight ment of symptoms and signs of celiac disease, assessment of loss as well as constipation and dyspepsia. Other manifesta- dietary adherence, and confirmation of normalized antibody tions include iron deficiency anemia, bone loss, abnormal levels. Antibody testing may be repeated at 6 and 12 months aminotransferase levels, neurologic symptoms, and dermatitis after diagnosis to assess response to the gluten-free diet and herpetiformis. Patients may also be asymptomatic. then annually. Repeat upper endoscopy with biopsies should be The best initial step is to test for IgA tissue transglutami- considered for individuals who have ongoing symptoms while nase antibodies. Because IgA deficiency is more common in adhering to a gluten-free diet. Assessment of bone density at celiac disease, total IgA levels may also need to be measured to diagnosis should be considered to ensure adequate bone health. prevent false-negative results. In patients with IgA deficiency, testing for anti-deamidated gliadin peptide IgG antibodies or tissue transglutaminase IgG antibodies can be used. Anti- Nonresponsive Celiac Disease endomysial IgA antibodies are highly specific; however, meas- The most common cause of ongoing celiac disease-related

Celiac Disease and Nonceliac biopsy can be pursued. There are specific recommendations for the biopsy procedure to minimize false-negative results. Gluten Sensitivity Celiac disease is confirmed by increased intraepithelial lym- Celiac disease is an immune-mediated disease that primarily phocytosis and blunting or atrophy of the duodenal villi. If affects the small intestine in response to dietary gluten. It is a biopsy results suggesting celiac disease are obtained before common cause of malabsorption and affects only genetically serologic testing, confirmatory serologic testing should be predisposed individuals. The immune reaction leads to performed. destruction of the small intestinal villi, starting in the proximal duodenum. Although antibodies are produced as part of the Management and Monitoring immune reaction, their contribution to the pathogenesis of Patients with celiac disease should be educated about the celiac disease is uncertain. gluten-free diet by a knowledgeable registered dietician. Treatment of celiac disease is lifelong avoidance of wheat, rye, Testing and barley, including in patients without symptoms. Patients Testing should be pursued in patients with typical gastrointes- should know hidden sources of gluten, such as soy sauce (which tinal symptoms or extraintestinal manifestations and should may contain wheat). Dietary oats are generally safe in celiac be considered in those with increased risk (type 1 diabetes disease but should be limited to those with a gluten-free label mellitus, autoimmune thyroid disease, or a first-degree family because cross-contact with gluten-containing grains is possible member with celiac disease). Gastrointestinal symptoms of in some processing settings. Monitoring includes clinical assess- celiac disease include chronic diarrhea, bloating, and weight ment of symptoms and signs of celiac disease, assessment of loss as well as constipation and dyspepsia. Other manifesta- dietary adherence, and confirmation of normalized antibody tions include iron deficiency anemia, bone loss, abnormal levels. Antibody testing may be repeated at 6 and 12 months aminotransferase levels, neurologic symptoms, and dermatitis after diagnosis to assess response to the gluten-free diet and herpetiformis. Patients may also be asymptomatic. then annually. Repeat upper endoscopy with biopsies should be The best initial step is to test for IgA tissue transglutami- considered for individuals who have ongoing symptoms while nase antibodies. Because IgA deficiency is more common in adhering to a gluten-free diet. Assessment of bone density at celiac disease, total IgA levels may also need to be measured to diagnosis should be considered to ensure adequate bone health. prevent false-negative results. In patients with IgA deficiency, testing for anti-deamidated gliadin peptide IgG antibodies or tissue transglutaminase IgG antibodies can be used. Anti- Nonresponsive Celiac Disease endomysial IgA antibodies are highly specific; however, meas- The most common cause of ongoing celiac disease-related urement is complex, and testing for these antibodies is symptoms is continued gluten exposure. When symptoms do

Celiac Disease and Nonceliac biopsy can be pursued. There are specific recommendations for the biopsy procedure to minimize false-negative results. Gluten Sensitivity Celiac disease is confirmed by increased intraepithelial lym- Celiac disease is an immune-mediated disease that primarily phocytosis and blunting or atrophy of the duodenal villi. If affects the small intestine in response to dietary gluten. It is a biopsy results suggesting celiac disease are obtained before common cause of malabsorption and affects only genetically serologic testing, confirmatory serologic testing should be predisposed individuals. The immune reaction leads to performed. destruction of the small intestinal villi, starting in the proximal duodenum. Although antibodies are produced as part of the Management and Monitoring immune reaction, their contribution to the pathogenesis of Patients with celiac disease should be educated about the celiac disease is uncertain. gluten-free diet by a knowledgeable registered dietician. Treatment of celiac disease is lifelong avoidance of wheat, rye, Testing and barley, including in patients without symptoms. Patients Testing should be pursued in patients with typical gastrointes- should know hidden sources of gluten, such as soy sauce (which tinal symptoms or extraintestinal manifestations and should may contain wheat). Dietary oats are generally safe in celiac be considered in those with increased risk (type 1 diabetes disease but should be limited to those with a gluten-free label mellitus, autoimmune thyroid disease, or a first-degree family because cross-contact with gluten-containing grains is possible member with celiac disease). Gastrointestinal symptoms of in some processing settings. Monitoring includes clinical assess- celiac disease include chronic diarrhea, bloating, and weight ment of symptoms and signs of celiac disease, assessment of loss as well as constipation and dyspepsia. Other manifesta- dietary adherence, and confirmation of normalized antibody tions include iron deficiency anemia, bone loss, abnormal levels. Antibody testing may be repeated at 6 and 12 months aminotransferase levels, neurologic symptoms, and dermatitis after diagnosis to assess response to the gluten-free diet and herpetiformis. Patients may also be asymptomatic. then annually. Repeat upper endoscopy with biopsies should be The best initial step is to test for IgA tissue transglutami- considered for individuals who have ongoing symptoms while nase antibodies. Because IgA deficiency is more common in adhering to a gluten-free diet. Assessment of bone density at celiac disease, total IgA levels may also need to be measured to diagnosis should be considered to ensure adequate bone health. prevent false-negative results. In patients with IgA deficiency, testing for anti-deamidated gliadin peptide IgG antibodies or tissue transglutaminase IgG antibodies can be used. Anti- Nonresponsive Celiac Disease endomysial IgA antibodies are highly specific; however, meas- The most common cause of ongoing celiac disease-related urement is complex, and testing for these antibodies is symptoms is continued gluten exposure. When symptoms do generally reserved for situations in which data conflict. Testing not resolve completely with adherence to a gluten-free diet,

endomysial IgA antibodies are highly specific; however, meas- The most common cause of ongoing celiac disease-related urement is complex, and testing for these antibodies is symptoms is continued gluten exposure. When symptoms do generally reserved for situations in which data conflict. Testing not resolve completely with adherence to a gluten-free diet, for anti-gliadin antibodies (IgA and IgG) should not be used the accuracy of the diagnosis should be reassessed. Other con- because of low sensitivity and specificity. ditions that may explain ongoing symptoms include IBS, lac- Antibody testing is less sensitive if the patient is on a glu- tose or fructose intolerance, bacterial overgrowth, microscopic ten-free diet. In such patients, genetic testing for HLA-DQ2 or colitis, and IBD. Evaluation to exclude these conditions is criti- HLA-DQ8 should be considered. Nearly all patients with celiac cal before refractory celiac disease can be diagnosed. disease carry the HLA-DQ2 or HLA-DQ8 haplotype; however, A small number of patients develop refractory celiac dis- up to 40% of the general population carries these mutations. ease, in which symptoms of malabsorption and small intestinal Therefore, genetic testing can rule out but not confirm disease. inflammation persist despite adherence to a strict gluten-free Among patients with a genetic mutation, gluten can be reintro- diet. These patients are typically older than 65 years and pre- duced, preferably daily for 1 to 3 months, and serologic testing sent with diarrhea, weight loss, dehydration, and nutritional and/or duodenal biopsy can be performed. Genetic testing may deficiencies. Possible medication-induced sprue, most com- also help rule out disease in patients who did not undergo sero- monly olmesartan enteropathy, should be managed by discon- logic testing at diagnosis or whose biopsy specimens show tinuing the offending medication. Patients with refractory histologic changes but negative serologic results. celiac disease should be managed in a specialized celiac dis- ease center.

logic testing at diagnosis or whose biopsy specimens show tinuing the offending medication. Patients with refractory histologic changes but negative serologic results. celiac disease should be managed in a specialized celiac dis- ease center. Diagnosis Although a markedly elevated (>10 times the upper limit of Dermatitis Herpetiformis normal) transglutaminase IgA antibody titer has a positive Dermatitis herpetiformis is an extremely pruritic subepidermal predictive value for celiac disease approaching 100%, all autoimmune bullous disease. It typically presents with intensely 29

Disorders of the Small and Large Bowel e The best initial test for celiac disease is testing for IgA tissue transglutaminase antibodies while the patient is maintaining a gluten-containing diet. ¢ HLA-DQ?2 or HLA-DQ8 haplotype is present in nearly all patients with celiac disease, but up to 40% of the general population carries it; thus, genetic testing is most useful in ruling out celiac disease. ¢ Treatment of celiac disease and dermatitis herpetiformis is lifelong avoidance of wheat, rye, and barley. e The most common cause of ongoing celiac disease-related symptoms is continued gluten exposure.

¢ Treatment of celiac disease and dermatitis herpetiformis is lifelong avoidance of wheat, rye, and barley. e The most common cause of ongoing celiac disease-related symptoms is continued gluten exposure. Malabsorption Small Intestinal Bacterial Overgrowth Small intestinal bacterial overgrowth (SIBO) is caused by vari- ous conditions, including impaired motility, strictures (e.g., in FIGURE 17. Dermatitis herpetiformis, a manifestation of celiac disease, is Crohn disease), or blind loops (e.g., small-bowel diverticula). characterized by pruritic papules and transient, almost immediately excoriated Some evidence suggests that SIBO could contribute to symp- blisters on the elbows, knees, and buttocks. toms in IBS-D in the absence of a predisposing structural lesion. Symptoms are often nonspecific and include abdomi- pruritic papules and fragile vesicles that rapidly break, leaving nal discomfort, flatulence, bloating, and diarrhea. tiny erosions. The elbows, knees, scalp, and lower back are the Classically, SIBO is defined by more than 10° colony- most common sites of involvement (Figure 17). Most patients forming units/mL of jejunal aspirate. Jejunal aspirate is con- have serologic and histologic evidence of celiac disease. sidered the gold standard but is rarely used in clinical practice Dapsone is quickly effective in inducing a clinical remission, because of the requirement for endoscopy to obtain cultures, but a gluten-free diet is the preferred long-term management the patchy nature of small intestinal overgrowth, and oro- of both the skin and bowel disease. Before initiating dapsone, pharyngeal contamination of the specimen. Glucose and lact- patients should be tested for glucose-6-phosphate dehydroge- ulose breath tests have acceptable specificity (around 80%) but nase deficiency. poor sensitivity (30%-40%) for diagnosing SIBO. Diagnosis requires typical symptoms and a confirmatory test (usually Nonceliac Gluten Sensitivity breath testing), although empiric antibody therapy with mon- Nonceliac gluten sensitivity is a clinical syndrome of unknown itoring for symptom relief may be reasonable in patients with pathophysiology defined by gastrointestinal and extraintesti- a high probability of SIBO. Treatment consists of antibiotics, nal symptoms that occur with gluten ingestion and subside with courses repeated if the underlying condition cannot be with gluten avoidance. By definition, the diagnosis of celiac resolved. disease must be excluded. Clinical symptoms of celiac disease and nonceliac gluten sensitivity are indistinguishable. Short Bowel Syndrome Because gluten-containing foods can also contain nonabsorb- Short bowel syndrome is defined by loss of functional small able carbohydrates (e.g., fructans), they can cause gastroin- bowel, with resultant loss of absorptive area leading to mal- testinal symptoms due to osmotic mechanisms as well as digestion, malabsorption, and malnutrition. Surgery for stran- fermentation by colonic bacteria. Other than assessing symp- gulated bowel, Crohn disease, ischemia, trauma, and obesity tom response after withdrawal of gluten, there is no diagnos- can lead to short bowel syndrome. tic test for nonceliac gluten sensitivity; treatment centers on Treatment centers on ensuring adequate nutrition and gluten avoidance. depends on degree of intestinal adaptation and whether the patient has an intact ileocecal valve and colon or an ileostomy. Patients with short bowel syndrome and an ileostomy usually e Microscopic colitis is characterized by normal mucosal require parenteral nutrition and hydration. Patients should be appearance on endoscopy, with inflammatory changes monitored for nutritional deficiencies, and those with exten- seen on histopathology; microscopic colitis is not asso- sive ileal resection should be tested for vitamin B,, deficiency. ciated with increased risk for colorectal cancer. Adjunctive therapies include antimotility agents, such as lop- (Continued) eramide, and antisecretory drugs, including proton pump

Malabsorption Small Intestinal Bacterial Overgrowth Small intestinal bacterial overgrowth (SIBO) is caused by vari- ous conditions, including impaired motility, strictures (e.g., in FIGURE 17. Dermatitis herpetiformis, a manifestation of celiac disease, is Crohn disease), or blind loops (e.g., small-bowel diverticula). characterized by pruritic papules and transient, almost immediately excoriated Some evidence suggests that SIBO could contribute to symp- blisters on the elbows, knees, and buttocks. toms in IBS-D in the absence of a predisposing structural lesion. Symptoms are often nonspecific and include abdomi- pruritic papules and fragile vesicles that rapidly break, leaving nal discomfort, flatulence, bloating, and diarrhea. tiny erosions. The elbows, knees, scalp, and lower back are the Classically, SIBO is defined by more than 10° colony- most common sites of involvement (Figure 17). Most patients forming units/mL of jejunal aspirate. Jejunal aspirate is con- have serologic and histologic evidence of celiac disease. sidered the gold standard but is rarely used in clinical practice Dapsone is quickly effective in inducing a clinical remission, because of the requirement for endoscopy to obtain cultures, but a gluten-free diet is the preferred long-term management the patchy nature of small intestinal overgrowth, and oro- of both the skin and bowel disease. Before initiating dapsone, pharyngeal contamination of the specimen. Glucose and lact- patients should be tested for glucose-6-phosphate dehydroge- ulose breath tests have acceptable specificity (around 80%) but nase deficiency. poor sensitivity (30%-40%) for diagnosing SIBO. Diagnosis requires typical symptoms and a confirmatory test (usually Nonceliac Gluten Sensitivity breath testing), although empiric antibody therapy with mon- Nonceliac gluten sensitivity is a clinical syndrome of unknown itoring for symptom relief may be reasonable in patients with pathophysiology defined by gastrointestinal and extraintesti- a high probability of SIBO. Treatment consists of antibiotics, nal symptoms that occur with gluten ingestion and subside with courses repeated if the underlying condition cannot be with gluten avoidance. By definition, the diagnosis of celiac resolved. disease must be excluded. Clinical symptoms of celiac disease and nonceliac gluten sensitivity are indistinguishable. Short Bowel Syndrome Because gluten-containing foods can also contain nonabsorb- Short bowel syndrome is defined by loss of functional small able carbohydrates (e.g., fructans), they can cause gastroin- bowel, with resultant loss of absorptive area leading to mal- testinal symptoms due to osmotic mechanisms as well as digestion, malabsorption, and malnutrition. Surgery for stran- fermentation by colonic bacteria. Other than assessing symp- gulated bowel, Crohn disease, ischemia, trauma, and obesity tom response after withdrawal of gluten, there is no diagnos- can lead to short bowel syndrome. tic test for nonceliac gluten sensitivity; treatment centers on Treatment centers on ensuring adequate nutrition and gluten avoidance. depends on degree of intestinal adaptation and whether the patient has an intact ileocecal valve and colon or an ileostomy. Patients with short bowel syndrome and an ileostomy usually e Microscopic colitis is characterized by normal mucosal require parenteral nutrition and hydration. Patients should be appearance on endoscopy, with inflammatory changes monitored for nutritional deficiencies, and those with exten- seen on histopathology; microscopic colitis is not asso- sive ileal resection should be tested for vitamin B,, deficiency. ciated with increased risk for colorectal cancer. Adjunctive therapies include antimotility agents, such as lop- (Continued) eramide, and antisecretory drugs, including proton pump 30

