Anatomy and Vascular Supply

The GI tract consists of three germ layers that are anatomically divided into segments according to arterial blood supply. The foregut includes the oral cavity, esophagus, stomach, and first portion of the duodenum. The liver, biliary tree, and pancreas arise from buds of the foregut. The midgut comprises the remaining entire small intestine and the proximal colon up to the proximal transverse colon. The hindgut includes the remaining colon, rectum, and upper portion of the anal canal. Branches of the superior mesenteric artery supply blood flow to the cecum, ascending colon, and proximal two thirds of the transverse colon. The remaining portion of the colon is supplied by branches of the inferior mesenteric artery. The rectum is supplied by the superior and middle rectal artery, and the anal canal is supplied by branches of the inferior mesenteric and internal iliac arteries. The remaining portion of the rectum is supplied by the inferior rectal artery.

Lower GI tract disorders mostly involve the colon, rectum, anus, and pelvic floor muscles. The anal canal has two sphincters that work to maintain fecal continence: 1) the internal anal sphincter, which is simply a continuation of the circular smooth muscle of the rectum, and 2) the external sphincter, which is a voluntary muscle that consists of skeletal muscle fibers. Hemorrhoids are dilated vascular channels at the anal canal that, in conjunction with the anal sphincters, help maintain stool continence by acting as vascular “pads.” These can become engorged and cause complications such as anal itching, rectal bleeding, and rectal pain.

Innervation and Motility

Motility of the lower GI tract is a result of the actions of smooth muscle tissue, except for the external anal sphincter. Neuronal control is mediated by the enteric nervous system. The enteric nervous system can function independently from the central nervous system (CNS); however, connections via the parasympathetic and sympathetic nerve fibers of the autonomic nervous system to the CNS are substantial. The myenteric plexus provides innervation to the smooth muscle cells to regulate colonic motility and stimulate secretion. Colonic activity is increased in response to oral intake by neuronal input of the vagus nerve and spinal cord; this phenomenon is known as the gastrocolic reflex. The interstitial cell of Cajal is another important component of the enteric nervous system; this motor regulatory cell stimulates and paces contractions.

Sensory nerve signals travel to the CNS through sensory afferent neurons along vagal and splanchnic nerves. Signals can be induced by visceral distension, content of nutrient components (such as glucose, amino acids, and fatty acids), and chemical stimuli from noxious agents.

Defecation requires a series of coordinated muscular events. As the rectum distends with stool, sacral spinal afferent mechanoreceptors are stimulated and the internal anal sphincter relaxes. This allows stool to descend slightly into the anal canal and increases the sense of urge for defecation. The levator ani muscles contract, the perineum descends, and stool descends into the anal canal. Stool is expelled with increasing rectal pressure by recruiting abdominal wall muscles to produce strain.

Physiology

The main functions of the lower GI tract are water absorption, lubrication and storage of stool, and expulsion of nonessential products. The colon receives approximately 2 L of fluid daily from the small bowel. Approximately 1.8 L of this is reabsorbed by the colon against impressive electrochemical gradients. Sodium is the chief ion that directs the absorption of water.

In addition to water absorption, the colon plays an important role in digestion of components that cannot be processed by small intestinal and pancreatic enzymes. This is accomplished not by the colon itself but by the multitude of bacteria that reside in the colon. Ingested nonstarch polysaccharides derived from plants, such as cellulose and hemicellulose, are resistant to the actions of small bowel and pancreatic enzymes and would otherwise not be digested without colonic bacteria. The bacteria process these polysaccharides into short-chain fatty acids, such as butyrate, propionate, and acetate. These compounds are then absorbed into colonic epithelial cells through active and passive mechanisms. In turn, fatty acid absorption also promotes absorption of sodium and chloride.

In the healthy state, colonic absorption of nutrients is minimal. However, in cases of small intestinal malabsorption, the colon can “salvage” some nutrients. The short-chain fatty acids generated by colonic bacterial digestion have caloric value. The colon absorbs these products with a 90% efficiency. Chronic malabsorption results in adaptive changes of the gut microbiota, which result in augmentation of this process. Short-chain fatty acids can contribute to the overall calorie balance of individuals.

Physiologic Changes and Concerns in Pregnancy

Changes in colonic motility during pregnancy have been well described 5. The increased concentration of progesterone is thought to contribute to the decrease in activity of colonic smooth muscle, causing constipation and bloating. The gravid uterus itself can present mechanical challenges to the flow of luminal contents as it compresses on intestinal loops. Other factors that contribute to decreased colonic motility include iron supplementation during pregnancy, decreased levels of motilin (a peptide hormone secreted by intestinal cells that increases intestinal motility), increased absorption of sodium and water by the colon, and decreased physical activity as pregnancy advances 6.