Disorders of the Small and Large Bowel inhibitors. Glucagon-like peptide 2 and its analog, teduglutide, have an insidious onset and often have been present for weeks may increase intestinal adaptation. or months by the time the patient seeks care, although ulcera- tive colitis may present acutely, mimicking infectious or Carbohydrate Malabsorption colonic ischemia. Carbohydrates can be classified as monosaccharides (glucose, Rectal inflammation (proctitis) causes frequent defeca- fructose), disaccharides (lactose, sucrose), oligosaccharides tory urges and passage of small liquid stools containing mucus (maltodextrose), or polyols (sorbitol, mannitol). These short- and blood. Although bloody diarrhea is considered the hall- chain carbohydrates are osmotically active and can lead to mark presentation of ulcerative colitis, diarrhea is not always increased luminal water retention and gas production through present. Patients with proctitis or proctosigmoiditis may have colonic fermentation. These actions can cause gastrointestinal constipation. Abdominal pain is usually not a prominent symptoms, including gas, bloating, and diarrhea. symptom of ulcerative colitis; however, most patients with Lactose malabsorption is commonly due to loss of the active disease experience vague lower-abdominal discomfort brush-border lactase enzyme in adolescence or adulthood. relieved with defecation. Physical examination in patients Fructose malabsorption can also cause gastrointestinal symp- with mild or moderate ulcerative colitis is usually normal but toms, such as bloating and diarrhea. Although both lactose may reveal mild lower-abdominal discomfort over the affected and fructose breath tests are available, testing is often not colonic segment. Fever, nausea, vomiting, or severe abdominal required because symptoms subside with elimination of the pain indicates a severe attack or complication, such as super- sugar from the diet and recur with ingestion of the sugar. imposed infection or toxic megacolon.

and fructose breath tests are available, testing is often not colonic segment. Fever, nausea, vomiting, or severe abdominal required because symptoms subside with elimination of the pain indicates a severe attack or complication, such as super- sugar from the diet and recur with ingestion of the sugar. imposed infection or toxic megacolon. Crohn Disease e Small intestinal bacterial overgrowth is caused by impaired The clinical presentation of Crohn disease may be subtle and motility, strictures, or blind loops and is treated with varies by location and severity of inflammation along the gut antibiotics. axis as well as the presence of intestinal complications (e.g., e Short bowel syndrome is defined by loss of functional abscess, stricture, or fistula). Abdominal pain is a more com- small bowel, with resultant loss of absorptive area lead- mon symptom of Crohn disease than of ulcerative colitis. The

Crohn Disease e Small intestinal bacterial overgrowth is caused by impaired The clinical presentation of Crohn disease may be subtle and motility, strictures, or blind loops and is treated with varies by location and severity of inflammation along the gut antibiotics. axis as well as the presence of intestinal complications (e.g., e Short bowel syndrome is defined by loss of functional abscess, stricture, or fistula). Abdominal pain is a more com- small bowel, with resultant loss of absorptive area lead- mon symptom of Crohn disease than of ulcerative colitis. The ing to maldigestion, malabsorption, and malnutrition. ileocecal area is the bowel segment most commonly affected by Crohn disease; disease in this area often presents insidi- e Lactose malabsorption is common; symptoms occur ously with mild diarrhea and abdominal cramping. Abdominal when lactose is ingested and subside with elimination examination may reveal fullness or a tender mass in the right of lactose from the diet. hypogastrium. Occasionally, the main presenting symptom is acute right-lower-quadrant pain, mimicking appendicitis. Tenesmus is less common in Crohn colitis than in ulcerative Inflammatory Bowel Disease colitis because the rectum is often less inflamed than other IBD is an idiopathic chronic inflammatory condition of the gut colonic segments. Perianal disease is a common presentation that includes ulcerative colitis and Crohn disease. Microscopic of Crohn disease, with anal fissures, ulcers, and stenosis. colitis is considered a type of IBD with distinct clinical and Fistulae, a frequent manifestation of the transmural nature pathologic features. The pathogenesis of IBD likely involves of Crohn disease, consist of abnormal connections between host genetic predisposition and abnormal immunologic two epithelial surfaces (perianal, enteroenteric, enterocutane- responses to endogenous gut bacteria. ous, rectovaginal, enterovesical). Drainage of fecal material from fistulae may lead to passage of feces through the vagina, Risk Factors urethra, or skin. Intra-abdominal abscesses may form; the clas- The primary risk factor for IBD is family history, with a risk of sic presentation is spiking fevers and focal abdominal tender- approximately 10% for first-degree relatives of affected ness, which may be masked by glucocorticoid use. Strictures patients. Individuals of Ashkenazi Jewish descent have may result from fibrosis or severe inflammatory luminal nar- increased risk for IBD. Tobacco smoking increases the risk for rowing and may occur in any segment of the gastrointestinal Crohn disease and is protective for ulcerative colitis. tract, although the terminal ileum is the most common site. IBD has a bimodal age presentation: an initial peak inci- Patients with intestinal strictures often initially present with dence in the second to fourth decades of life followed by a less colicky postprandial abdominal pain and bloating that may prominent second peak in the seventh and eighth decades. progress to complete intestinal obstruction. Table 19 summarizes the features of ulcerative colitis and Clinical Manifestations Crohn disease. Ulcerative Colitis The major symptoms of ulcerative colitis include diarrhea, Extraintestinal Manifestations abdominal discomfort, rectal bleeding, and tenesmus; symp- Inflammatory conditions involving extraintestinal structures toms vary by disease extent and severity. Symptoms typically may occur with IBD. These manifestations are categorized as

ing to maldigestion, malabsorption, and malnutrition. ileocecal area is the bowel segment most commonly affected by Crohn disease; disease in this area often presents insidi- e Lactose malabsorption is common; symptoms occur ously with mild diarrhea and abdominal cramping. Abdominal when lactose is ingested and subside with elimination examination may reveal fullness or a tender mass in the right of lactose from the diet. hypogastrium. Occasionally, the main presenting symptom is acute right-lower-quadrant pain, mimicking appendicitis. Tenesmus is less common in Crohn colitis than in ulcerative Inflammatory Bowel Disease colitis because the rectum is often less inflamed than other IBD is an idiopathic chronic inflammatory condition of the gut colonic segments. Perianal disease is a common presentation that includes ulcerative colitis and Crohn disease. Microscopic of Crohn disease, with anal fissures, ulcers, and stenosis. colitis is considered a type of IBD with distinct clinical and Fistulae, a frequent manifestation of the transmural nature pathologic features. The pathogenesis of IBD likely involves of Crohn disease, consist of abnormal connections between host genetic predisposition and abnormal immunologic two epithelial surfaces (perianal, enteroenteric, enterocutane- responses to endogenous gut bacteria. ous, rectovaginal, enterovesical). Drainage of fecal material from fistulae may lead to passage of feces through the vagina, Risk Factors urethra, or skin. Intra-abdominal abscesses may form; the clas- The primary risk factor for IBD is family history, with a risk of sic presentation is spiking fevers and focal abdominal tender- approximately 10% for first-degree relatives of affected ness, which may be masked by glucocorticoid use. Strictures patients. Individuals of Ashkenazi Jewish descent have may result from fibrosis or severe inflammatory luminal nar- increased risk for IBD. Tobacco smoking increases the risk for rowing and may occur in any segment of the gastrointestinal Crohn disease and is protective for ulcerative colitis. tract, although the terminal ileum is the most common site. IBD has a bimodal age presentation: an initial peak inci- Patients with intestinal strictures often initially present with dence in the second to fourth decades of life followed by a less colicky postprandial abdominal pain and bloating that may prominent second peak in the seventh and eighth decades. progress to complete intestinal obstruction. Table 19 summarizes the features of ulcerative colitis and Clinical Manifestations Crohn disease. Ulcerative Colitis The major symptoms of ulcerative colitis include diarrhea, Extraintestinal Manifestations abdominal discomfort, rectal bleeding, and tenesmus; symp- Inflammatory conditions involving extraintestinal structures toms vary by disease extent and severity. Symptoms typically may occur with IBD. These manifestations are categorized as 31

Disorders of the Small and Large Bowel TABLE 19. Features of Ulcerative Colitis and Crohn Disease Feature Ulcerative Colitis Crohn Disease Depth of inflammation Mucosa Transmural Pattern of disease Contiguous and symmetric Skips areas and asymmetric Location Colorectum Mouth to anus | Rectal involvement Nearly 100% Less common lleal disease Backwash ileitis (15%) Common | Fistulas, abscess, and strictures Rare Common Perianal disease Rare Common Granulomas Unlikely In approximately 30% Overt rectal bleeding Common Less common Tobacco use Protective Exacerbates

Granulomas Unlikely In approximately 30% Overt rectal bleeding Common Less common Tobacco use Protective Exacerbates associated with active bowel disease or independent of bowel Ocular IBD manifestations include episcleritis and uveitis. inflammation. An extraintestinal manifestation occurs in up to Episcleritis is more common and consists of injection of the 30% of patients with IBD at some time during the disease sclera and conjunctiva. It does not affect visual acuity and is course. Peripheral arthritis is the most common manifestation associated with active bowel disease. Uveitis presents with (see MKSAP 19 Rheumatology). headache, blurred vision, and photophobia. This ocular emer- The two most common dermatologic manifestations are gency threatens vision and requires immediate referral to an erythema nodosum and pyoderma gangrenosum, both of which ophthalmologist. See MKSAP 19 General Internal Medicine 2 for usually correspond to underlying IBD activity. Erythema nodo- discussion of episcleritis and uveitis. Primary sclerosing chol- sum most commonly presents as single or multiple tender nod- angitis is the major liver manifestation of IBD, occurring in 5% ules on extensor surfaces of the lower extremities (Figure 18). It of patients. Patients most often present with isolated elevations usually resolves spontaneously over 4 to 6 weeks. Pyoderma of serum alkaline phosphatase. The liver disease is typically gangrenosum typically presents with an exquisitely tender progressive and independent of IBD outcome. See Disorders of papule, pustule, or nodule that rapidly develops into an exuda- the Liver for discussion of primary sclerosing cholangitis. tive ulcer with undermined and violaceous borders (Figure 19). The most frequent location is the lower leg; however, pyoderma Diagnosis gangrenosum is also frequently associated with a stoma site Diagnosis of IBD relies on integration of clinical presentation, (peristomal) after ostomy placement. It is diagnosed after endoscopic appearance, histologic assessment of mucosal exclusion of other causes of ulceration. Management of pyo- biopsy specimens, radiologic features, and exclusion of derma gangrenosum includes local wound care, immunosup- pressants, and avoiding trauma and surgical debridement because of pathergy (i.e., it occurs at sites of trauma).

associated with active bowel disease or independent of bowel Ocular IBD manifestations include episcleritis and uveitis. inflammation. An extraintestinal manifestation occurs in up to Episcleritis is more common and consists of injection of the 30% of patients with IBD at some time during the disease sclera and conjunctiva. It does not affect visual acuity and is course. Peripheral arthritis is the most common manifestation associated with active bowel disease. Uveitis presents with (see MKSAP 19 Rheumatology). headache, blurred vision, and photophobia. This ocular emer- The two most common dermatologic manifestations are gency threatens vision and requires immediate referral to an erythema nodosum and pyoderma gangrenosum, both of which ophthalmologist. See MKSAP 19 General Internal Medicine 2 for usually correspond to underlying IBD activity. Erythema nodo- discussion of episcleritis and uveitis. Primary sclerosing chol- sum most commonly presents as single or multiple tender nod- angitis is the major liver manifestation of IBD, occurring in 5% ules on extensor surfaces of the lower extremities (Figure 18). It of patients. Patients most often present with isolated elevations usually resolves spontaneously over 4 to 6 weeks. Pyoderma of serum alkaline phosphatase. The liver disease is typically gangrenosum typically presents with an exquisitely tender progressive and independent of IBD outcome. See Disorders of papule, pustule, or nodule that rapidly develops into an exuda- the Liver for discussion of primary sclerosing cholangitis. tive ulcer with undermined and violaceous borders (Figure 19). The most frequent location is the lower leg; however, pyoderma Diagnosis gangrenosum is also frequently associated with a stoma site Diagnosis of IBD relies on integration of clinical presentation, (peristomal) after ostomy placement. It is diagnosed after endoscopic appearance, histologic assessment of mucosal exclusion of other causes of ulceration. Management of pyo- biopsy specimens, radiologic features, and exclusion of derma gangrenosum includes local wound care, immunosup- pressants, and avoiding trauma and surgical debridement because of pathergy (i.e., it occurs at sites of trauma). FIGURE 19. Pyoderma gangrenosum, a manifestation of inflammatory bowel disease, typically begins as a small pustule or red nodule that rapidly expands into FIGURE 18. Erythema nodosum, a manifestation of inflammatory bowel a painful, exudative wet ulcer with an edematous, infiltrated, actively inflamed disease, typically appears as ill-defined erythema overlying subcutaneous, tender border. The border is characteristically violaceous with an edge that overhangs nodules most commonly symmetrically located on the anterior shins. the ulcer.

FIGURE 19. Pyoderma gangrenosum, a manifestation of inflammatory bowel disease, typically begins as a small pustule or red nodule that rapidly expands into FIGURE 18. Erythema nodosum, a manifestation of inflammatory bowel a painful, exudative wet ulcer with an edematous, infiltrated, actively inflamed disease, typically appears as ill-defined erythema overlying subcutaneous, tender border. The border is characteristically violaceous with an edge that overhangs nodules most commonly symmetrically located on the anterior shins. the ulcer. 32

Disorders of the Small and Large Bowel infectious enteropathogens. IBD should be considered in any patient with chronic or bloody diarrhea. It is paramount to exclude infection, particularly with C. difficile and Shiga toxin-producing E. coli, by stool tests, especially in patients with acute symptom onset. An elevated fecal calprotectin level may help differentiate IBD from IBS. Antibody tests (e.g., anti- saccharomyces cerevisiae antibodies and perinuclear antineu- trophil cytoplasmic antibodies) are available, but their role in diagnosis is undefined; they should not replace endoscopy or biopsy. Laboratory testing helps assess disease activity. Common findings include anemia, thrombocytosis, leukocy- tosis, and hypoalbuminemia. Iron deficiency anemia often develops from chronic blood loss. Persistently abnormal serum alkaline phosphatase levels should prompt investigation for primary sclerosing cholangitis. Endoscopy (sigmoidoscopy or colonoscopy) with biopsy is needed to diagnose IBD. Colonoscopy is most commonly used to assess disease extent and severity. At presentation, 50% of patients with ulcerative colitis have disease limited to the rec- tum and sigmoid (proctosigmoiditis), 20% have left-sided dis- ease (to the splenic flexure), and 30% present with pancolitis (to the cecum). Endoscopic findings range from decreased vascular pattern with erythema and edema in mild disease to large and deep ulcerations in severe disease. Histopathology shows features of chronic colitis, with distorted and branching colonic crypts along with crypt abscesses. Distribution pattern differs between Crohn disease and FIGURE 20. CTscan of the abdomen and pelvis in a patient with Crohn disease, ulcerative colitis: 50% of patients have ileocolonic disease; 30%, showing small-bowel obstruction with dilated loops of small intestine (arrows) and isolated small bowel disease; and 20%, colonic disease. A matted loops of bowel (arrowhead) in the pelvis. minority of patients have isolated upper gastrointestinal tract or perianal disease without small-bowel or colonic inflamma- rather than symptom resolution alone. Four categories of tion. The earliest endoscopic findings of Crohn disease include drugs are used: 5-aminosalicylates, glucocorticoids, immu-

isolated small bowel disease; and 20%, colonic disease. A matted loops of bowel (arrowhead) in the pelvis. minority of patients have isolated upper gastrointestinal tract or perianal disease without small-bowel or colonic inflamma- rather than symptom resolution alone. Four categories of tion. The earliest endoscopic findings of Crohn disease include drugs are used: 5-aminosalicylates, glucocorticoids, immu- aphthous ulcers, which can coalesce to form stellate ulcers, and nomodulators, and biologics. Stratification based on clinical a “cobblestone” mucosal appearance. A characteristic mucosal severity is important in guiding IBD management. There are feature of Crohn disease is the “skip lesion,” consisting of no validated or consensus definitions of mild, moderate, or affected areas separated by normal mucosa. Granulomatous severe IBD. For this synopsis, mild ulcerative colitis is defined inflammation is characteristic of Crohn disease but is uncom- as fewer than four bowel movements per day, mild to moderate monly found on mucosal biopsy specimens. Histopathology in rectal bleeding, no constitutional symptoms, and low overall small intestinal Crohn disease shows chronic jejunitis or ileitis, inflammatory burden. Severe ulcerative colitis is marked by and Crohn colitis has histology similar to that of ulcerative more than six bloody stools per day plus signs of systemic colitis, except for granulomas. toxicity (e.g., fever, tachycardia, and leukocytosis). Mild Crohn Imaging establishes the location, extent, and severity of disease is characterized in patients who are ambulatory and IBD. Patients with a severe attack of IBD require plain abdomi- are eating and drinking normally, with weight loss less than nal radiography to assess for a dilated colon (indicating evolv- 10% and no disease-related complications, although patients ing toxic megacolon) or small-bowel obstruction (Figure 20). may have diarrhea and abdominal pain. Patients with severe CT or magnetic resonance enterography provides information Crohn disease may be cachectic, with significant weight loss, about location and severity of small-bowel disease and pres- and may have disease-related complications. These patients

ing toxic megacolon) or small-bowel obstruction (Figure 20). may have diarrhea and abdominal pain. Patients with severe CT or magnetic resonance enterography provides information Crohn disease may be cachectic, with significant weight loss, about location and severity of small-bowel disease and pres- and may have disease-related complications. These patients ence of complicating fistula, abscess, or stricture. Video capsule are often hospitalized. Patients with moderate disease lie endoscopy is highly sensitive for detecting small inflammatory between the extremes. lesions of the intestine but is not commonly required. Patients with IBD have markedly increased risk for venous thromboembolism. Hospitalized patients with IBD Treatment should receive venous thromboembolism prophylaxis with Goals of IBD therapy are to induce and maintain remission and subcutaneous heparin unless massive gastrointestinal bleed- prevent disease- and treatment-related complications. ing is present. In such cases, mechanical prophylaxis should Remission is defined by endoscopic healing of bowel mucosa be used. 33

Disorders of the Small and Large Bowel TABLE 20. Medical Treatment of Inflammatory Bowel Disease Disease Activity Ulcerative Colitis Crohn Disease Mild Oral and topical 5-ASAs? Sulfasalazine for colitis Steroid suppository and enema? Budesonide for ileocolonic disease Multimatrix budesonide | Moderate Oral and topical 5-ASAs? Oral and intravenous glucocorticoids? | Azathioprine/6-mercaptopurine® Budesonide for ileocolonic disease Multimatrix budesonide and oral glucocorticoids” Azathioprine/6-mercaptopurine® Biologic agents (infliximab, adalimumab, golimumab, Methotrexate® vedolizumab, ustekinumals> Biologic agents (infliximab, adalimumab, certolizumab, Tofacitinib? vedolizumab, natalizumab, ustekinumab)* Severe Oral or intravenous glucocorticoids® Oral or intravenous glucocorticoids® Cyclosporine® Biologic agents (infliximab, adalimumab, certolizumab, vedolizumab, natalizumab, ustekinumab)? Biologic agents (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab)? Tofacitinib? 5-ASA = 5-aminosalicylate. *Remission and maintenance. >Remission. “Maintenance, glucocorticoid-sparing.