Anal sphincter injury during vaginal delivery is a common concern. Fecal incontinence later in life is associated with previous deliveries, vaginal or cesarean. In fact, overall, women are twice as likely to report moderate or severe fecal incontinence compared with men 7. Although delivery is a risk factor for fecal incontinence, regardless of the method, incontinence during pregnancy and the postpartum period is relatively uncommon 8. Hemorrhoids are a common occurrence during and immediately after pregnancy. They are caused by increased pressure within the anal canal. Constipation exacerbates symptoms caused by hemorrhoids, which include pruritus, pain or burning, and bleeding.

Special Concerns for Older Patients

Special consideration must be given to the older patient. Increases in comorbidities and polypharmacy can affect bowel function. The prevalence of constipation is greater in the elderly population than in other age groups. It can result from a primary motility disorder (i.e., slow transit of the colon or dyssynergic defecation) or can occur secondarily to other underlying illness. A loss of enteric neurons also occurs with aging 9 and is accompanied by an increase in elastin and collagen fiber deposition in the myenteric ganglia. Confounding factors add to the prevalence of constipation, including physical inactivity, use of anticholinergic medications, poor diet, and depression. Moreover, other medical conditions can cause secondary constipation. Metabolic abnormalities, such as hypercalcemia, thyroid derangements, and diabetes mellitus, can affect colonic transit. Neurologic conditions, such as parkinsonism, multiple sclerosis, and spinal cord injuries, can cause constipation. Structural problems can impede normal colonic transit, such as colonic strictures caused by recurrent diverticular disease, pelvic irradiation, IBD, or colorectal neoplasia.

The prevalence of fecal incontinence also increases with age, especially in individuals who reside in long-term care facilities. Several factors can contribute to incontinence, such as decreased rectal accommodation (ability to store the increased stool volume) and sensation, pelvic floor dyssynergia, abnormal sphincter function, pudendal or spinal cord nerve injury or dysfunction, medications, and cognitive decline.

Risk Factors

Clear risk factors for the development of colorectal cancer include advancing age, environmental factors, and genetic mutations Box 1. The risk of colorectal cancer increases with age, most markedly beginning at age 50 years in the general population. Chronic inflammatory states, such as ulcerative colitis or Crohn disease, also confer an increased risk and will be discussed later. A high-fat, low-fiber diet has been shown to be associated with colorectal cancer 13. Obesity and physical inactivity are well-known risk factors for colorectal cancer. Other factors associated with lifestyle habits, such as cigarette smoking and excessive alcohol intake, have been shown to increase the risk 13.

The chemoprotective effect of some medications continues to gain attention. Calcium and nonsteroidal antiinflammatory drugs (NSAIDs) have been examined as a protective factor for colorectal cancer 14. Before initiating chemoprophylaxis, the risks of daily NSAID therapy must be weighed against the benefits. These risks include ulcer formation and kidney disease. Estrogen is thought to decrease adenoma formation via mechanisms of the estrogen receptor genes. Several studies have demonstrated a 20–34% reduction in colorectal cancer incidence, but not mortality rates, in postmenopausal women who take hormone therapy 15 16.

Pathophysiology

Adenomatous polyps develop into carcinoma via a series of potential steps known as the “adenoma–carcinoma” sequence. Accumulation of mutations in genes such as KRAS and inactivation of the APC tumor suppressor gene lead to cancer. Microsatellite instability mutations of mismatch repair genes are responsible for hereditary nonpolyposis colorectal cancer. The two most common conditions associated with increased risk of colorectal cancer are familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, or Lynch syndrome.

Genetic Factors and Syndromes

Genetic factors play an important role in determining an individual’s risk of developing colorectal cancer. Those with a first-degree relative with sporadic colorectal cancer are at a twofold to threefold increased risk. Those who have a family history of a polyposis syndrome, such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, are at an increased risk and should be screened for the associated genetic mutations 17 18. In addition, patients with a previous history of gynecologic cancer, such as endometrial or ovarian cancer, also may be at an increased risk of colorectal cancer 19.

Patients with familial adenomatous polyposis develop colon adenomas at approximately age 12–15 years, with potential to develop colon cancer by 30 years. They also can develop polyps in the stomach and small intestine and, therefore, require periodic upper endoscopy. Once polyps are observed, prophylactic colectomy is recommended to prevent development of colorectal cancer. As an alternative, genetic testing can be performed to evaluate directly for the APC mutation. Patients with familial adenomatous polyposis also are at a slightly increased risk of developing liver, pancreas, ovarian, and thyroid cancer.

Patients with hereditary nonpolyposis colorectal cancer have a 52% lifetime risk of developing cancer 20. These individuals should undergo colonoscopy every 1–2 years, beginning at age 20–25 years, or 5 years earlier than the youngest affected family member at diagnosis (whichever comes first). Patients with hereditary nonpolyposis colorectal cancer also have increased risk of endometrial, ovarian, gastric, and urothelial cancer. The lifetime risk of endometrial cancer in patients with hereditary nonpolyposis colorectal cancer mutations is up to 60% 20. Annual screening for endometrial and ovarian cancer should begin at age 30–35 years with pelvic examinations, endometrial biopsy and transvaginal ultrasonography. It is reasonable to discuss prophylactic hysterectomy with bilateral salpingo-oophorectomy after childbearing years.

BRCA1 and BRCA2 mutations also appear to be associated with a slight increased risk of colorectal cancer. A 2013 prospective study followed more than 7,000 women with a BRCA mutation for incidence of CRC. The standardized incidence ratio in BRCA1 carriers was 0.92, compared with 0.82 for BRCA2 carriers. There was higher incidence overall in women under 50 years old for both genes combined. There are currently no updated guidelines for earlier colorectal cancer screening for breast cancer gene carriers, but these data should be taken into consideration when evaluating these patients. Until such time as more evidence and directed guidelines are established, breast cancer gene mutation carriers should undergo screening in accordance with recommendations for the general population (or sooner if positive family history as discussed above) 21. After a diagnosis is established, carcinoembryonic antigen (CEA) is useful to monitor the patient’s response to treatment. Several other tumors and conditions are associated with elevated CEA levels Box 2.

Warning Signs

Colorectal cancer advances slowly, and patients may harbor disease for 5 years or more before developing signs or symptoms. A common sign is occult blood loss, which results in iron deficiency anemia. Distal colonic tumors can produce visible blood in the stool. Other symptoms include abdominal pain and change in stool caliber. Large tumors can cause obstruction or even perforation. A differential diagnosis of colorectal cancer is detailed in Box 3.

Screening

Colorectal cancer arises from adenomatous polyps 22. Adenomatous polyps are further classified into tubular, villous, or mixed tubulovillous types. The serrated adenoma also is considered to have malignant potential. The most common non-neoplastic polyp is the hyperplastic form.

The estimated timeframe for progression from adenoma to carcinoma is 7–10 years. In studies that evaluated 50-year-old patients undergoing screening colonoscopy, 25–30% of these patients had adenomatous polyps on presentation 23 24. Because of the growing incidence of colorectal cancer in patients under 50 years old, the American Cancer Society and the United States Preventive Services Task Force recommend starting colon cancer screening at 45 years of age 25 26. Screening modalities include colonoscopy (the current gold standard), flexible sigmoidoscopy, and stool and imaging studies. Colonoscopy detects and allows for removal of precancerous polyps and, thus, has the advantage of directly preventing the development of cancer by removal of polyps. The National Polyp Study showed that colonoscopy with adenoma removal reduced the incidence of colorectal cancer by 76–90% in the United States 27, with similar results found in a large multicenter European study 28. Flexible sigmoidoscopy screening tests can miss proximal polyps or cancers and have decreased visibility because of poor preparation. Imaging modalities for CRC screening include computed tomography (CT) colonography. The colon is insufflated with air, and CT images are obtained. Detection of smaller polyps, at least 6 mm in size, has slightly decreased sensitivity (78%) and specificity (88%) compared with colonoscopy 29. Currently, the recommendation is that all patients found to have polyps 10 mm or greater in size or three polyps at least 6 mm in size on CT colonography should undergo follow-up colonoscopy for removal. The SIGGAR trial in 2013, a multicenter randomized control trial, compared rates of additional colonic investigation after CT colonography or colonoscopy for detecting polyps greater than 1 cm in patients with symptoms suggestive of colorectal cancer. Results revealed that although 30% of CT colonography patients had subsequent colonic investigation (versus 8% in the colonoscopy group), both had similar detection rates of colorectal cancer 30.

Stool tests are a noninvasive option for colorectal cancer screening. Fecal occult blood testing requires two to three samples to increase sensitivity. False-positive results can occur when patients ingest red meat, cruciferous vegetables, and some fruit because of the peroxidase activity of hemoglobin. Fecal immunochemical testing is an antibody to human globin and measures colonic blood. Overall sensitivity and specificity rates for fecal immunochemical testing are 79% and 94% respectively in systematic review studies. Cologuard, a multi-targeted stool DNA test, was approved in 2014. A prospective study of 10,000 patients comparing Cologuard to fecal immunochemical testing revealed a 92% sensitivity for Cologuard versus a 73% sensitivity for fecal immunochemical testing in detecting colorectal cancer 31. Screening guidelines and test options are summarized in Box 4.

Staging and Management

Staging is based on the tumor–node–metastasis system and is important in providing prognosis and guiding therapy. This system is summarized in Table 1. The stage of cancer at diagnosis confers prognosis. Surgical resection is the only treatment that offers potential cure. Before surgery, full colonoscopy should be performed, if possible, to assess for synchronous lesions. The affected segment of the colon is removed by wide resection, along with its lymphatic drainage.