Cyclosporine® Biologic agents (infliximab, adalimumab, certolizumab, vedolizumab, natalizumab, ustekinumab)? Biologic agents (infliximab, adalimumab, golimumab, vedolizumab, ustekinumab)? Tofacitinib? 5-ASA = 5-aminosalicylate. *Remission and maintenance. >Remission. “Maintenance, glucocorticoid-sparing. Table 20 summarizes medical treatment of ulcerative for maintenance therapy and have significant adverse effects. colitis and Crohn disease. Multimatrix budesonide is a colonic delivery system that allows directed therapy throughout the colon with fewer sys- Pharmacotherapy for Ulcerative Colitis temic side effects given its high first-pass hepatic metabolism. 5-Aminosalicylates It induces remission in mild to moderate ulcerative colitis 5-Aminosalicylates (5-ASAs) are believed to have an anti- unresponsive to 5-ASAs and in moderate to severe disease. inflammatory mechanism of action. Unconjugated 5-ASA (mesalamine) is rapidly absorbed in the jejunum, allowing Immunomodulators only 20% of the drug to reach the ileum and colon. Oral 5-ASA Thiopurines (azathioprine and mercaptopurine [6-MP]) are is modified to reduce upper gastrointestinal absorption and immunomodulators used as glucocorticoid-sparing agents enhance drug delivery to the colon (olsalazine, balsalazide). in ulcerative colitis. They have a slow onset of action The main therapeutic 5-ASAs are sulfasalazine, olsalazine, (2-3 months), and patients require a tapering glucocorticoid balsalazide, and delayed- and controlled-release mesalamine. regimen to bridge the interval until thiopurines take effect. Sulfasalazine has the most adverse effects, including fever, Thiopurines are no more effective than placebo in inducing rash, nausea, and headache, and requires concomitant folate remission. Thiopurine methyltransferase, a key enzyme in the supplementation. Sulfasalazine is not considered first-line metabolism of azathioprine and 6-MP, exhibits a population therapy but is a reasonable choice in patients already taking it polymorphism. Before initiation of thiopurines, testing for the who are in remission or have prominent arthritic symptoms. TPMT genotype or phenotype (enzyme activity) is recom- 5-ASAs are the mainstay of treatment of mild to moderate mended to prevent bone marrow toxicity by identifying indi- ulcerative colitis, with a dose-dependent response when used viduals with low or absent TPMT enzyme activity. However, all to induce remission. Patients with proctitis should receive patients taking thiopurines require monitoring with complete 5-ASA suppositories. Patients with left-sided disease should blood counts and liver chemistry testing because 70% of receive 5-ASA enemas. In mild to moderate ulcerative colitis, patients who develop leukopenia while using these agents do combined 5-ASA therapy (oral and topical) is superior for not have TPMT mutations. inducing remission compared with oral or topical therapies Azathioprine and 6-MP are effective in maintaining remis- alone. 5-ASAs are effective in maintaining remission. sion in ulcerative colitis, should be considered in glucocorticoid- dependent patients, and can be combined with biologic agents. Glucocorticoids This includes patients who require two courses of glucocorticoids Oral and intravenous glucocorticoids are commonly used to for induction of remission within 1 year and patients who require treat moderate to severe flares of ulcerative colitis and can intravenous glucocorticoids for acute disease flare. The immu- induce remission. However, glucocorticoids are not effective nomodulator methotrexate is not effective in ulcerative colitis.

Table 20 summarizes medical treatment of ulcerative for maintenance therapy and have significant adverse effects. colitis and Crohn disease. Multimatrix budesonide is a colonic delivery system that allows directed therapy throughout the colon with fewer sys- Pharmacotherapy for Ulcerative Colitis temic side effects given its high first-pass hepatic metabolism. 5-Aminosalicylates It induces remission in mild to moderate ulcerative colitis 5-Aminosalicylates (5-ASAs) are believed to have an anti- unresponsive to 5-ASAs and in moderate to severe disease. inflammatory mechanism of action. Unconjugated 5-ASA (mesalamine) is rapidly absorbed in the jejunum, allowing Immunomodulators only 20% of the drug to reach the ileum and colon. Oral 5-ASA Thiopurines (azathioprine and mercaptopurine [6-MP]) are is modified to reduce upper gastrointestinal absorption and immunomodulators used as glucocorticoid-sparing agents enhance drug delivery to the colon (olsalazine, balsalazide). in ulcerative colitis. They have a slow onset of action The main therapeutic 5-ASAs are sulfasalazine, olsalazine, (2-3 months), and patients require a tapering glucocorticoid balsalazide, and delayed- and controlled-release mesalamine. regimen to bridge the interval until thiopurines take effect. Sulfasalazine has the most adverse effects, including fever, Thiopurines are no more effective than placebo in inducing rash, nausea, and headache, and requires concomitant folate remission. Thiopurine methyltransferase, a key enzyme in the supplementation. Sulfasalazine is not considered first-line metabolism of azathioprine and 6-MP, exhibits a population therapy but is a reasonable choice in patients already taking it polymorphism. Before initiation of thiopurines, testing for the who are in remission or have prominent arthritic symptoms. TPMT genotype or phenotype (enzyme activity) is recom- 5-ASAs are the mainstay of treatment of mild to moderate mended to prevent bone marrow toxicity by identifying indi- ulcerative colitis, with a dose-dependent response when used viduals with low or absent TPMT enzyme activity. However, all to induce remission. Patients with proctitis should receive patients taking thiopurines require monitoring with complete 5-ASA suppositories. Patients with left-sided disease should blood counts and liver chemistry testing because 70% of receive 5-ASA enemas. In mild to moderate ulcerative colitis, patients who develop leukopenia while using these agents do combined 5-ASA therapy (oral and topical) is superior for not have TPMT mutations. inducing remission compared with oral or topical therapies Azathioprine and 6-MP are effective in maintaining remis- alone. 5-ASAs are effective in maintaining remission. sion in ulcerative colitis, should be considered in glucocorticoid- dependent patients, and can be combined with biologic agents. Glucocorticoids This includes patients who require two courses of glucocorticoids Oral and intravenous glucocorticoids are commonly used to for induction of remission within 1 year and patients who require treat moderate to severe flares of ulcerative colitis and can intravenous glucocorticoids for acute disease flare. The immu- induce remission. However, glucocorticoids are not effective nomodulator methotrexate is not effective in ulcerative colitis. 34

Disorders of the Small and Large Bowel Biologic Agents should be considered for alleviating signs and symptoms of Tumor necrosis factor (TNF)-a, a proinflammatory cytokine, steroid-dependent Crohn disease and for maintaining remis- plays a critical role in the pathogenesis of IBD. The anti-TNF sion. Side effects of methotrexate include hepatotoxicity and agents infliximab, adalimumab, and golimumab induce and interstitial pneumonitis, which can manifest with cough and maintain remission in moderate to severe ulcerative colitis, dyspnea of insidious onset; concomitant folate administration is with infliximab being the preferred initial agent. Early use of also necessary. biologics is appropriate after failure of 5-ASA treatment. Infliximab is administered by intravenous infusion; adali- Biologic Agents mumab and golimumab are given subcutaneously. Combination The anti-TNF agents infliximab, adalimumab, and certoli- therapy with biologics and immunomodulators (thiopurines or zumab treat moderate to severe Crohn disease resistant to

biologics is appropriate after failure of 5-ASA treatment. Infliximab is administered by intravenous infusion; adali- Biologic Agents mumab and golimumab are given subcutaneously. Combination The anti-TNF agents infliximab, adalimumab, and certoli- therapy with biologics and immunomodulators (thiopurines or zumab treat moderate to severe Crohn disease resistant to methotrexate) is more efficacious than monotherapy with glucocorticoids or immunomodulators. Combination therapy either agent in achieving glucocorticoid-free remission and with infliximab and azathioprine is more efficacious than mucosal healing. Before initiating anti-TNF agents, patients monotherapy with either agent alone in achieving glucocorti- should undergo testing for latent tuberculosis because of an coid-free remission and mucosal healing. Increasing evidence increased risk for tuberculosis reactivation during therapy. supports biologic agents early in the disease. Those with latent tuberculosis should receive treatment before The antiadhesion agents vedolizumab and natalizumab or with anti-TNF therapy initiation. Patients should also be are effective in inducing and maintaining remission of moder- assessed for chronic hepatitis B virus infection before starting ate to severe Crohn disease. Natalizumab, however, should be anti-TNF therapy and receive treatment if needed. used to maintain natalizumab-induced remission of Crohn Ustekinumab, a monoclonal antibody that blocks the bio- disease only if serum antibody to JC virus is negative because logic activity of interleukin-12 and -23 by inhibiting receptors of risk for progressive multifocal leukoencephalopathy (a cen- for these cytokines on T cells, is effective in inducing and main- tral nervous system demyelinating infection caused by reacti- taining remission in patients with moderate to severe ulcerative vation of the JC virus). Testing for anti-JC virus antibody colitis. Vedolizumab is also effective in inducing and maintain- should be repeated every 6 months and treatment stopped if ing remission in moderate to severe ulcerative colitis as well as the result is positive. Ustekinumab, a monoclonal antibody in inducing remission when anti-TNF agents have failed. As that blocks the biologic activity of interleukin-12 and -23 by with vedolizumab, the small-molecule Janus kinase inhibitor inhibiting receptors for these cytokines on T cells, is also effi- tofacitinib is effective as primary therapy in inducing and cacious in severe Crohn disease, including when anti-TNF maintaining remission in moderate to severe ulcerative colitis therapies prove ineffective. and as secondary therapy when anti-TNF agents have failed. Medical Therapy for Fistulizing Disease Cyclosporine Fistulizing Crohn disease is difficult to manage. The most Cyclosporine is an immunosuppressive used as an induction appropriate therapy requires expert evaluation and coordi- agent in select hospitalized patients with severe ulcerative nation of care between internal medicine and surgery. As colitis that is unresponsive to intravenous glucocorticoids. It part of multimodality therapy, metronidazole and cipro- acts as a potential bridge therapy to a slower-onset immu- floxacin may be effective in simple perianal fistula.

methotrexate) is more efficacious than monotherapy with glucocorticoids or immunomodulators. Combination therapy either agent in achieving glucocorticoid-free remission and with infliximab and azathioprine is more efficacious than mucosal healing. Before initiating anti-TNF agents, patients monotherapy with either agent alone in achieving glucocorti- should undergo testing for latent tuberculosis because of an coid-free remission and mucosal healing. Increasing evidence increased risk for tuberculosis reactivation during therapy. supports biologic agents early in the disease. Those with latent tuberculosis should receive treatment before The antiadhesion agents vedolizumab and natalizumab or with anti-TNF therapy initiation. Patients should also be are effective in inducing and maintaining remission of moder- assessed for chronic hepatitis B virus infection before starting ate to severe Crohn disease. Natalizumab, however, should be anti-TNF therapy and receive treatment if needed. used to maintain natalizumab-induced remission of Crohn Ustekinumab, a monoclonal antibody that blocks the bio- disease only if serum antibody to JC virus is negative because logic activity of interleukin-12 and -23 by inhibiting receptors of risk for progressive multifocal leukoencephalopathy (a cen- for these cytokines on T cells, is effective in inducing and main- tral nervous system demyelinating infection caused by reacti- taining remission in patients with moderate to severe ulcerative vation of the JC virus). Testing for anti-JC virus antibody colitis. Vedolizumab is also effective in inducing and maintain- should be repeated every 6 months and treatment stopped if ing remission in moderate to severe ulcerative colitis as well as the result is positive. Ustekinumab, a monoclonal antibody in inducing remission when anti-TNF agents have failed. As that blocks the biologic activity of interleukin-12 and -23 by with vedolizumab, the small-molecule Janus kinase inhibitor inhibiting receptors for these cytokines on T cells, is also effi- tofacitinib is effective as primary therapy in inducing and cacious in severe Crohn disease, including when anti-TNF maintaining remission in moderate to severe ulcerative colitis therapies prove ineffective. and as secondary therapy when anti-TNF agents have failed. Medical Therapy for Fistulizing Disease Cyclosporine Fistulizing Crohn disease is difficult to manage. The most Cyclosporine is an immunosuppressive used as an induction appropriate therapy requires expert evaluation and coordi- agent in select hospitalized patients with severe ulcerative nation of care between internal medicine and surgery. As colitis that is unresponsive to intravenous glucocorticoids. It part of multimodality therapy, metronidazole and cipro- acts as a potential bridge therapy to a slower-onset immu- floxacin may be effective in simple perianal fistula. nomodulatory or biologic agent. Infliximab can be effective for perianal, enterocutaneous, and rectovaginal fistulae, and tacrolimus can be effective for Pharmacotherapy for Crohn Disease perianal and cutaneous fistulae. The combination of inflixi- 5-Aminosalicylates mab and antibiotics is more effective than infliximab alone 5-ASAs are not efficacious in small-bowel Crohn disease, but for perianal fistulae. sulfasalazine is effective for remission and maintenance ther- apy for mild to moderate colonic Crohn disease. Surgery In patients with ulcerative colitis, total proctocolectomy with Glucocorticoids end-ileostomy or ileal pouch-anal anastomosis is performed for Oral and intravenous glucocorticoids are commonly used to medically refractory disease, toxic megacolon, or carcinoma.

nomodulatory or biologic agent. Infliximab can be effective for perianal, enterocutaneous, and rectovaginal fistulae, and tacrolimus can be effective for Pharmacotherapy for Crohn Disease perianal and cutaneous fistulae. The combination of inflixi- 5-Aminosalicylates mab and antibiotics is more effective than infliximab alone 5-ASAs are not efficacious in small-bowel Crohn disease, but for perianal fistulae. sulfasalazine is effective for remission and maintenance ther- apy for mild to moderate colonic Crohn disease. Surgery In patients with ulcerative colitis, total proctocolectomy with Glucocorticoids end-ileostomy or ileal pouch-anal anastomosis is performed for Oral and intravenous glucocorticoids are commonly used to medically refractory disease, toxic megacolon, or carcinoma. treat moderate to severe flares of Crohn disease and are Indications for surgery in Crohn disease include medi- effective in inducing remission. However, as with ulcerative cally refractory fistula, fibrotic stricture with obstructive colitis, glucocorticoids are not effective for maintenance ther- symptoms, symptoms refractory to medical therapy, and apy. Controlled-release budesonide is effective in inducing cancer. The guiding principle of surgery in Crohn disease is remission in mild to moderate ileocolonic Crohn disease. preservation of bowel length and function because disease frequently recurs after segmental resection. Patients with Immunomodulators Crohn disease who undergo surgery require aggressive anti- Thiopurines are also used in Crohn disease as steroid-sparing TNF and/or immunomodulator treatment to decrease the rate therapy but are not effective in inducing remission. Methotrexate of postoperative disease recurrence. 35