Even in the setting of metastatic disease, resection can be considered to prevent intestinal obstruction and bleeding. In patients who have hepatic metastases, either at diagnosis or after surgical resection of the primary tumor, resection of these metastases can be an option. Candidates for resection of hepatic metastases include those who have undergone resection of the primary tumor with curative intent and have no evidence of additional, extrahepatic disease.

Despite complete surgical resection, patients with stage II and stage III diseases have postoperative recurrence rates of 20% and 50–80%, respectively. The addition of adjuvant chemotherapy to eliminate remaining microscopic tumor has been shown to improve survival in these patients. Multiple agents are available for patients with initial advanced disease or those who develop recurrence after resection. Agents can be tailored based on mutation type to improve efficacy. In addition to imaging, baseline CEA level should be measured before treatment begins to estimate response to therapy.

Rectal Cancer

Rectal cancer is frequently discussed with colon cancer but deserves special mention because of a few epidemiologic differences and treatment considerations between these two types of cancer. Recurrence after resection is higher for rectal cancer than for colon cancer. Generally, neoadjuvant chemoradiation is offered to patients with stage II and stage III disease because this intervention has been shown to decrease local relapse rates 33. Treatment decisions are based on the depth of tumor invasion and involvement of adjacent lymph nodes. These factors can be evaluated via rectal endoscopic ultrasonography or magnetic resonance imaging (MRI). Preoperative radiation with chemotherapy for locally advanced nonmetastatic disease is associated with a decrease in complications.

Surgical resection of rectal lesions is based on the location of the tumor. In the upper rectum and rectosigmoid region, a procedure known as low anterior resection can be performed. In this procedure, the distal sigmoid, rectum, and anus are removed, and a permanent sigmoid colostomy is constructed. Patients who have undergone radiation therapy before or after surgical resection with colo-anal or recto-anal anastomosis are at risk of developing long-term complications such as chronic radiation proctitis with rectal bleeding, anastomotic strictures, and fecal incontinence.

Classification

The Rome Foundation is an organization of physicians and researchers that promotes clinical recognition and scientific understanding of the pathophysiology of functional GI disorders. These disorders include IBS, functional constipation, functional diarrhea, functional abdominal bloating/distension, and unspecified functional bowel disorder. Anorectal disorders that also lead to motility problems include functional fecal incontinence and defecation disorders, such as dyssynergic defecation and inadequate defecatory propulsion. Box 5 lists the Rome IV functional lower GI disorders 34. These disorders will be discussed in the following sections.

Chronic Constipation

Constipation is a prevalent condition that affects up to 15–30% of the population. The incidence is higher in women than in men, particularly elderly women 35. The definition of constipation can vary from individual to individual. Some patients describe constipation as passing hard stool, straining, or both. Others describe it as infrequent bowel movements. Still others may have regular bowel movements but feel they are bloated and full and classify this as constipation. The generally accepted medical definition of constipation is three or fewer bowel movements per week. However, average stool frequency correlates poorly with patients’ reports of symptoms. The Rome Foundation developed a list of criteria for functional constipation to classify symptoms better 36. For example, such criteria include fewer than three spontaneous bowel movements per week, straining in at least 25% of bowel movements, and sensation of incomplete evacuation with bowel movements. In addition, patients must have insufficient criteria for a diagnosis of IBS.

Risk factors for constipation include advanced age, female gender, non-White ethnicity, physical inactivity, and a low socioeconomic level. The prevalence of constipation is nearly two to three times higher in women than in men 35. The reason for this is unclear, but hormonal differences may play a role. The prevalence of constipation in elderly patients increases to 30% overall, with nearly 50% of nursing home residents affected 9. Constipation tends to affect elderly individuals as a result of straining and hard stools as opposed to infrequent bowel movements. Such changes might be increased by decreased eating, decreased mobility, and weakening of the abdominal and pelvic floor muscles. Medications often contribute to constipation in elderly patients. Diet and physical activity appear to play a role, although a clear causative link is yet to be determined. A survey of more than 3,300 women revealed that those who ate a high-fiber diet and those who participated in regular physical activity were less likely to experience constipation (defined in this study as two or fewer bowel movements per week) 37.