Disorders of the Small and Large Bowel IBD Management in Pregnancy inflammation. Long-standing colorectal inflammation Most medications used to treat IBD are safe in pregnancy. increases cancer risk. In patients with ulcerative colitis with Methotrexate must be stopped at least 3 months before con- disease proximal to the sigmoid colon (or beyond the rectum, ception because of its teratogenic effects. Biologic agents and according to some guidelines) or Crohn disease involving more thiopurines are considered low risk during pregnancy and than one third of the colon, surveillance colonoscopy should breastfeeding and should be continued to maintain disease be done 8 years after diagnosis and every 1 to 3 years thereaf- remission. Although data on tofacitinib in pregnancy are lim- ter. Primary sclerosing cholangitis increases the risk for colo- ited, it should be avoided in pregnancy. See MKSAP 19 rectal cancer; surveillance colonoscopy should begin at Rheumatology for a list of biologic agents and associated risks diagnosis and occur yearly thereafter. posed in pregnancy. Women with IBD have an increased risk for cervical dys- plasia; this risk is greater in women using immunosuppres- Health Care Considerations sive therapy. Women with IBD receiving immunosuppressive Patients with IBD have increased risk for vaccine-preventable therapy should undergo Pap testing annually and receive illnesses. Inactivated vaccines can be safely administered to all human papillomavirus vaccination according to established patients with IBD, regardless of immunosuppression. Patients guidelines. with IBD should receive the annual influenza vaccine as well Patients with IBD also have an increased risk for mela- as the COVID-19 vaccine, the 13-valent pneumococcal conju- noma and nonmelanoma skin cancers. Most of the risk is gate vaccine, and the 23-valent pneumococcal polysaccharide associated with specific treatments, such as anti-TNF agents vaccine. Ideally, all immunizatons should occur before immu- (melanoma) and immunomodulators (nonmelanoma); how- nosuppressive therapy begins. Hepatitis B virus vaccination ever, evidence suggests that the increased risk for melanoma is should be considered, especially if biologic therapy is likely to independent of treatment. Patients with ulcerative colitis and be required. The safety of administering live vaccines to Crohn disease should undergo yearly melanoma screening. In patients with IBD depends on the level of immunosuppres- addition, patients receiving immunomodulators (azathioprine sion. Certain live vaccines (e.g., measles or herpes zoster) can and 6-MP) should be screened for nonmelanoma squamous be given to patients with low-level immunosuppression. Low- cell cancer while using these agents. All patients with IBD level immunosuppression refers to receipt of less than 20 mg should use sunscreen, wear protective clothing, avoid tanning of systemic glucocorticoids per day; methotrexate, 0.4 mg/kg beds, and undergo dermatologic surveillance. or less per week; and azathioprine (<3 mg/kg per day) or 6-MP (<1.5 mg/kg per day). Patients receiving anti-TNFs should not be given live vaccines (e.g., measles, mumps, rubella; varicella; ¢ Combined oral and topical 5-aminosalicylate (ASA) ther- and herpes zoster). See MKSAP 19 General Internal Medicine 2 apy is superior for inducing remission in mild to moder-

IBD Management in Pregnancy inflammation. Long-standing colorectal inflammation Most medications used to treat IBD are safe in pregnancy. increases cancer risk. In patients with ulcerative colitis with Methotrexate must be stopped at least 3 months before con- disease proximal to the sigmoid colon (or beyond the rectum, ception because of its teratogenic effects. Biologic agents and according to some guidelines) or Crohn disease involving more thiopurines are considered low risk during pregnancy and than one third of the colon, surveillance colonoscopy should breastfeeding and should be continued to maintain disease be done 8 years after diagnosis and every 1 to 3 years thereaf- remission. Although data on tofacitinib in pregnancy are lim- ter. Primary sclerosing cholangitis increases the risk for colo- ited, it should be avoided in pregnancy. See MKSAP 19 rectal cancer; surveillance colonoscopy should begin at Rheumatology for a list of biologic agents and associated risks diagnosis and occur yearly thereafter. posed in pregnancy. Women with IBD have an increased risk for cervical dys- plasia; this risk is greater in women using immunosuppres- Health Care Considerations sive therapy. Women with IBD receiving immunosuppressive Patients with IBD have increased risk for vaccine-preventable therapy should undergo Pap testing annually and receive illnesses. Inactivated vaccines can be safely administered to all human papillomavirus vaccination according to established patients with IBD, regardless of immunosuppression. Patients guidelines. with IBD should receive the annual influenza vaccine as well Patients with IBD also have an increased risk for mela- as the COVID-19 vaccine, the 13-valent pneumococcal conju- noma and nonmelanoma skin cancers. Most of the risk is gate vaccine, and the 23-valent pneumococcal polysaccharide associated with specific treatments, such as anti-TNF agents vaccine. Ideally, all immunizatons should occur before immu- (melanoma) and immunomodulators (nonmelanoma); how- nosuppressive therapy begins. Hepatitis B virus vaccination ever, evidence suggests that the increased risk for melanoma is should be considered, especially if biologic therapy is likely to independent of treatment. Patients with ulcerative colitis and be required. The safety of administering live vaccines to Crohn disease should undergo yearly melanoma screening. In patients with IBD depends on the level of immunosuppres- addition, patients receiving immunomodulators (azathioprine sion. Certain live vaccines (e.g., measles or herpes zoster) can and 6-MP) should be screened for nonmelanoma squamous be given to patients with low-level immunosuppression. Low- cell cancer while using these agents. All patients with IBD level immunosuppression refers to receipt of less than 20 mg should use sunscreen, wear protective clothing, avoid tanning of systemic glucocorticoids per day; methotrexate, 0.4 mg/kg beds, and undergo dermatologic surveillance. or less per week; and azathioprine (<3 mg/kg per day) or 6-MP (<1.5 mg/kg per day). Patients receiving anti-TNFs should not be given live vaccines (e.g., measles, mumps, rubella; varicella; ¢ Combined oral and topical 5-aminosalicylate (ASA) ther- and herpes zoster). See MKSAP 19 General Internal Medicine 2 apy is superior for inducing remission in mild to moder- for discussion of vaccination strategies. ate ulcerative colitis; 5S-ASAs are effective in maintaining

IBD Management in Pregnancy inflammation. Long-standing colorectal inflammation Most medications used to treat IBD are safe in pregnancy. increases cancer risk. In patients with ulcerative colitis with Methotrexate must be stopped at least 3 months before con- disease proximal to the sigmoid colon (or beyond the rectum, ception because of its teratogenic effects. Biologic agents and according to some guidelines) or Crohn disease involving more thiopurines are considered low risk during pregnancy and than one third of the colon, surveillance colonoscopy should breastfeeding and should be continued to maintain disease be done 8 years after diagnosis and every 1 to 3 years thereaf- remission. Although data on tofacitinib in pregnancy are lim- ter. Primary sclerosing cholangitis increases the risk for colo- ited, it should be avoided in pregnancy. See MKSAP 19 rectal cancer; surveillance colonoscopy should begin at Rheumatology for a list of biologic agents and associated risks diagnosis and occur yearly thereafter. posed in pregnancy. Women with IBD have an increased risk for cervical dys- plasia; this risk is greater in women using immunosuppres- Health Care Considerations sive therapy. Women with IBD receiving immunosuppressive Patients with IBD have increased risk for vaccine-preventable therapy should undergo Pap testing annually and receive illnesses. Inactivated vaccines can be safely administered to all human papillomavirus vaccination according to established patients with IBD, regardless of immunosuppression. Patients guidelines. with IBD should receive the annual influenza vaccine as well Patients with IBD also have an increased risk for mela- as the COVID-19 vaccine, the 13-valent pneumococcal conju- noma and nonmelanoma skin cancers. Most of the risk is gate vaccine, and the 23-valent pneumococcal polysaccharide associated with specific treatments, such as anti-TNF agents vaccine. Ideally, all immunizatons should occur before immu- (melanoma) and immunomodulators (nonmelanoma); how- nosuppressive therapy begins. Hepatitis B virus vaccination ever, evidence suggests that the increased risk for melanoma is should be considered, especially if biologic therapy is likely to independent of treatment. Patients with ulcerative colitis and be required. The safety of administering live vaccines to Crohn disease should undergo yearly melanoma screening. In patients with IBD depends on the level of immunosuppres- addition, patients receiving immunomodulators (azathioprine sion. Certain live vaccines (e.g., measles or herpes zoster) can and 6-MP) should be screened for nonmelanoma squamous be given to patients with low-level immunosuppression. Low- cell cancer while using these agents. All patients with IBD level immunosuppression refers to receipt of less than 20 mg should use sunscreen, wear protective clothing, avoid tanning of systemic glucocorticoids per day; methotrexate, 0.4 mg/kg beds, and undergo dermatologic surveillance. or less per week; and azathioprine (<3 mg/kg per day) or 6-MP (<1.5 mg/kg per day). Patients receiving anti-TNFs should not be given live vaccines (e.g., measles, mumps, rubella; varicella; ¢ Combined oral and topical 5-aminosalicylate (ASA) ther- and herpes zoster). See MKSAP 19 General Internal Medicine 2 apy is superior for inducing remission in mild to moder- for discussion of vaccination strategies. ate ulcerative colitis; 5S-ASAs are effective in maintaining All patients with IBD should be encouraged to stop smok- remission.

IBD Management in Pregnancy inflammation. Long-standing colorectal inflammation Most medications used to treat IBD are safe in pregnancy. increases cancer risk. In patients with ulcerative colitis with Methotrexate must be stopped at least 3 months before con- disease proximal to the sigmoid colon (or beyond the rectum, ception because of its teratogenic effects. Biologic agents and according to some guidelines) or Crohn disease involving more thiopurines are considered low risk during pregnancy and than one third of the colon, surveillance colonoscopy should breastfeeding and should be continued to maintain disease be done 8 years after diagnosis and every 1 to 3 years thereaf- remission. Although data on tofacitinib in pregnancy are lim- ter. Primary sclerosing cholangitis increases the risk for colo- ited, it should be avoided in pregnancy. See MKSAP 19 rectal cancer; surveillance colonoscopy should begin at Rheumatology for a list of biologic agents and associated risks diagnosis and occur yearly thereafter. posed in pregnancy. Women with IBD have an increased risk for cervical dys- plasia; this risk is greater in women using immunosuppres- Health Care Considerations sive therapy. Women with IBD receiving immunosuppressive Patients with IBD have increased risk for vaccine-preventable therapy should undergo Pap testing annually and receive illnesses. Inactivated vaccines can be safely administered to all human papillomavirus vaccination according to established patients with IBD, regardless of immunosuppression. Patients guidelines. with IBD should receive the annual influenza vaccine as well Patients with IBD also have an increased risk for mela- as the COVID-19 vaccine, the 13-valent pneumococcal conju- noma and nonmelanoma skin cancers. Most of the risk is gate vaccine, and the 23-valent pneumococcal polysaccharide associated with specific treatments, such as anti-TNF agents vaccine. Ideally, all immunizatons should occur before immu- (melanoma) and immunomodulators (nonmelanoma); how- nosuppressive therapy begins. Hepatitis B virus vaccination ever, evidence suggests that the increased risk for melanoma is should be considered, especially if biologic therapy is likely to independent of treatment. Patients with ulcerative colitis and be required. The safety of administering live vaccines to Crohn disease should undergo yearly melanoma screening. In patients with IBD depends on the level of immunosuppres- addition, patients receiving immunomodulators (azathioprine sion. Certain live vaccines (e.g., measles or herpes zoster) can and 6-MP) should be screened for nonmelanoma squamous be given to patients with low-level immunosuppression. Low- cell cancer while using these agents. All patients with IBD level immunosuppression refers to receipt of less than 20 mg should use sunscreen, wear protective clothing, avoid tanning of systemic glucocorticoids per day; methotrexate, 0.4 mg/kg beds, and undergo dermatologic surveillance. or less per week; and azathioprine (<3 mg/kg per day) or 6-MP (<1.5 mg/kg per day). Patients receiving anti-TNFs should not be given live vaccines (e.g., measles, mumps, rubella; varicella; ¢ Combined oral and topical 5-aminosalicylate (ASA) ther- and herpes zoster). See MKSAP 19 General Internal Medicine 2 apy is superior for inducing remission in mild to moder- for discussion of vaccination strategies. ate ulcerative colitis; 5S-ASAs are effective in maintaining All patients with IBD should be encouraged to stop smok- remission. ing. Smoking increases Crohn disease activity and the risk for e The anti-tumor necrosis factor agents can induce and extraintestinal manifestations. Smoking cessation may tempo- maintain remission in moderate to severe inflammatory rarily worsen ulcerative colitis, but overall health benefits bowel disease. exceed this risk. Patients with IBD are at increased risk for e Azathioprine and 6-mercaptopurine are used in inflam- metabolic bone disease due to glucocorticoid use and dimin- matory bowel disease as steroid-sparing therapy; meth- ished vitamin D and calcium absorption. Bone mineral density otrexate can be used in Crohn disease. testing is recommended in all patients starting oral glucocor- e Patients with inflammatory bowel disease have increased ticoid therapy. Otherwise, patients with IBD should be risk for colorectal, cervical, and skin cancers. screened for osteoporosis based on established guidelines for the general population. See MKSAP 19 General Internal Medicine 2 for discussion of screening for osteoporosis. Patients with IBD should avoid using NSAIDs when possible Constipation because these drugs can exacerbate disease activity. Depression Constipation is common, affecting 20% of the general popula- and anxiety are more common in patients with IBD than the tion. Constipation can present with symptoms such as infre- general population and are associated with medication non- quent, difficult, or incomplete defecation. It can be acute or adherence. Therefore, screening for depression and anxiety is chronic and secondary or idiopathic. Medications are the most recommended in patients with IBD. common cause of secondary constipation; other causes Patients with IBD have increased risk for colorectal, cervi- include mechanical obstruction, systemic illnesses, altered cal, and skin cancers. Some immunosuppressive treatments physiologic states, and psychosocial conditions (Table 21). also increase the risk for cancer, although this risk is out- Once secondary causes have been excluded, chronic weighed by the protective effect of mucosal healing and result- constipation is considered functional (idiopathic). Functional ant reduced risk for cancers associated with chronic mucosal constipation is subcategorized as slow transit, normal transit,

ing. Smoking increases Crohn disease activity and the risk for e The anti-tumor necrosis factor agents can induce and extraintestinal manifestations. Smoking cessation may tempo- maintain remission in moderate to severe inflammatory rarily worsen ulcerative colitis, but overall health benefits bowel disease. exceed this risk. Patients with IBD are at increased risk for e Azathioprine and 6-mercaptopurine are used in inflam- metabolic bone disease due to glucocorticoid use and dimin- matory bowel disease as steroid-sparing therapy; meth- ished vitamin D and calcium absorption. Bone mineral density otrexate can be used in Crohn disease. testing is recommended in all patients starting oral glucocor- e Patients with inflammatory bowel disease have increased ticoid therapy. Otherwise, patients with IBD should be risk for colorectal, cervical, and skin cancers. screened for osteoporosis based on established guidelines for the general population. See MKSAP 19 General Internal Medicine 2 for discussion of screening for osteoporosis. Patients with IBD should avoid using NSAIDs when possible Constipation because these drugs can exacerbate disease activity. Depression Constipation is common, affecting 20% of the general popula- and anxiety are more common in patients with IBD than the tion. Constipation can present with symptoms such as infre- general population and are associated with medication non- quent, difficult, or incomplete defecation. It can be acute or adherence. Therefore, screening for depression and anxiety is chronic and secondary or idiopathic. Medications are the most recommended in patients with IBD. common cause of secondary constipation; other causes Patients with IBD have increased risk for colorectal, cervi- include mechanical obstruction, systemic illnesses, altered cal, and skin cancers. Some immunosuppressive treatments physiologic states, and psychosocial conditions (Table 21). also increase the risk for cancer, although this risk is out- Once secondary causes have been excluded, chronic weighed by the protective effect of mucosal healing and result- constipation is considered functional (idiopathic). Functional ant reduced risk for cancers associated with chronic mucosal constipation is subcategorized as slow transit, normal transit, 36

Disorders of the Small and Large Bowel TABLE 21. Secondary Causes of Constipation scintigraphy, or wireless motility capsule). In normal-transit constipation, colonic transit times are adequate based on | Medications objective transit testing. Dyssynergic defecation (also termed Opioids | pelvic floor dyssynergia, obstructed defecation, or outlet Antidiarrheals obstruction) is difficulty with or inability to expel stool due Anticholinergics (antispasmodics, antiparkinsonian drugs, to abnormalities in contraction and/or relaxation of pelvic tricyclic antidepressants, antipsychotics) floor muscles during defecation. Functional constipation can Antihistamines result from slow-transit constipation and coexistent dyssyn- NSAIDs ergic defecation. lron supplements

TABLE 21. Secondary Causes of Constipation scintigraphy, or wireless motility capsule). In normal-transit constipation, colonic transit times are adequate based on | Medications objective transit testing. Dyssynergic defecation (also termed Opioids | pelvic floor dyssynergia, obstructed defecation, or outlet Antidiarrheals obstruction) is difficulty with or inability to expel stool due Anticholinergics (antispasmodics, antiparkinsonian drugs, to abnormalities in contraction and/or relaxation of pelvic tricyclic antidepressants, antipsychotics) floor muscles during defecation. Functional constipation can Antihistamines result from slow-transit constipation and coexistent dyssyn- NSAIDs ergic defecation. lron supplements Calcium supplements Evaluation A careful history identifies most causes of secondary constipa- Bismuth tion. The medication history should focus on the temporal Antihypertensives (calcium channel blockers, diuretics, relationship between medications and constipation onset. The clonidine) history should include assessment for alarm features: hema- Serotonergic antagonists (ondansetron) tochezia, acute constipation in elderly patients, unintentional Mechanical Causes weight loss, family history of colorectal cancer, unexplained Colorectal cancer anemia, and age older than 50 years with no previous colonos-

Calcium supplements Evaluation A careful history identifies most causes of secondary constipa- Bismuth tion. The medication history should focus on the temporal Antihypertensives (calcium channel blockers, diuretics, relationship between medications and constipation onset. The clonidine) history should include assessment for alarm features: hema- Serotonergic antagonists (ondansetron) tochezia, acute constipation in elderly patients, unintentional Mechanical Causes weight loss, family history of colorectal cancer, unexplained Colorectal cancer anemia, and age older than 50 years with no previous colonos- Rectocele copy. Anorectal examination, including digital examination dur- ing the Valsalva maneuver, is important because it may identify Rectal intussusception anatomic or functional causes of an evacuation disorder. Rectal prolapse Flat-plate radiography of the abdomen is the most use- Sigmoidocele ful initial study because it can assess for the presence and | Enterocele distribution of excessive stool in the colon and/or rectum. Anastomotic stricture Colonoscopy indications include blood in the stool, a sud-

Rectocele copy. Anorectal examination, including digital examination dur- ing the Valsalva maneuver, is important because it may identify Rectal intussusception anatomic or functional causes of an evacuation disorder. Rectal prolapse Flat-plate radiography of the abdomen is the most use- Sigmoidocele ful initial study because it can assess for the presence and | Enterocele distribution of excessive stool in the colon and/or rectum. Anastomotic stricture Colonoscopy indications include blood in the stool, a sud- Anal stenosis/stricture den change in bowel habits, or unexplained anemia. It is also used for colon cancer screening in patients at average Extrinsic compression from pelvic/abdominal process | and increased risk due to family history of colorectal cancer. Pelvic floor dysfunction Additional imaging or laboratory studies should be consid- Systemic Illnesses ered only if clinically indicated. Physiologic testing, includ- Endocrinologic | ing colon transit testing, anorectal manometry, balloon Diabetes mellitus expulsion testing, or defecography, is reserved for patients with symptoms that do not respond to laxative therapy. Hypothyroidism

Anal stenosis/stricture den change in bowel habits, or unexplained anemia. It is also used for colon cancer screening in patients at average Extrinsic compression from pelvic/abdominal process | and increased risk due to family history of colorectal cancer. Pelvic floor dysfunction Additional imaging or laboratory studies should be consid- Systemic Illnesses ered only if clinically indicated. Physiologic testing, includ- Endocrinologic | ing colon transit testing, anorectal manometry, balloon Diabetes mellitus expulsion testing, or defecography, is reserved for patients with symptoms that do not respond to laxative therapy. Hypothyroidism Panhypopituitarism Management Pheochromocytoma Treatment strategies that may be beneficial when lifestyle and Glucagonoma dietary interventions have been ineffective include bulking Neuropathy/myopathy | agents, stimulant laxatives, osmotic laxatives, secretagogues,

Panhypopituitarism Management Pheochromocytoma Treatment strategies that may be beneficial when lifestyle and Glucagonoma dietary interventions have been ineffective include bulking Neuropathy/myopathy | agents, stimulant laxatives, osmotic laxatives, secretagogues, Altered Physiologic State and/or biofeedback (Table 22). The evidence for efficacy is strongest for polyethylene glycol, lubiprostone, and linaclo- Hypercalcemia tide. Fiber supplements, polyethylene glycol, magnesium, Hypokalemia senna, docusate, and bisacodyl are available without a pre- Pregnancy scription. For refractory constipation, combination therapy Porphyria should include agents with different mechanisms of action, Heavy-metal poisoning (arsenic, lead, mercury) such as an osmotic plus a stimulant laxative. For the manage- ment of opioid-induced constipation, see MKSAP 19 General Psychosocial Internal Medicine 1. Depression Cognitive impairment | Immobility e The most common cause of secondary constipation is medication. e Treatments include dietary and lifestyle modification, or dyssynergic defecation. Slow-transit constipation is the addressing causes of secondary constipation, and various delayed passage of fecal contents through the colon based pharmacologic agents. on objective transit testing (radiopaque marker study, 37

Disorders of the Small and Large Bowel TABLE 22. Treatments for Constipation Intervention Mechanism of Action Considerations Bulk Laxative Increases ability of stool to retain water Start with a low dose and increase slowly Soluble fiber (psyllium, methylcellulose, Bulks stool Soluble fiber works better than insoluble fiber calcium polycarbophil, wheat dextrin) Speeds movement of stool through colon Bloating, distention, flatulence, and cramping Insoluble fiber (bran, rye, flaxseed) may be limiting Stool Softener A detergent that allows water to penetrate Minimal effectiveness in clinical trials the stool Docusate sodium, docusate calcium Only role is in mild constipation symptoms Well tolerated Few side effects Osmotic Laxative Poorly absorbed compounds Polyethylene glycol 3350 and lactulose improve stool frequency and consistency; Polyethylene glycol 3350 Creates an osmotic gradient others have not been tested in clinical trials Lactulose Water moves into the bowel lumen Bloating and gas can be limiting Magnesium hydroxide/magnesium Caution with use of magnesium in renal citrate insufficiency Sorbitol

Osmotic Laxative Poorly absorbed compounds Polyethylene glycol 3350 and lactulose improve stool frequency and consistency; Polyethylene glycol 3350 Creates an osmotic gradient others have not been tested in clinical trials Lactulose Water moves into the bowel lumen Bloating and gas can be limiting Magnesium hydroxide/magnesium Caution with use of magnesium in renal citrate insufficiency Sorbitol Stimulant Laxative Irritates the colon wall, increasing Quickest acting (works in 8-12 hours of contractions ingestion) | Anthraquinones (senna, cascara) Stimulates sensory nerves lining the colon Senna can cause melanosis coli (benign Diphenylmethanes (bisacodyl, sodium pigmentation of the colon) picosulfate) May inhibit water absorption in the colon Diarrhea, cramping, bloating, and nausea can be limiting

Stimulant Laxative Irritates the colon wall, increasing Quickest acting (works in 8-12 hours of contractions ingestion) | Anthraquinones (senna, cascara) Stimulates sensory nerves lining the colon Senna can cause melanosis coli (benign Diphenylmethanes (bisacodyl, sodium pigmentation of the colon) picosulfate) May inhibit water absorption in the colon Diarrhea, cramping, bloating, and nausea can be limiting Secretagogue Lubiprostone activates type 2 chloride Lubiprostone improves stool form and channels on enterocytes lining the gut frequency, straining, and abdominal pain; Lubiprostone lumen, causing chloride ions to move into nausea is acommon side effect Linaclotide the colonic lumen with sodium and water Linaclotide and plecanatide improve stool following the ionic gradient Plecanatide form and frequency, straining, bloating, and Linaclotide and plecanatide activate abdominal pain; diarrhea is acommon side guanylate cyclase C receptors on effect enterocytes, leading to chloride channel activation througha series of processes within the cell

Secretagogue Lubiprostone activates type 2 chloride Lubiprostone improves stool form and channels on enterocytes lining the gut frequency, straining, and abdominal pain; Lubiprostone lumen, causing chloride ions to move into nausea is acommon side effect Linaclotide the colonic lumen with sodium and water Linaclotide and plecanatide improve stool following the ionic gradient Plecanatide form and frequency, straining, bloating, and Linaclotide and plecanatide activate abdominal pain; diarrhea is acommon side guanylate cyclase C receptors on effect enterocytes, leading to chloride channel activation througha series of processes within the cell Serotonergic Agent Increases intestinal contractions Approved for chronic idiopathic constipation Prucalopride Increases intestinal secretion Neuromuscular Re-education Retrains the skeletal muscle involved in Effective for dyssynergic defecation (biofeedback) defecation (abdominal wall, pelvic floor, Requires a specially trained physical therapist anorectal) Corrects altered rectal sensation Irritable Bowel Syndrome Evaluation

Neuromuscular Re-education Retrains the skeletal muscle involved in Effective for dyssynergic defecation (biofeedback) defecation (abdominal wall, pelvic floor, Requires a specially trained physical therapist anorectal) Corrects altered rectal sensation Irritable Bowel Syndrome Evaluation Irritable bowel syndrome (IBS) is a heterogeneous group of Diagnosis of IBS is no longer one of exclusion but instead can functional bowel disorders defined by abdominal pain in asso- reliably be made by clinical criteria in the absence of alarm ciation with defecation and/or change in bowel habits. Pain features. Diagnosis requires recurrent abdominal pain at may worsen or subside with defecation. Altered bowel habits least 1 day a week for 3 months along with at least two of the may include constipation, diarrhea, or both. Other common following: defecation-related pain, change in stool fre- symptoms include abdominal bloating and abdominal disten- quency, or change in stool consistency. IBS can be further tion. IBS is associated with diverse pathophysiologic mecha- subtyped into IBS with predominant constipation (IBS-C), nisms, including increased colonic transit, abnormal intestinal IBS with predominant diarrhea (IBS-D), IBS with mixed or colorectal sensation, increased colonic bile acid concentra- bowel habits, or IBS unclassified. Evaluation for IBS relies on tion, and epithelial barrier dysfunction. IBS is more common a comprehensive history and physical examination. In in women and adults younger than 50 years and is frequently patients with IBS-D, stool testing for giardiasis, testing for associated with psychosocial disturbance. No reliable bio- celiac disease, and fecal calprotectin testing to differentiate markers define IBS. from IBD is recommended. 38

Disorders of the Small and Large Bowel Management Alosetron (a selective 5-HT; antagonist) is recommended IBS management includes lifestyle modification, changes in for women with refractory IBS-D; it alleviates abdominal pain diet, probiotics, pharmacotherapy, and cognitive behavioral and global symptoms. Because of the risk for severe constipa- therapy. Limited evidence suggests that exercise, stress man- tion and colonic ischemia, prescribers must be enrolled in an agement, and correction of impaired sleep can alleviate IBS FDA-mandated risk evaluation and mitigation strategy pro- symptoms. Evidence is mixed on the effectiveness of probiot- gram in order to prescribe alosetron. ics for IBS-D, and this remains an area in need of rigorous Other medications with clinical evidence for treatment clinical trials. of IBS-D include loperamide, antispasmodics, tricyclic anti- The most common dietary intervention is to increase fiber depressants, and bile acid sequestrants. Loperamide, an through diet or fiber supplements. Water-soluble fiber supple- opioid receptor agonist, slows colonic transit and increases ments, such as psyllium, are more effective than insoluble fluid absorption. It reduces stool frequency and improves dietary fiber, such as bran. Dietary restrictions can include stool consistency in IBS-D but does not alleviate abdominal avoiding trigger foods; gluten (in the absence of celiac disease); pain. Antispasmodics (e.g., dicyclomine and peppermint oil) dairy products; and fermentable oligosaccharides, disaccha- decrease abdominal pain and global symptoms of IBS. rides, monosaccharides, and polyols (FODMAPs) (see Table 18). Tricyclic antidepressants modestly relieve the abdominal Because these substances are poorly absorbed in the small pain and global symptoms of IBS-D. The mechanism of intestine, they induce osmotic effects or are fermented in the action of tricyclic antidepressants in IBS may include colon, leading to decreased stool consistency and bloating. reduced activation of pain centers in the brain and periph- Some studies show that 20 to 60 minutes of moderate to vigor- eral mechanisms that affect pain sensation. Approximately

intestine, they induce osmotic effects or are fermented in the action of tricyclic antidepressants in IBS may include colon, leading to decreased stool consistency and bloating. reduced activation of pain centers in the brain and periph- Some studies show that 20 to 60 minutes of moderate to vigor- eral mechanisms that affect pain sensation. Approximately ous physical activity 3 to 5 days per week improves IBS symp- 25% of patients with IBS-D have evidence of bile acid malab- tom scores. If fiber supplementation, diet manipulations, and sorption; a bile acid binder, such as colesevelam, reduces exercise fail to relieve symptoms, medications are used. stool frequency and improves stool consistency in these Evidence supporting the various agents varies; few rigorous patients. Psychological therapies (e.g., cognitive behavioral studies show long-term effectiveness. therapy, hypnotherapy, multicomponent psychological ther- apy, and dynamic psychotherapy) are beneficial in the Therapy for Irritable Bowel Syndrome With treatment of IBS. Predominant Constipation Several peripherally acting medications are efficacious for treating IBS-C, including polyethylene glycol and intestinal e Diagnosis of irritable bowel syndrome (IBS) requires recur- rent abdominal pain at least 1 day a week for 3 months secretagogues (see Table 22). The three intestinal secretagogues for IBS-C are lubiprostone, linaclotide, and plecanatide and along with at least two of the following: defecation-related pain, change in stool frequency, or change in stool con- are typically used to treat symptoms refractory to osmotic laxatives. Probiotics have uncertain benefit and should be used sistency.

studies show long-term effectiveness. therapy, hypnotherapy, multicomponent psychological ther- apy, and dynamic psychotherapy) are beneficial in the Therapy for Irritable Bowel Syndrome With treatment of IBS. Predominant Constipation Several peripherally acting medications are efficacious for treating IBS-C, including polyethylene glycol and intestinal e Diagnosis of irritable bowel syndrome (IBS) requires recur- rent abdominal pain at least 1 day a week for 3 months secretagogues (see Table 22). The three intestinal secretagogues for IBS-C are lubiprostone, linaclotide, and plecanatide and along with at least two of the following: defecation-related pain, change in stool frequency, or change in stool con- are typically used to treat symptoms refractory to osmotic laxatives. Probiotics have uncertain benefit and should be used sistency. in the context of a clinical trial. e In patients with IBS with predominant diarrhea, stool testing for giardiasis, testing for celiac disease, and fecal Therapy for Irritable Bowel Syndrome calprotectin testing to differentiate from inflammatory With Predominant Diarrhea bowel disease is recommended. FDA-approved prescription medications for treatment of e Initial treatment of IBS includes water-soluble fiber IBS-D include rifaximin, eluxadoline, and alosetron. A 14-day supplements, avoiding trigger foods (i.e., gluten and course of rifaximin (a nonabsorbable antibiotic) relieves global fermentable oligosaccharides, disaccharides, mono- symptoms, bloating, and loose stools associated with IBS-D for saccharides, and polyols), and exercise. up to 10 weeks after treatment. Re-treatment of patients with e Pharmacotherapy should target predominant symp- recurring IBS-D relieves abdominal bloating and improves toms and be used if conservative treatment is not stool consistency for 4 weeks after treatment. effective. Eluxadoline (a combination of a x- and p-opioid receptor agonist and a 6-opioid receptor antagonist) relieves diarrhea and abdominal pain in adults with IBS-D. Adverse effects are Centrally Mediated Abdominal mainly nausea and headache. Rare cases of pancreatitis and sphincter of Oddi spasm have been reported. Eluxadoline is Pain Syndrome and Narcotic contraindicated in patients without a gallbladder and those Bowel Syndrome with known or suspected biliary obstruction, sphincter of Centrally mediated abdominal pain syndrome (CAPS) results Oddi disease or dysfunction, ingestion of three or more alco- from central sensitization with disinhibition of pain signals. holic beverages a day, history of pancreatitis or structural dis- When abdominal pain is the primary symptom and is unrelated ease of the pancreas, severe hepatic impairment, or history of to food intake and defecation, CAPS should be considered. The severe constipation. abdominal pain is described as constant, nearly constant, or

in the context of a clinical trial. e In patients with IBS with predominant diarrhea, stool testing for giardiasis, testing for celiac disease, and fecal Therapy for Irritable Bowel Syndrome calprotectin testing to differentiate from inflammatory With Predominant Diarrhea bowel disease is recommended. FDA-approved prescription medications for treatment of e Initial treatment of IBS includes water-soluble fiber IBS-D include rifaximin, eluxadoline, and alosetron. A 14-day supplements, avoiding trigger foods (i.e., gluten and course of rifaximin (a nonabsorbable antibiotic) relieves global fermentable oligosaccharides, disaccharides, mono- symptoms, bloating, and loose stools associated with IBS-D for saccharides, and polyols), and exercise. up to 10 weeks after treatment. Re-treatment of patients with e Pharmacotherapy should target predominant symp- recurring IBS-D relieves abdominal bloating and improves toms and be used if conservative treatment is not stool consistency for 4 weeks after treatment. effective. Eluxadoline (a combination of a x- and p-opioid receptor agonist and a 6-opioid receptor antagonist) relieves diarrhea and abdominal pain in adults with IBS-D. Adverse effects are Centrally Mediated Abdominal mainly nausea and headache. Rare cases of pancreatitis and sphincter of Oddi spasm have been reported. Eluxadoline is Pain Syndrome and Narcotic contraindicated in patients without a gallbladder and those Bowel Syndrome with known or suspected biliary obstruction, sphincter of Centrally mediated abdominal pain syndrome (CAPS) results Oddi disease or dysfunction, ingestion of three or more alco- from central sensitization with disinhibition of pain signals. holic beverages a day, history of pancreatitis or structural dis- When abdominal pain is the primary symptom and is unrelated ease of the pancreas, severe hepatic impairment, or history of to food intake and defecation, CAPS should be considered. The severe constipation. abdominal pain is described as constant, nearly constant, or 39