Evaluation

History

Obtaining the patient’s medical history is one of the most important components of the evaluation. A description of the specific symptoms should be elicited, such as the stool form, frequency, presence of straining, and sense of complete evacuation, which are all clues that can help differentiate the type of constipation. The Bristol Stool Scale Figure 1 is a standardized numeric stool scale associated with pictures and words that can help patients describe their stool form. It is important to ask about other associated symptoms, such as weight loss, rectal bleeding, severe abdominal pain, and family history of colorectal cancer, that might suggest an alternative diagnosis. Reviewing the past medical history is an important step in identifying any confounding conditions that may contribute to constipation. Frequently, patients with neuromuscular disorders, such as Parkinson disease, are affected by constipation. In addition, a thorough review of medications is important to identify any with anticholinergic adverse effects. Herbal supplementation and the use of other modalities of complementary and alternative medicine (CAM) also should be reviewed, including colon cleansers and other products and techniques patients may be using to alleviate their symptoms. A review of dietary habits, including types of food included in the diet and the timing and frequency of meals, is important because food stimulates colonic motility. For example, postprandial stimulation is strongest in the morning with the breakfast meal. It is worthwhile to ask about psychosocial issues, as these can frequently intertwine with constipation. Screening for symptoms of depression, including change in sleep patterns, anhedonia, loss of confidence, and energy loss, is important as well.

Physical Examination

The physical examination can help identify anatomic or secondary causes of constipation. The patient’s general appearance can reveal signs of hypothyroidism, scleroderma, or dermatomyositis. If a spinal cord defect is suspected, a thorough neurologic examination that involves sensory testing of the dermatomes is in order. The abdomen should be thoroughly percussed and palpated for the presence of distension, tympany, hard feces within the colon, or a palpable inflammatory mass.

The rectal examination is an essential component of the physical examination of the constipated patient. It is best performed with the patient in the left lateral decubitus position. Initial visual inspection with the perineum at rest for perianal abnormalities such as scars, skin tags, hemorrhoids, and anal fissures is performed. The patient should then be asked to strain, and the perineum should descend 1–4 cm. A descent greater than 4 cm suggests descending perineal syndrome. Perineal syndrome is characterized by excessive strain. With this syndrome, patients express concerns of incomplete evacuation, which is caused by lack of straightening of the anorectal angle. Failure to descend at least 1 cm could indicate dyssynergic dysfunction with an inability to relax the pelvic floor muscles during defecation. Rectal prolapse also can be observed during the strain maneuver. A digital rectal examination should be performed to evaluate the tone of the anal sphincter and potential stricture in the anal canal as well as to palpate for rectal masses or fecal impaction. During the examination, the puborectalis muscle is palpated along the posterior aspect of the rectum. Tenderness along this area may indicate pelvic floor spasm. Additionally, the patient is asked to squeeze as if holding in a bowel movement to evaluate the sphincter for increase in tone. A lax sphincter can signify previous trauma or neurologic deficits. After the squeeze exercise, the patient is asked to bear down a second time with the examiner’s finger remaining in the anal canal. As the patient strains, the examiner should feel the anal sphincter relax and again observe the perineum descend.

Testing

Further diagnostic testing is warranted when concern exists for a systemic or structural diagnosis that has not been identified or when a first-line treatment fails, and a thorough understanding of the pathophysiology is needed. Laboratory testing to evaluate thyroid function and to rule out metabolic derangements (such as hypocalcemia, hypomagnesemia, and hyperglycemia) is commonly performed in the patient who does not respond to simple treatment. Hemoglobin levels and inflammatory markers, such as erythrocyte sedimentation rate, can provide clues toward inflammatory or neoplastic disorders.

Any patient of appropriate screening age who presents with constipation and has not undergone colorectal cancer screening should undergo colonoscopy. Double-contrast barium enema or CT colonography are acceptable alternatives that also can identify other structural lesions besides tumors, such as a colonic stricture. Additionally, if warning symptoms are present, such as weight loss, blood in the stool, or family history of colorectal cancer, a colonoscopy should be performed soon. As an adjunct to a structural evaluation, patients with refractory constipation can undergo physiologic testing. Assessment of the rate of colonic transit and objective measures of defecation dynamics can be useful in identifying specific abnormalities, and this can guide treatment.

Colonic motility can be assessed in different ways. Normal colon transit time is approximately 72 hours. A plastic marker study (in which the patient swallows a gel capsule containing 25 radiopaque markers and then has an abdominal X-ray 5 days later to count remaining markers) is a relatively inexpensive and noninvasive method to estimate colonic motility. A more detailed procedure known as a SmartPill study assesses whole gut transit, including the colon, and measures colonic contractions as well. This is accomplished through a capsule swallowed by the patient that collects data on pH, temperature, pressure, and transit time. Patients who report constipation but have a normal colon transit study result are more likely to have symptom features consistent with IBS, such as abdominal bloating and discomfort.

Defecation dynamics can be evaluated with anorectal manometry, balloon expulsion testing, electromyography, and defecography. Anorectal manometry involves inserting a small-caliber catheter through the anal sphincter while the patient is in the left lateral decubitus position. Pressure sensors along the catheter measure anal sphincter resting and squeeze tone. A small balloon is connected to the end of the catheter. Its volume can be controlled to assess rectal sensation. This procedure can reveal features of dyssynergic defecation, rectal hyposensitivity or hypersensitivity, or abnormalities in anal resting or squeeze pressures and can assess for the recto-anal inhibitory reflex. Rectal hypersensitivity frequently is associated with IBS. Spinal arc, or cough reflex, is confirmed by observing short spikes in sphincter pressure with cough. This mechanism prevents fecal incontinence with the increased intra-abdominal pressure that is generated during a cough. In patients with suspected spinal cord deficits, electromyography of the anal sphincter and puborectalis muscle can be performed, but these tests rarely are indicated.

Defecography provides real-time images of defecation and can identify structural abnormalities, such as rectoceles, which can cause functional obstructions of rectal emptying during defecation. The procedure can be somewhat embarrassing for the patient, so it is ordered only when it will provide information that will guide management, such as the decision for surgical repair. During the procedure, thickened barium is instilled into the rectum and the patient is asked to sit on a radiolucent commode. Radiographic images are obtained as the patient defecates the barium. This reveals the ability of the rectum to empty, the degree of straightening of the anorectal angle, and the degree of perineal descent. Prolapse and rectoceles can be identified. Most rectoceles are forward herniations of the anterior rectal wall into the vaginal vault. Generally, they result from trauma during childbirth or episiotomy. Rectoceles also can form when a patient repeatedly strains against a paradoxically contracted anal sphincter. Usefulness of defecographic findings is limited by variation in technique and the radiologist’s interpretation. Dynamic pelvic floor MRI (also called MR defecography) is increasingly gaining favor. It is a noninvasive method of evaluating the pelvic floor muscles in multiple tissue planes with excellent resolution of the associated muscles and ligaments. In addition, the technique avoids ionizing radiation. This technique has been shown to be as good as fluoroscopy in diagnosing rectoceles and prolapse, with the additional advantage of high-resolution imaging 38. However, it is associated with an increased cost and lack of availability in some locations.

Treatment

Reassurance and Behavior Modification

Initial therapy for mild to moderate constipation includes nonmedical interventions of increasing exercise and fluid intake and fiber intake, through either dietary measures or supplementation. Reviewing dietary habits and encouraging the patient to shift toward a low-fat, high-fiber diet are helpful. Dehydration can contribute to constipation, so it is important to ensure adequate fluid intake. Some patients express concern if they do not have a daily regular bowel movement, citing family members’ or friends’ advice or reports from the media. Reassurance that variation in bowel habits is normal, constipation is common, and their symptoms are unlikely to cause harm can help patients overcome these preconceived notions. Another important nonmedical intervention is the encouragement to be vigilant to one’s body signal to defecate and to set aside adequate time for defecation. For example, because the gastrocolic reflex is strongest after the breakfast meal, setting aside unhurried time after breakfast for defecation can be a beneficial intervention.

Fiber

Dietary or supplemental fiber intake has long been a recommended treatment for constipation. For nearly 40 years, fiber has been known to increase stool weight and decrease colonic transit time 39. Fiber intake is helpful in patients with mild to moderate constipation. However, patients with slow-transit constipation, dyssynergic defecation, or severe constipation have little benefit with fiber supplementation. In these patients, fiber can worsen symptoms by creating excessive stool mass and increasing bloating symptoms.

For patients with mild to moderate normal-transit constipation, supplementation with 20–25 g/d of fiber can increase stool frequency and lead to softer stools. It is important to advise patients to increase the fiber supplementation slowly over several weeks until the goal is reached and to drink adequate water with increasing fiber intake. Failure to do so can lead to increased bloating and worsening constipation.

Several types of fiber supplements are available and are summarized in Table 2. Dietary sources such as cereals, fruit, and vegetables are preferred, if tolerated. A randomized 8-week clinical trial demonstrated that dried plums or prunes, ingested twice a day, resulted in more spontaneous bowel movements than twice-daily psyllium supplements (3 g of fiber twice daily provided by each method) 40. Wheat bran also can be added to meals to increase fiber content.

Pharmacotherapy

Several forms of laxatives are available for the treatment of constipation. Each generally works in one of two ways: 1) through osmotic mechanisms or 2) by stimulation. Osmotic laxatives work by drawing fluid into the intestinal lumen, thus softening stool and increasing frequency of defecation. Polyethylene glycol (PEG-3350) is a metabolically inert substance that binds water molecules. It passes through the intestinal tract unaltered. This compound, mixed in a solution with electrolytes, often is administered in large amounts for colon lavage preparation for colonoscopy. Generally, a dose of 17 g of polyethylene glycol powder dissolved in 120–180 mL of noncarbonated beverage once a day is a starting point for therapy. The dosage frequency and amount can be titrated as needed to achieve frequent stools. Polyethylene glycol solution is the laxative of choice in pregnancy and is considered safe 41. When colonoscopy is indicated in pregnant individuals, polyethylene glycol solution is the recommended option for bowel preparation 42. Other osmotic laxatives include nonabsorbable saccharides, such as lactulose and sorbitol. Lactulose, a synthetic disaccharide, and sorbitol, a sugar alcohol frequently used as an artificial sweetener, are not absorbed in the GI tract; thus, they allow osmotic passage of water into the colonic lumen. Sorbitol and lactulose are associated with more frequent adverse effects, such as abdominal bloating and discomfort, than polyethylene glycol. Finally, poorly absorbed ions, such as magnesium, sulfate, and phosphate compounds, create a hyperosmolar colonic environment, thus promoting water transfer into the lumen. Examples of these laxatives include magnesium hydroxide, magnesium sulfate, and sodium phosphate. Such laxatives must be used with caution in patients with renal or cardiac disease.