Disorders of the Small and Large Bowel frequently recurring; is not localized; and may include 85 years and older. Most patients with diverticulosis are extraintestinal symptoms, such as musculoskeletal pain. It asymptomatic, but 15% develop complications, including can be associated with impairment in activities of daily liv- bleeding and diverticulitis. ing and psychosocial issues. Limited evaluation is needed Diverticulitis results from a diverticulum becoming for patients with chronic pain meeting CAPS diagnostic blocked, trapping of bacteria, and development of inflamma- criteria. Initial evaluation should include a detailed medical tion. Diverticulitis can be classified as uncomplicated or com- and psychosocial history, physical examination, and limited plicated. Complicated diverticulitis is marked by abscess, laboratory studies to exclude gastrointestinal bleeding and fistula, obstruction, or perforation. In some patients, a focal inflammation. area of colitis can develop in a segment of diverticulosis, called Successful treatment depends on the patient-physician segmental colitis associated with diverticulosis. relationship and should focus on setting appropriate goals The clinical presentation of uncomplicated diverticulitis and expectations. A combination of pharmacologic and/or is colicky abdominal pain relieved with flatus or a bowel psychological therapies may be needed, including tricyclic movement. On physical examination, abdominal tenderness antidepressants, selective serotonin reuptake inhibitors, or (usually in the left lower quadrant) is often present. Patients serotonin-norepinephrine reuptake inhibitors. Four classes of with colovesical fistula may present with dysuria, urinary fre- psychotherapy have shown benefits in CAPS when combined quency, pneumaturia, fecaluria, and recurrent urinary infec- with medical therapy: cognitive behavioral therapy, psychody- tion. Patients with diverticulitis uncommonly present with namic-interpersonal therapy, mindfulness- and acceptance- rectal bleeding.

frequently recurring; is not localized; and may include 85 years and older. Most patients with diverticulosis are extraintestinal symptoms, such as musculoskeletal pain. It asymptomatic, but 15% develop complications, including can be associated with impairment in activities of daily liv- bleeding and diverticulitis. ing and psychosocial issues. Limited evaluation is needed Diverticulitis results from a diverticulum becoming for patients with chronic pain meeting CAPS diagnostic blocked, trapping of bacteria, and development of inflamma- criteria. Initial evaluation should include a detailed medical tion. Diverticulitis can be classified as uncomplicated or com- and psychosocial history, physical examination, and limited plicated. Complicated diverticulitis is marked by abscess, laboratory studies to exclude gastrointestinal bleeding and fistula, obstruction, or perforation. In some patients, a focal inflammation. area of colitis can develop in a segment of diverticulosis, called Successful treatment depends on the patient-physician segmental colitis associated with diverticulosis. relationship and should focus on setting appropriate goals The clinical presentation of uncomplicated diverticulitis and expectations. A combination of pharmacologic and/or is colicky abdominal pain relieved with flatus or a bowel psychological therapies may be needed, including tricyclic movement. On physical examination, abdominal tenderness antidepressants, selective serotonin reuptake inhibitors, or (usually in the left lower quadrant) is often present. Patients serotonin-norepinephrine reuptake inhibitors. Four classes of with colovesical fistula may present with dysuria, urinary fre- psychotherapy have shown benefits in CAPS when combined quency, pneumaturia, fecaluria, and recurrent urinary infec- with medical therapy: cognitive behavioral therapy, psychody- tion. Patients with diverticulitis uncommonly present with namic-interpersonal therapy, mindfulness- and acceptance- rectal bleeding. based therapy, and hypnotherapy. Acute diverticulitis is often a clinical diagnosis, usually Narcotic bowel syndrome, also known as opiate-induced not requiring imaging. However, CT may be performed to gastrointestinal hyperalgesia, is characterized by the para- assess for an alternative diagnosis or suspected complicated doxical increase in abdominal pain with increasing doses of disease (e.g., abscess). narcotics despite clinical evidence showing improvement or Uncomplicated diverticulitis is usually treated with oral stability of the underlying condition. Patients with this con- antibiotics (ciprofloxacin or metronidazole) and a liquid diet. dition often fear tapering off narcotics, believing that Close observation without antibiotics may be considered in the narcotics are “the only thing that helps.” The only treat- some patients. Intravenous antibiotics and hospitalization are ment is complete detoxification and cessation of narcotic required in patients unable to tolerate an oral diet; patients use. Enrollment in a supervised detoxification program is with severe comorbidities, advanced age, or immunosuppres- recommended. sion; and patients for whom oral antibiotics have been ineffective. Treatment of complicated diverticulitis depends on ill- ¢ Centrally mediated abdominal pain syndrome should be ness severity and CT findings. If the CT scan shows a large considered when abdominal pain is the primary symp- (>3 cm) abscess, CT-guided drainage may be needed. Surgery tom and is unrelated to food intake and defecation; is indicated for patients who present with or develop peritoni- the abdominal pain is described as constant, nearly tis, perforation, obstruction, or persistent sepsis. constant, or frequently recurring; is not localized; and A high-fiber diet is recommended to prevent recurrent may include extraintestinal symptoms. diverticulitis. No evidence supports restricting such foods as HVC e Evaluation for centrally mediated pain syndrome requires nuts, berries, and seeds to prevent recurrent diverticulitis. a detailed medical and psychosocial history and physical Unless performed within the prior year, colonoscopy should examination, with limited laboratory testing. be completed in all patients after symptoms resolve to rule out

based therapy, and hypnotherapy. Acute diverticulitis is often a clinical diagnosis, usually Narcotic bowel syndrome, also known as opiate-induced not requiring imaging. However, CT may be performed to gastrointestinal hyperalgesia, is characterized by the para- assess for an alternative diagnosis or suspected complicated doxical increase in abdominal pain with increasing doses of disease (e.g., abscess). narcotics despite clinical evidence showing improvement or Uncomplicated diverticulitis is usually treated with oral stability of the underlying condition. Patients with this con- antibiotics (ciprofloxacin or metronidazole) and a liquid diet. dition often fear tapering off narcotics, believing that Close observation without antibiotics may be considered in the narcotics are “the only thing that helps.” The only treat- some patients. Intravenous antibiotics and hospitalization are ment is complete detoxification and cessation of narcotic required in patients unable to tolerate an oral diet; patients use. Enrollment in a supervised detoxification program is with severe comorbidities, advanced age, or immunosuppres- recommended. sion; and patients for whom oral antibiotics have been ineffective. Treatment of complicated diverticulitis depends on ill- ¢ Centrally mediated abdominal pain syndrome should be ness severity and CT findings. If the CT scan shows a large considered when abdominal pain is the primary symp- (>3 cm) abscess, CT-guided drainage may be needed. Surgery tom and is unrelated to food intake and defecation; is indicated for patients who present with or develop peritoni- the abdominal pain is described as constant, nearly tis, perforation, obstruction, or persistent sepsis. constant, or frequently recurring; is not localized; and A high-fiber diet is recommended to prevent recurrent may include extraintestinal symptoms. diverticulitis. No evidence supports restricting such foods as HVC e Evaluation for centrally mediated pain syndrome requires nuts, berries, and seeds to prevent recurrent diverticulitis. a detailed medical and psychosocial history and physical Unless performed within the prior year, colonoscopy should examination, with limited laboratory testing. be completed in all patients after symptoms resolve to rule out e Narcotic bowel syndrome, also known as opiate-induced concomitant malignancy.

based therapy, and hypnotherapy. Acute diverticulitis is often a clinical diagnosis, usually Narcotic bowel syndrome, also known as opiate-induced not requiring imaging. However, CT may be performed to gastrointestinal hyperalgesia, is characterized by the para- assess for an alternative diagnosis or suspected complicated doxical increase in abdominal pain with increasing doses of disease (e.g., abscess). narcotics despite clinical evidence showing improvement or Uncomplicated diverticulitis is usually treated with oral stability of the underlying condition. Patients with this con- antibiotics (ciprofloxacin or metronidazole) and a liquid diet. dition often fear tapering off narcotics, believing that Close observation without antibiotics may be considered in the narcotics are “the only thing that helps.” The only treat- some patients. Intravenous antibiotics and hospitalization are ment is complete detoxification and cessation of narcotic required in patients unable to tolerate an oral diet; patients use. Enrollment in a supervised detoxification program is with severe comorbidities, advanced age, or immunosuppres- recommended. sion; and patients for whom oral antibiotics have been ineffective. Treatment of complicated diverticulitis depends on ill- ¢ Centrally mediated abdominal pain syndrome should be ness severity and CT findings. If the CT scan shows a large considered when abdominal pain is the primary symp- (>3 cm) abscess, CT-guided drainage may be needed. Surgery tom and is unrelated to food intake and defecation; is indicated for patients who present with or develop peritoni- the abdominal pain is described as constant, nearly tis, perforation, obstruction, or persistent sepsis. constant, or frequently recurring; is not localized; and A high-fiber diet is recommended to prevent recurrent may include extraintestinal symptoms. diverticulitis. No evidence supports restricting such foods as HVC e Evaluation for centrally mediated pain syndrome requires nuts, berries, and seeds to prevent recurrent diverticulitis. a detailed medical and psychosocial history and physical Unless performed within the prior year, colonoscopy should examination, with limited laboratory testing. be completed in all patients after symptoms resolve to rule out e Narcotic bowel syndrome, also known as opiate-induced concomitant malignancy. gastrointestinal hyperalgesia, is characterized by the paradoxical increase in abdominal pain with increasing e Acute diverticulitis is often a clinical diagnosis, usually HVC doses of narcotics. not requiring abdominal imaging unless an alternative diagnosis or complicated disease is suspected.

gastrointestinal hyperalgesia, is characterized by the paradoxical increase in abdominal pain with increasing e Acute diverticulitis is often a clinical diagnosis, usually HVC doses of narcotics. not requiring abdominal imaging unless an alternative diagnosis or complicated disease is suspected. e Uncomplicated diverticulitis is usually treated with oral Diverticular Disease antibiotics (ciprofloxacin or metronidazole) and a liquid A diverticulum is herniation of the mucosa and submucosa diet. through a weakness in the muscle wall. Diverticulosis (pres- e Intravenous antibiotics and hospitalization are required ence of diverticula) is the most common finding identified in patients with uncomplicated diverticulitis unable to during colonoscopy. The mechanism is thought to involve diet, tolerate an oral diet; patients with severe comorbidities, microbiota, genetics, and colonic motility. Diverticulosis inci- advanced age, or immunosuppression; and patients for dence continues to rise in the Western world and increases whom oral antibiotics have been ineffective. with age, with a reported prevalence of 80% in persons age 40

TABLE 23. Gastrointestinal Ischemic Syndromes | Problem Cause Symptoms Diagnosis Treatment Acute mesenteric Arterial embolus (most Severe periumbilical CT mesenteric Urgent laparotomy if ischemia common) pain; pain is out of angiography peritoneal signs; proportion to exam embolectomy or thrombectomy Chronic mesenteric Mesenteric Postprandial pain, CT or MR mesenteric Angioplasty with stenting ischemia atherosclerosis sitophobia, weight loss angiography or surgical bypass Colonic ischemia Low-flow states or drugs Mild-to-moderate left- Abdominal CT; Supportive care with lower-quadrant pain colonoscopy with biopsy: intravenous fluids and and bloody diarrhea segmental mucosal injury bowel rest

Colonic ischemia Low-flow states or drugs Mild-to-moderate left- Abdominal CT; Supportive care with lower-quadrant pain colonoscopy with biopsy: intravenous fluids and and bloody diarrhea segmental mucosal injury bowel rest CT angiography is recommended for diagnosing AMI. Ischemic Bowel Disease Although magnetic resonance angiography avoids the risks of Ischemic bowel disease represents a decrease in blood flow to radiation and contrast exposure, it takes longer and is less the small or large intestine that is insufficient to meet intesti- sensitive for distal and nonocclusive disease. Duplex ultra- nal cellular metabolic function. It represents a spectrum of sonography is an effective low-cost method for assessing the conditions that can be related to acute or chronic alterations of proximal mesenteric vessels, but adequate ultrasonography arterial or venous intestinal blood flow. Ischemic bowel dis- often cannot be performed in patients with AMI. The classic ease can be broadly subcategorized into three major clinical angiographic finding is an embolus or thrombus in the supe- syndromes: acute mesenteric ischemia, chronic mesenteric rior mesenteric artery. ischemia, and colonic ischemia (Table 23).

CT angiography is recommended for diagnosing AMI. Ischemic Bowel Disease Although magnetic resonance angiography avoids the risks of Ischemic bowel disease represents a decrease in blood flow to radiation and contrast exposure, it takes longer and is less the small or large intestine that is insufficient to meet intesti- sensitive for distal and nonocclusive disease. Duplex ultra- nal cellular metabolic function. It represents a spectrum of sonography is an effective low-cost method for assessing the conditions that can be related to acute or chronic alterations of proximal mesenteric vessels, but adequate ultrasonography arterial or venous intestinal blood flow. Ischemic bowel dis- often cannot be performed in patients with AMI. The classic ease can be broadly subcategorized into three major clinical angiographic finding is an embolus or thrombus in the supe- syndromes: acute mesenteric ischemia, chronic mesenteric rior mesenteric artery. ischemia, and colonic ischemia (Table 23). Treatment Acute Mesenteric Ischemia After aggressive fluid resuscitation, abdominal decompression, Clinical Features pain management, and administration of broad-spectrum anti- Acute mesenteric ischemia (AMI) is a rare condition caused by biotics, emergent surgery is indicated if imaging findings sig- an abrupt decrease in blood flow to the small intestine that can nifying mesenteric infarction, such as pneumatosis intestinalis be obstructive or nonobstructive. Obstructive causes of AMI (gas within the intestinal wall) or portal venous gas, are pre- include cardiogenic emboli or thrombosis related to underly- sent. Otherwise, angiography with selective catheterization of ing atherosclerotic disease. Nonobstructive AMI is most the mesenteric vessels may be performed along with endovas- commonly caused by vasoconstriction of the mesenteric cular intervention if possible. Patients with mesenteric arterial vasculature in the setting of severe sepsis or marked reduction or venous occlusion should begin receiving systemic antico- in effective circulating volume (low-flow states). Mesenteric agulation to prevent thrombus propagation, and anticoagula- vein thrombosis may also cause AMI and often is associated tion should be continued after surgery to prevent additional with malignancy, hypercoagulable states, or intra-abdominal thrombus formation. inflammatory conditions. Bowel infarction occurs with pro-

Treatment Acute Mesenteric Ischemia After aggressive fluid resuscitation, abdominal decompression, Clinical Features pain management, and administration of broad-spectrum anti- Acute mesenteric ischemia (AMI) is a rare condition caused by biotics, emergent surgery is indicated if imaging findings sig- an abrupt decrease in blood flow to the small intestine that can nifying mesenteric infarction, such as pneumatosis intestinalis be obstructive or nonobstructive. Obstructive causes of AMI (gas within the intestinal wall) or portal venous gas, are pre- include cardiogenic emboli or thrombosis related to underly- sent. Otherwise, angiography with selective catheterization of ing atherosclerotic disease. Nonobstructive AMI is most the mesenteric vessels may be performed along with endovas- commonly caused by vasoconstriction of the mesenteric cular intervention if possible. Patients with mesenteric arterial vasculature in the setting of severe sepsis or marked reduction or venous occlusion should begin receiving systemic antico- in effective circulating volume (low-flow states). Mesenteric agulation to prevent thrombus propagation, and anticoagula- vein thrombosis may also cause AMI and often is associated tion should be continued after surgery to prevent additional with malignancy, hypercoagulable states, or intra-abdominal thrombus formation. inflammatory conditions. Bowel infarction occurs with pro- longed reduction of blood flow; this is the most important Chronic Mesenteric Ischemia prognostic factor for adverse outcome. Clinical Features AMI commonly presents with abrupt onset of severe, Chronic mesenteric ischemia (CMI) is an uncommon condi- constant periumbilical abdominal pain followed by the urge to tion that involves a gradual decrease in blood flow to the small defecate along with loose nonbloody stools. Hematochezia intestine over months to years. It most commonly results from occurs in a minority of cases of AMI (15%), and its presence atherosclerotic narrowing of the mesenteric arteries. signifies concomitant right colon ischemia. Although patients The classic symptom triad of CMI is postprandial abdomi- report severe abdominal pain, the abdominal examination in nal pain, sitophobia (fear of eating), and weight loss. However, early disease is unimpressive and shows no peritoneal signs this triad is seen in only 30% of patients with CMI, and CMI (pain out of proportion to physical examination findings). This should be suspected in the setting of recurrent postprandial should immediately raise suspicion of early AMI. With delayed abdominal pain. Pain begins approximately 30 minutes after or late presentation, intestinal ischemia progresses to infarc- food ingestion as the fixed narrowing of the mesenteric arter- tion, and the mortality rate is high. ies prevents blood flow from increasing and meeting the increased functional demand of the small bowel, with result- Diagnosis ant ischemia. Laboratory and abdominal imaging findings in early AMI, before intestinal infarction develops, are nonspecific. Most patients Diagnosis have elevated leukocyte counts. A serum lactate concentration The diagnosis of CMI requires exclusion of alternative causes may be normal, and this should not exclude the diagnosis. of postprandial abdominal pain and weight loss along with

longed reduction of blood flow; this is the most important Chronic Mesenteric Ischemia prognostic factor for adverse outcome. Clinical Features AMI commonly presents with abrupt onset of severe, Chronic mesenteric ischemia (CMI) is an uncommon condi- constant periumbilical abdominal pain followed by the urge to tion that involves a gradual decrease in blood flow to the small defecate along with loose nonbloody stools. Hematochezia intestine over months to years. It most commonly results from occurs in a minority of cases of AMI (15%), and its presence atherosclerotic narrowing of the mesenteric arteries. signifies concomitant right colon ischemia. Although patients The classic symptom triad of CMI is postprandial abdomi- report severe abdominal pain, the abdominal examination in nal pain, sitophobia (fear of eating), and weight loss. However, early disease is unimpressive and shows no peritoneal signs this triad is seen in only 30% of patients with CMI, and CMI (pain out of proportion to physical examination findings). This should be suspected in the setting of recurrent postprandial should immediately raise suspicion of early AMI. With delayed abdominal pain. Pain begins approximately 30 minutes after or late presentation, intestinal ischemia progresses to infarc- food ingestion as the fixed narrowing of the mesenteric arter- tion, and the mortality rate is high. ies prevents blood flow from increasing and meeting the increased functional demand of the small bowel, with result- Diagnosis ant ischemia. Laboratory and abdominal imaging findings in early AMI, before intestinal infarction develops, are nonspecific. Most patients Diagnosis have elevated leukocyte counts. A serum lactate concentration The diagnosis of CMI requires exclusion of alternative causes may be normal, and this should not exclude the diagnosis. of postprandial abdominal pain and weight loss along with 41

Disorders of the Small and Large Bowel compatible imaging findings. CT or magnetic resonance angi- ography findings suggesting CMI include severe stenosis (>70%) of two of the three mesenteric arteries. Treatment CMI is treated with percutaneous endovascular stenting or surgical revascularization. Periprocedural morbidity and mor- tality are lower with endovascular stenting; however, this method is less durable than surgical revascularization. Colonic Ischemia Colonic ischemia is the most common form of ischemic bowel disease. It most commonly results from a nonocclusive low flow state in microvessels, which occurs with hypovolemia or hypotension. Risk factors include age (>60 years), female sex, vasoconstrictive and antihypertension medications, constipa- tion, thrombophilia, and COPD. Clinical Features Colonic ischemia presents with the abrupt onset of lower abdominal discomfort that is mild to moderate and cramping, followed within 24 hours by diarrhea and hematochezia. See Gastrointestinal Bleeding for discussion of lower gastrointesti- nal bleeding. FIGURE 21. CT scan showing colonic ischemia causing segmental thickening Diagnosis (arrow) of the transverse colon wall. Physical examination most commonly reveals mild lower abdominal tenderness over the involved bowel segment with- rest, restoration of intravascular volume, antimicrobial ther- out peritoneal signs. Laboratory studies may show mildly ele- apy in many cases, and close observation. Only a small per- vated leukocyte count and blood urea nitrogen level. centage of patients require operative intervention for necrotic Abdominal CT is indicated to assess the severity, phase, bowel or irreversible complications, such as stricture. and distribution of colonic ischemia. CT findings in colonic ischemia are nonspecific and include bowel-wall thickening (Figure 21) and pericolonic fat stranding (an increase in den- e Acute abdominal pain out of proportion to physical sity within pericolonic fat secondary to inflammation), often examination findings should immediately raise suspi- in the distribution of the “watershed” areas of the colon cion for early acute mesenteric ischemia.

FIGURE 21. CT scan showing colonic ischemia causing segmental thickening Diagnosis (arrow) of the transverse colon wall. Physical examination most commonly reveals mild lower abdominal tenderness over the involved bowel segment with- rest, restoration of intravascular volume, antimicrobial ther- out peritoneal signs. Laboratory studies may show mildly ele- apy in many cases, and close observation. Only a small per- vated leukocyte count and blood urea nitrogen level. centage of patients require operative intervention for necrotic Abdominal CT is indicated to assess the severity, phase, bowel or irreversible complications, such as stricture. and distribution of colonic ischemia. CT findings in colonic ischemia are nonspecific and include bowel-wall thickening (Figure 21) and pericolonic fat stranding (an increase in den- e Acute abdominal pain out of proportion to physical sity within pericolonic fat secondary to inflammation), often examination findings should immediately raise suspi- in the distribution of the “watershed” areas of the colon cion for early acute mesenteric ischemia. (splenic flexure and rectosigmoid junction). Infections that e CT angiography is the recommended method for the can mimic colonic ischemia, such as with cytomegalovirus, diagnosis of acute mesenteric ischemia. C. difficile, and enterohemorrhagic E. coli, must be excluded. e Chronic mesenteric ischemia should be suspected in Colonoscopy with biopsy is the test of choice to confirm the the setting of recurrent postprandial abdominal pain. diagnosis of colonic ischemia. ¢ Colonic ischemia presents with the abrupt onset of lower Because colonic ischemia is most commonly caused by a abdominal discomfort that is mild to moderate and nonocclusive low-flow state, dedicated imaging of the mesen- cramping, followed within 24 hours by diarrhea and teric vasculature is of low yield and generally not indicated. hematochezia. The exception is right-sided colonic ischemia, which can be the harbinger of AMI caused by a focal thrombus or embolus of the superior mesenteric artery. Therefore, patients with right-sided colonic ischemia require noninvasive imaging of Anorectal Disorders the mesenteric vasculature to exclude an occlusive process of Perianal Disorders the superior mesenteric artery. Perianal symptoms, including bright red blood per rectum, anal pain, anal itching, or a reported anal mass, should prompt Treatment a detailed evaluation of the anus, anal canal, and rectum that Most cases of colonic ischemia are mild and transient, with includes visual inspection of the anus and digital rectal exami- rapid spontaneous resolution. Patients with more severe dis- nation. Anoscopy or proctoscopy may be required to establish ease require hospitalization for supportive care with bowel the diagnosis. Colonoscopy is indicated when additional alarm

(splenic flexure and rectosigmoid junction). Infections that e CT angiography is the recommended method for the can mimic colonic ischemia, such as with cytomegalovirus, diagnosis of acute mesenteric ischemia. C. difficile, and enterohemorrhagic E. coli, must be excluded. e Chronic mesenteric ischemia should be suspected in Colonoscopy with biopsy is the test of choice to confirm the the setting of recurrent postprandial abdominal pain. diagnosis of colonic ischemia. ¢ Colonic ischemia presents with the abrupt onset of lower Because colonic ischemia is most commonly caused by a abdominal discomfort that is mild to moderate and nonocclusive low-flow state, dedicated imaging of the mesen- cramping, followed within 24 hours by diarrhea and teric vasculature is of low yield and generally not indicated. hematochezia. The exception is right-sided colonic ischemia, which can be the harbinger of AMI caused by a focal thrombus or embolus of the superior mesenteric artery. Therefore, patients with right-sided colonic ischemia require noninvasive imaging of Anorectal Disorders the mesenteric vasculature to exclude an occlusive process of Perianal Disorders the superior mesenteric artery. Perianal symptoms, including bright red blood per rectum, anal pain, anal itching, or a reported anal mass, should prompt Treatment a detailed evaluation of the anus, anal canal, and rectum that Most cases of colonic ischemia are mild and transient, with includes visual inspection of the anus and digital rectal exami- rapid spontaneous resolution. Patients with more severe dis- nation. Anoscopy or proctoscopy may be required to establish ease require hospitalization for supportive care with bowel the diagnosis. Colonoscopy is indicated when additional alarm 42

Disorders of the Small and Large Bowel features are present; these include age older than 50 years, altered bowel habits, anemia, IBD, unexplained weight loss, and/or family history of colorectal cancer. Hemorrhoids Risk factors for symptomatic hemorrhoids include ascites, pregnancy, excessive sitting or squatting, systemic rheumatic disorders, low dietary-fiber intake, obesity, and sedentary lifestyle. Recurrent straining and persistent bowel alterations (constipation or diarrhea) can lead to engorgement of hemor- rhoid plexuses, causing symptoms of bleeding, prolapse, and swelling. Age-related changes can cause the hemorrhoid beds to slide back and forth during defecation, resulting in mucoid anal discharge, perianal wetness, soiling, irritation, and/or pruritus. Pain is not a common symptom of uncomplicated hemorrhoids and should raise suspicion for hemorrhoid com- plications, including thrombosis, ischemia, or incarceration from prolapse, or for an alternative diagnosis, such as anal fissure, perirectal infection, or perianal abscess. Hemorrhoids are categorized as internal if proximal to the dentate line, external if distal to the dentate line, or mixed if crossing the dentate line. Evaluation of hemorrhoids should always include a care- ful perianal and digital rectal examination. Symptomatic hem- orrhoids can be confused with rectal mucosal prolapse, full-thickness rectal prolapse, or a prolapsed rectal polyp. Prolapsed concentric folds indicate rectal prolapse as opposed FIGURE 22. Hemorrhoids are vascular cushions that support the muscles

pregnancy, excessive sitting or squatting, systemic rheumatic disorders, low dietary-fiber intake, obesity, and sedentary lifestyle. Recurrent straining and persistent bowel alterations (constipation or diarrhea) can lead to engorgement of hemor- rhoid plexuses, causing symptoms of bleeding, prolapse, and swelling. Age-related changes can cause the hemorrhoid beds to slide back and forth during defecation, resulting in mucoid anal discharge, perianal wetness, soiling, irritation, and/or pruritus. Pain is not a common symptom of uncomplicated hemorrhoids and should raise suspicion for hemorrhoid com- plications, including thrombosis, ischemia, or incarceration from prolapse, or for an alternative diagnosis, such as anal fissure, perirectal infection, or perianal abscess. Hemorrhoids are categorized as internal if proximal to the dentate line, external if distal to the dentate line, or mixed if crossing the dentate line. Evaluation of hemorrhoids should always include a care- ful perianal and digital rectal examination. Symptomatic hem- orrhoids can be confused with rectal mucosal prolapse, full-thickness rectal prolapse, or a prolapsed rectal polyp. Prolapsed concentric folds indicate rectal prolapse as opposed FIGURE 22. Hemorrhoids are vascular cushions that support the muscles to a prolapsed hemorrhoid or anal polyp (Figure 22). Further of the anal sphincter by swelling up as needed to maintain stool continence. Prolapsed hemorrhoids (A) are internal hemorrhoids that protrude out of the direct evaluation of the anorectum can be considered with rectum. The hallmark of rectal prolapse (B) is the identification of concentric rings anoscopy or flexible sigmoidoscopy. of the rectum protruding through the anus. Prolapsed polyps (C, D) present as First line therapy for hemorrhoids includes increased mucosa-covered globular masses protruding from the anus. fiber intake, adequate liquid intake, and avoidance of strain- Images courtesy of Richard E. Burney, MD, Professor of Surgery, Michigan Medicine at the University of Michigan.

to a prolapsed hemorrhoid or anal polyp (Figure 22). Further of the anal sphincter by swelling up as needed to maintain stool continence. Prolapsed hemorrhoids (A) are internal hemorrhoids that protrude out of the direct evaluation of the anorectum can be considered with rectum. The hallmark of rectal prolapse (B) is the identification of concentric rings anoscopy or flexible sigmoidoscopy. of the rectum protruding through the anus. Prolapsed polyps (C, D) present as First line therapy for hemorrhoids includes increased mucosa-covered globular masses protruding from the anus. fiber intake, adequate liquid intake, and avoidance of strain- Images courtesy of Richard E. Burney, MD, Professor of Surgery, Michigan Medicine at the University of Michigan. ing. Various topical agents may reduce hemorrhoid symptoms but are not necessary for curative therapy. Patients with inter- nal hemorrhoids unresponsive to medical therapy should be considered for banding. Other options, including sclerother- apy and infrared coagulation, are less effective. Thrombosed external hemorrhoids are best treated with surgical excision within 72 hours of symptom onset. Surgical hemorrhoidectomy should be reserved for refractory hemor- rhoids, large external hemorrhoids, or combined internal and external hemorrhoids with rectal prolapse.

but are not necessary for curative therapy. Patients with inter- nal hemorrhoids unresponsive to medical therapy should be considered for banding. Other options, including sclerother- apy and infrared coagulation, are less effective. Thrombosed external hemorrhoids are best treated with surgical excision within 72 hours of symptom onset. Surgical hemorrhoidectomy should be reserved for refractory hemor- rhoids, large external hemorrhoids, or combined internal and external hemorrhoids with rectal prolapse. Anal Fissure Anal fissures are longitudinal mucosal tears in the anal canal characterized by anorectal pain that is worsened by bowel movements and sitting (Figure 23). Rectal bleeding with bowel movements or wiping is common. Anal fissures are idiopathic or result from trauma due to passage of hard stool, receptive anal intercourse, or insertion of a foreign body (such as an enema or endoscope). Lateral anal fissures should raise con- cern for other entities, including Crohn disease, ulcerative colitis, tuberculosis, syphilis, HIV infection, psoriasis, or anal FIGURE 23. Anal fissures are painful longitudinal mucosal tears in the anal cancer. Anal fissures lasting more than 8 to 12 weeks are con- canal. sidered chronic and may be characterized by edema and Image courtesy of Richard E. Burney, MD, Professor of Surgery, Michigan Medicine at the University of Michigan. 43

Disorders of the Small and Large Bowel fibrosis as well as a sentinel pile (appearing as a skin tag) or hypertrophied anal papilla within the anal canal. Acute anal fissures generally resolve within a few weeks with the use of sitz baths, psyllium, and bulking agents. Topical anesthetics and anti-inflammatory agents can be con- sidered to address pain or bleeding but are not required to promote fissure healing. Rectal spasm is the major reason for anal fissures becoming chronic and should be treated with topical calcium channel blockers or nitrates. Patients with chronic fissures unresponsive to these measures should be referred for internal sphincter botulinum toxin injection or surgical sphincterotomy. Fecal Incontinence Fecal incontinence is recurrent, uncontrolled passage of fecal FIGURE 24. Anal cancer presenting as an ulcerated mass protruding from the material of at least 3 months’ duration. Fecal incontinence anal canal. The presentation of anal cancer can vary from an obstructing anal mass to a nonprotruding polyp or flat growth in the anal canal. does not include passage of clear mucus or flatus inconti- nence. Fecal incontinence is grossly underreported because of Image courtesy of Richard E. Burney, MD, Professor of Surgery, Michigan Medicine at the University of Michigan.