Stimulant laxatives alter intestinal ion transport and help increase colonic motility. Two categories exist: 1) anthraquinones (eg, aloe and senna), and 2) diphenylmethane derivatives (eg, bisacodyl). Stimulant laxatives, by nature of their mechanism of action, can cause abdominal cramping and, occasionally, diarrhea. They are useful for occasional constipation and are mostly available over-the-counter. Despite early theories, they do not seem to be associated with adverse effects on colonic motility if used over the long term.

Stool softeners and surfactants frequently are used by patients, but little data are available to support their efficacy. Docusate sodium is a surfactant that acts by decreasing the surface tension of stool, thus allowing an increased amount of water to mix with it. Docusate has been shown to be inferior compared with psyllium in improving stool frequency and form in patients with chronic idiopathic constipation 43. Mineral oil has been used in the past because it becomes emulsified into the stool, thus softening and lubricating it. However, its use is markedly limited because long-term ingestion can lead to fat-soluble vitamin deficiency and anal seepage.

In the past decade, new agents with alternative mechanisms of action have been introduced to the market. Lubiprostone is a chloride channel activator that increases intestinal fluid secretion and is approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic idiopathic constipation, constipation-predominant IBS, and opioid-induced constipation. In randomized double-blind clinical trials, lubiprostone has shown significant improvements in the number of spontaneous bowel movements and in stool consistency and straining for the duration of therapy 44. Subsequent open-label trials showed symptom improvement in patients who took it for more than 1 year. Most participants in the lubiprostone clinical studies were women 45 46. Linaclotide and plecanatide are guanylate cyclase C receptor activators, and both are approved for chronic idiopathic constipation and constipation-predominant IBS. Guanylate cyclase C receptors reside on the luminal border of intestinal epithelial cells and, when activated, result in cell-signaling cascades that in turn result in an increase in luminal chloride and bicarbonate secretion, which leads to increased fluid secretion and increased intestinal transit. As a result, concentrations of extracellular cyclic guanosine monophosphate increase. This is thought to help diminish visceral hypersensitivity, which may partially explain beneficial effects of linaclotide on IBS 47. Prucalopride was approved by the FDA in 2018; it improves colonic motility by activating the serotonin type 4 receptor.

Suppositories, such as rectal bisacodyl, can be helpful not only by delivering medication but by the digital stimulation of the rectum. Glycerin suppositories also can be useful by the latter mechanism and provide some lubrication for stool. Patients with fecal impaction often require manual disimpaction followed by administration of a tap-water or mineral-oil enema. The entire colon can be evacuated with the use of 4 L of polyethylene glycol–electrolyte solution typically used for bowel preparation before colonoscopy. Patients are encouraged to drink the solution slowly while they continue to undergo daily tap-water or saline enemas for 1–3 days. Sodium phosphate enemas, although effective, should be avoided in older patients because hyperphosphatemia and hypocalcemia can result if the enema is retained too long. After the colon is cleared of stool, a daily regimen of polyethylene glycol solution, lactulose, or sorbitol should be considered to help prevent stool buildup. Patients should be encouraged to visit the restroom after meals to attempt regular bowel movements. Bisacodyl can then be used as needed if osmotic laxatives fail to produce regular bowel movements. Bedridden older patients may need to undergo the occasional bowel cleansing as described previously. They may even require delivery of a polyethylene glycol solution through a nasogastric tube for colonic lavage if their mental status precludes them from drinking the solution. After improvement has been noted, regular administration of an enema once or twice a week, in addition to a daily osmotic laxative regimen, may help prevent recurrence of impaction. Table 3 summarizes medications used to treat chronic constipation.

For patients who have pelvic floor dysfunction, such as in dyssynergic defecation, pelvic floor physical therapy with or without anorectal biofeedback can improve symptoms of constipation in nearly 70% of patients 35. Before a referral to a pelvic floor physical therapist, patients should undergo anorectal manometry to identify particular abnormalities, such as paradoxical anal sphincter contraction with strain or rectal hypersensitivity. It is important to refer patients to experienced therapists who are knowledgeable of pelvic floor retraining and biofeedback therapy. Insurance coverage for this treatment varies. Success also is based, in part, on the patient’s adherence to therapy.