Fecal Incontinence Fecal incontinence is recurrent, uncontrolled passage of fecal FIGURE 24. Anal cancer presenting as an ulcerated mass protruding from the material of at least 3 months’ duration. Fecal incontinence anal canal. The presentation of anal cancer can vary from an obstructing anal mass to a nonprotruding polyp or flat growth in the anal canal. does not include passage of clear mucus or flatus inconti- nence. Fecal incontinence is grossly underreported because of Image courtesy of Richard E. Burney, MD, Professor of Surgery, Michigan Medicine at the University of Michigan. associated embarrassment; health care providers should inquire about it during clinic visits in patients at risk. Fecal incidence has been rising by 2.2% each year for the last decade. incontinence is more common in multiparous women and in Delayed diagnosis by up to 2 years in more than half of cases has patients with advanced age; obesity; diarrhea or urinary resulted in increased need for aggressive surgical intervention. incontinence; or history of obstetric complications, anorectal Human papillomavirus infection and intraepithelial neo- surgery, or anorectal disease. Factors contributing to fecal plasia are strongly linked with anal cancer. Risk is increased in incontinence include loose stools, impaired rectal storage men who have sex with men and in patients with HIV infec- capacity, altered rectal sensation, and reduced anal sphincter tion, history of condylomata, or kidney or liver transplanta- tone. Constipation with resultant fecal loading and overflow tion. Presenting symptoms of anal cancer may include diarrhea can also cause fecal incontinence. bleeding, pain, or pruritus; however, 25% of cases present A digital rectal examination is essential in the evaluation. without any anorectal symptoms. Rates of anal squamous cell It can identify reduced anal sphincter tone, prolapse of hemor- cancer are 1 in 100,000 in patients with IBD or ulcerative coli- rhoids or rectum, or rectal stool impaction. Additional diagnos- tis and 2 in 100,000 in patients with Crohn disease, largely in tic testing is determined by the history and rectal examination. those with perianal disease. These statistics warrant height- If fecal loading is suspected, an abdominal radiograph can be ened vigilance in patients with long-standing perianal disease. diagnostic. If diarrhea is present, stool testing and/or colonos- Cancer occurs at a young age in patients with Crohn disease copy should be considered. If weak sphincter tone is appreci- (mean age, 42 years), with a typical presentation of anal pain. ated or rectal urgency is reported, evaluation may include Anal cancer is aggressive in patients with Crohn disease; most neurologic evaluation for spinal cord disorders, anorectal patients require radical surgery, and cumulative overall and manometry to assess anal sphincter pressure and rectal sensa- disease-free survival is 37% at 5 years. tion, anal endosonography for anal sphincter defects, or Although no recommendations address screening for defecography for structural evaluation of the pelvic floor. anal dysplasia in at-risk populations, screening modalities Initial treatment should be directed at reversible factors, include digital rectal examination, an anal Pap test, human such as diarrhea, constipation, offending medications, smok- papillomavirus testing, and high-resolution anoscopy. ing, obesity, and physical inactivity. Effective dietary modifica- Biopsy is required to diagnose anal cancer. tions include fiber supplementation and avoidance of trigger For treatment and follow-up of anal cancer, see MKSAP 19 foods. If there is no response to conservative measures, the Oncology. next step is pelvic floor muscle training with physical thera- pists. In cases not responding to biofeedback therapy, other treatment options include anal plugs, anal wicking, minimally e First-line therapy for hemorrhoids includes increased invasive procedures (e.g., injectable bulking agents or sacral fiber intake, adequate liquid intake, and avoidance of nerve stimulation), or surgery (e.g., sphincteroplasty). straining.

associated embarrassment; health care providers should inquire about it during clinic visits in patients at risk. Fecal incidence has been rising by 2.2% each year for the last decade. incontinence is more common in multiparous women and in Delayed diagnosis by up to 2 years in more than half of cases has patients with advanced age; obesity; diarrhea or urinary resulted in increased need for aggressive surgical intervention. incontinence; or history of obstetric complications, anorectal Human papillomavirus infection and intraepithelial neo- surgery, or anorectal disease. Factors contributing to fecal plasia are strongly linked with anal cancer. Risk is increased in incontinence include loose stools, impaired rectal storage men who have sex with men and in patients with HIV infec- capacity, altered rectal sensation, and reduced anal sphincter tion, history of condylomata, or kidney or liver transplanta- tone. Constipation with resultant fecal loading and overflow tion. Presenting symptoms of anal cancer may include diarrhea can also cause fecal incontinence. bleeding, pain, or pruritus; however, 25% of cases present A digital rectal examination is essential in the evaluation. without any anorectal symptoms. Rates of anal squamous cell It can identify reduced anal sphincter tone, prolapse of hemor- cancer are 1 in 100,000 in patients with IBD or ulcerative coli- rhoids or rectum, or rectal stool impaction. Additional diagnos- tis and 2 in 100,000 in patients with Crohn disease, largely in tic testing is determined by the history and rectal examination. those with perianal disease. These statistics warrant height- If fecal loading is suspected, an abdominal radiograph can be ened vigilance in patients with long-standing perianal disease. diagnostic. If diarrhea is present, stool testing and/or colonos- Cancer occurs at a young age in patients with Crohn disease copy should be considered. If weak sphincter tone is appreci- (mean age, 42 years), with a typical presentation of anal pain. ated or rectal urgency is reported, evaluation may include Anal cancer is aggressive in patients with Crohn disease; most neurologic evaluation for spinal cord disorders, anorectal patients require radical surgery, and cumulative overall and manometry to assess anal sphincter pressure and rectal sensa- disease-free survival is 37% at 5 years. tion, anal endosonography for anal sphincter defects, or Although no recommendations address screening for defecography for structural evaluation of the pelvic floor. anal dysplasia in at-risk populations, screening modalities Initial treatment should be directed at reversible factors, include digital rectal examination, an anal Pap test, human such as diarrhea, constipation, offending medications, smok- papillomavirus testing, and high-resolution anoscopy. ing, obesity, and physical inactivity. Effective dietary modifica- Biopsy is required to diagnose anal cancer. tions include fiber supplementation and avoidance of trigger For treatment and follow-up of anal cancer, see MKSAP 19 foods. If there is no response to conservative measures, the Oncology. next step is pelvic floor muscle training with physical thera- pists. In cases not responding to biofeedback therapy, other treatment options include anal plugs, anal wicking, minimally e First-line therapy for hemorrhoids includes increased invasive procedures (e.g., injectable bulking agents or sacral fiber intake, adequate liquid intake, and avoidance of nerve stimulation), or surgery (e.g., sphincteroplasty). straining. e Initial treatment of fecal incontinence is directed at Anal Cancer reversible factors, such as diarrhea, constipation, offend- Anal cancer (Figure 24) is rare, with a yearly incidence of 8000 ing medications, smoking, obesity, and physical inactivity. cases in the United States. Squamous cell cancer is the most (Continued) common type, representing 80% of all anal cancers. The

e Initial treatment of fecal incontinence is directed at Anal Cancer reversible factors, such as diarrhea, constipation, offend- Anal cancer (Figure 24) is rare, with a yearly incidence of 8000 ing medications, smoking, obesity, and physical inactivity. cases in the United States. Squamous cell cancer is the most (Continued) common type, representing 80% of all anal cancers. The 44

e Presenting symptoms of anal cancer may include bleed- ing, pain, or pruritus; however, 25% of cases present without any anorectal symptoms. e Patients with Crohn disease with long-standing perianal disease are particularly at risk for anal cancer.

e Presenting symptoms of anal cancer may include bleed- ing, pain, or pruritus; however, 25% of cases present without any anorectal symptoms. e Patients with Crohn disease with long-standing perianal disease are particularly at risk for anal cancer. Colorectal Neoplasia Epidemiology Colorectal cancer is the third most common cancer and sec- ond most common cause of cancer-related mortality among men and women in the United States. There are approximately 145,600 new cases in the United States annually, and lifetime risk for colorectal cancer is 4.5% for men and 4.1% for women. FIGURE 25. Aserrated lesion in the ascending colon, showing flat morphology The incidence and mortality for colorectal cancer have that can make these lesions difficult to identify on colonoscopy. decreased over the past 30 years because of changes in risk factors (e.g., decreased smoking) and early detection. of colon cancer. Germline mutations in APC lead to familial However, the number of colorectal cancer cases in patients adenomatous polyposis. younger than 50 years has steadily increased for unknown Microsatellites are dozens to hundreds of repetitive nucle- reasons. Survival rates exceed 90% with localized disease, otide sequences seen throughout the human genome. The underscoring the importance of early detection. Between term microsatellite instability refers to mismatched bases at 20% and 53% of adults older than 50 years have premalignant repeated DNA microsatellites. Microsatellite instability colon adenomas detected on screening, and 3% to 8% of the accounts for about 15% of colorectal cancers and is character- adenomas have advanced histologic features. Despite strong ized by defective DNA mismatch repair, leading to multiple evidence supporting colorectal cancer screening, only about mutations, adenomas, and cancer. Defective mismatch repair 63% of Americans older than 50 years are up to date for rec- can occur if there is a germline mutation in a mismatch repair ommended testing. gene in Lynch syndrome (including MLH1, MSH2, MSH6, and PMS2) or in the epithelial cell adhesion molecule gene (EPCAM) or as a result of sporadic methylation of the MLH1 e The number of colorectal cancer cases in patients younger promoter. than 50 years is increasing. The third mechanism involves hypermethylation of e Between 20% and 53% of adults older than 50 years have tumor suppressor genes and the development of serrated premalignant colon adenomas detected on screening, lesions and cancer. Serrated lesions are a heterogeneous but only about 63% of Americans older than 50 years group of lesions classified by their sawtooth appearance on are up to date for recommended screening. histology. They are often found in the proximal colon and may be flat and difficult to distinguish from normal mucosa (Figure 25). Pathogenesis Colorectal cancer develops through one of three mechanisms: chromosomal instability, microsatellite instability, and hyper- ¢ Colorectal cancer develops through one of three mecha-

Colorectal Neoplasia Epidemiology Colorectal cancer is the third most common cancer and sec- ond most common cause of cancer-related mortality among men and women in the United States. There are approximately 145,600 new cases in the United States annually, and lifetime risk for colorectal cancer is 4.5% for men and 4.1% for women. FIGURE 25. Aserrated lesion in the ascending colon, showing flat morphology The incidence and mortality for colorectal cancer have that can make these lesions difficult to identify on colonoscopy. decreased over the past 30 years because of changes in risk factors (e.g., decreased smoking) and early detection. of colon cancer. Germline mutations in APC lead to familial However, the number of colorectal cancer cases in patients adenomatous polyposis. younger than 50 years has steadily increased for unknown Microsatellites are dozens to hundreds of repetitive nucle- reasons. Survival rates exceed 90% with localized disease, otide sequences seen throughout the human genome. The underscoring the importance of early detection. Between term microsatellite instability refers to mismatched bases at 20% and 53% of adults older than 50 years have premalignant repeated DNA microsatellites. Microsatellite instability colon adenomas detected on screening, and 3% to 8% of the accounts for about 15% of colorectal cancers and is character- adenomas have advanced histologic features. Despite strong ized by defective DNA mismatch repair, leading to multiple evidence supporting colorectal cancer screening, only about mutations, adenomas, and cancer. Defective mismatch repair 63% of Americans older than 50 years are up to date for rec- can occur if there is a germline mutation in a mismatch repair ommended testing. gene in Lynch syndrome (including MLH1, MSH2, MSH6, and PMS2) or in the epithelial cell adhesion molecule gene (EPCAM) or as a result of sporadic methylation of the MLH1 e The number of colorectal cancer cases in patients younger promoter. than 50 years is increasing. The third mechanism involves hypermethylation of e Between 20% and 53% of adults older than 50 years have tumor suppressor genes and the development of serrated premalignant colon adenomas detected on screening, lesions and cancer. Serrated lesions are a heterogeneous but only about 63% of Americans older than 50 years group of lesions classified by their sawtooth appearance on are up to date for recommended screening. histology. They are often found in the proximal colon and may be flat and difficult to distinguish from normal mucosa (Figure 25). Pathogenesis Colorectal cancer develops through one of three mechanisms: chromosomal instability, microsatellite instability, and hyper- ¢ Colorectal cancer develops through one of three mecha- methylation of tumor suppressor genes. nisms: chromosomal instability, microsatellite instability,

Colorectal Neoplasia Epidemiology Colorectal cancer is the third most common cancer and sec- ond most common cause of cancer-related mortality among men and women in the United States. There are approximately 145,600 new cases in the United States annually, and lifetime risk for colorectal cancer is 4.5% for men and 4.1% for women. FIGURE 25. Aserrated lesion in the ascending colon, showing flat morphology The incidence and mortality for colorectal cancer have that can make these lesions difficult to identify on colonoscopy. decreased over the past 30 years because of changes in risk factors (e.g., decreased smoking) and early detection. of colon cancer. Germline mutations in APC lead to familial However, the number of colorectal cancer cases in patients adenomatous polyposis. younger than 50 years has steadily increased for unknown Microsatellites are dozens to hundreds of repetitive nucle- reasons. Survival rates exceed 90% with localized disease, otide sequences seen throughout the human genome. The underscoring the importance of early detection. Between term microsatellite instability refers to mismatched bases at 20% and 53% of adults older than 50 years have premalignant repeated DNA microsatellites. Microsatellite instability colon adenomas detected on screening, and 3% to 8% of the accounts for about 15% of colorectal cancers and is character- adenomas have advanced histologic features. Despite strong ized by defective DNA mismatch repair, leading to multiple evidence supporting colorectal cancer screening, only about mutations, adenomas, and cancer. Defective mismatch repair 63% of Americans older than 50 years are up to date for rec- can occur if there is a germline mutation in a mismatch repair ommended testing. gene in Lynch syndrome (including MLH1, MSH2, MSH6, and PMS2) or in the epithelial cell adhesion molecule gene (EPCAM) or as a result of sporadic methylation of the MLH1 e The number of colorectal cancer cases in patients younger promoter. than 50 years is increasing. The third mechanism involves hypermethylation of e Between 20% and 53% of adults older than 50 years have tumor suppressor genes and the development of serrated premalignant colon adenomas detected on screening, lesions and cancer. Serrated lesions are a heterogeneous but only about 63% of Americans older than 50 years group of lesions classified by their sawtooth appearance on are up to date for recommended screening. histology. They are often found in the proximal colon and may be flat and difficult to distinguish from normal mucosa (Figure 25). Pathogenesis Colorectal cancer develops through one of three mechanisms: chromosomal instability, microsatellite instability, and hyper- ¢ Colorectal cancer develops through one of three mecha- methylation of tumor suppressor genes. nisms: chromosomal instability, microsatellite instability, Chromosomal instability is the most common mecha- and hypermethylation of tumor suppressor genes; chro-

Colorectal Neoplasia Epidemiology Colorectal cancer is the third most common cancer and sec- ond most common cause of cancer-related mortality among men and women in the United States. There are approximately 145,600 new cases in the United States annually, and lifetime risk for colorectal cancer is 4.5% for men and 4.1% for women. FIGURE 25. Aserrated lesion in the ascending colon, showing flat morphology The incidence and mortality for colorectal cancer have that can make these lesions difficult to identify on colonoscopy. decreased over the past 30 years because of changes in risk factors (e.g., decreased smoking) and early detection. of colon cancer. Germline mutations in APC lead to familial However, the number of colorectal cancer cases in patients adenomatous polyposis. younger than 50 years has steadily increased for unknown Microsatellites are dozens to hundreds of repetitive nucle- reasons. Survival rates exceed 90% with localized disease, otide sequences seen throughout the human genome. The underscoring the importance of early detection. Between term microsatellite instability refers to mismatched bases at 20% and 53% of adults older than 50 years have premalignant repeated DNA microsatellites. Microsatellite instability colon adenomas detected on screening, and 3% to 8% of the accounts for about 15% of colorectal cancers and is character- adenomas have advanced histologic features. Despite strong ized by defective DNA mismatch repair, leading to multiple evidence supporting colorectal cancer screening, only about mutations, adenomas, and cancer. Defective mismatch repair 63% of Americans older than 50 years are up to date for rec- can occur if there is a germline mutation in a mismatch repair ommended testing. gene in Lynch syndrome (including MLH1, MSH2, MSH6, and PMS2) or in the epithelial cell adhesion molecule gene (EPCAM) or as a result of sporadic methylation of the MLH1 e The number of colorectal cancer cases in patients younger promoter. than 50 years is increasing. The third mechanism involves hypermethylation of e Between 20% and 53% of adults older than 50 years have tumor suppressor genes and the development of serrated premalignant colon adenomas detected on screening, lesions and cancer. Serrated lesions are a heterogeneous but only about 63% of Americans older than 50 years group of lesions classified by their sawtooth appearance on are up to date for recommended screening. histology. They are often found in the proximal colon and may be flat and difficult to distinguish from normal mucosa (Figure 25). Pathogenesis Colorectal cancer develops through one of three mechanisms: chromosomal instability, microsatellite instability, and hyper- ¢ Colorectal cancer develops through one of three mecha- methylation of tumor suppressor genes. nisms: chromosomal instability, microsatellite instability, Chromosomal instability is the most common mecha- and hypermethylation of tumor suppressor genes; chro- nism, accounting for approximately 85% of colorectal cancers. mosomal instability is the most common mechanism,

methylation of tumor suppressor genes. nisms: chromosomal instability, microsatellite instability, Chromosomal instability is the most common mecha- and hypermethylation of tumor suppressor genes; chro- nism, accounting for approximately 85% of colorectal cancers. mosomal instability is the most common mechanism, Chromosomal instability is characterized by abnormal cells accounting for 85% of cases. that gain or lose whole or large fractions of chromosomes (aneuploidy) at an increased rate compared with normal cells. Stepwise accumulation of mutations leads to progression from Risk Factors normal colon to adenoma to cancer. The most commonly Nonmodifiable risk factors for colon cancer include age mutated gene in this pathway is the adenomatous polyposis (250 years), male sex, Black race, and personal or family history coli (APC) gene, a multifunctional tumor suppressor gene. of colon adenomas or colorectal cancer. The risk doubles with APC mutations are implicated in the development and spread a family history of colorectal cancer in a first-degree relative. 45