Occasionally, alternative measures are undertaken in severe, debilitating constipation. Patients with spinal cord injuries in whom conservative measures fail often benefit from a cecostomy, in which a permanent or intermittent catheter inserted through a stoma in the skin, through the GI tract, and into the cecum serves as an access point. Polyethylene glycol solution or other medications can be instilled directly into the colon, in a fashion known as an anterograde continent enema. Surgery is an option for patients with severe, incapacitating refractory constipation. Surgical options include total colectomy with ileorectal anastomosis, subtotal colectomy with primary anastomosis, or partial or full colectomy with creation of a stoma. Patients must meet strict criteria to be considered for surgery. These include:

• objective studies that demonstrate slow-transit constipation

• severe, refractory, chronic symptoms that are detrimental to quality of life (such patients often have a bowel movement as infrequently as once every 3–4 weeks only with the help of enemas or other maneuvers)

• no evidence of intestinal obstruction or pseudo-obstruction by radiographic or manometric testing

• in patients who will likely undergo anastomosis, no evidence of pelvic floor dysfunction on anorectal manometry

Surgery can result in substantial changes in bowel behavior, including increased stool frequency. Surgery may not improve bothersome symptoms, such as abdominal bloating and discomfort, which occur in patients with overlapping IBS or functional GI disorders. As such, surgical candidates should be in good psychologic health, because surgery tends to yield poor results in individuals with psychologic disorders.

Diarrhea

Diarrhea is a common symptom that every human experiences at some point in his or her life. It is the second most common GI symptom that prompts an outpatient clinic visit, abdominal pain being the most common symptom 48. Most episodes of diarrhea are acute and self-limited. However, diarrhea can be life-threatening at times, especially in patients who are immunocompromised, older, or have multiple comorbidities. Most acute diarrheal illnesses are infectious in nature. Symptoms that last more than 4 weeks approach a subacute to chronic diarrhea, and at this point alternative diagnoses should be sought. Chronic diarrhea can have long-term consequences, such as malabsorption, dehydration, and weight loss.

Diarrhea, like constipation, can be defined differently by patients, based on their own perspectives of normal bowel habits. For consistency, the general medical definition of diarrhea is three or more bowel movements a day and stool weight over 200 g. This can be altered in patients who consume a high-fiber diet.

Diarrhea can be classified in many ways, such as acute versus chronic, osmotic versus secretory, and watery versus inflammatory. As one might expect, not all disorders fit neatly into one category versus another, but these general classifications can provide diagnostic clues as to the underlying etiology. Acute diarrhea usually is caused by infectious agents. This type of diarrhea usually resolves with conservative management or is easily treated with antimicrobial therapy when needed. Diarrhea that persists longer than 4 weeks suggests a noninfectious cause, such as an underlying inflammatory disorder or medication adverse effect. However, some organisms can cause chronic diarrhea, such as Giardia lamblia, Yersinia species, and Tropheryma whipplei. Box 7 provides a summary of infectious causes of diarrhea.

Osmotic diarrhea results from the ingestion of poorly absorbed ions and other substances, such as mannitol, sorbitol, or magnesium. Lactase deficiency is a common cause of osmotic diarrhea, because of the presence of undigested lactose (see discussion in the section “Lactose Intolerance”). Characteristically, diarrhea of osmotic etiology ceases with fasting or stopping ingestion of the inciting agent. Secretory diarrhea occurs by one of two ways: 1) net secretion of anions into the gut lumen (chloride or bicarbonate) or 2) inhibition of net sodium absorption. The colon absorbs water by actively absorbing sodium ions. If sodium absorption is altered, water absorption also is affected. Infectious microbes producing enterotoxins that affect sodium absorption are a common cause of secretory diarrhea (such as in the case of cholera). Neuroendocrine tumors can secrete peptides that stimulate intestinal secretion. Various medications or toxins and endogenous neurotransmitters, such as histamine and acetylcholine, can increase secretion. Secretory diarrhea also can result from epithelial injury, which leads to a decreased absorptive surface area, such as in the case of IBD or celiac disease. Short bowel syndrome caused by intestinal resection can cause secretory diarrhea by removal of a large portion of the absorptive surface of the intestine. Some neuropathic disorders can cause rapid intestinal transit by decreasing the exposure time of luminal fluid to the bowel epithelium, thus decreasing absorption. Neuropathy from diabetes mellitus or vagotomy can affect intestinal transit time.

Characterizing diarrhea as watery or inflammatory can give clues as to what types of organisms (if infectious) may be involved and which segments of the bowel are affected. Large-volume, watery diarrhea implies a defect in water absorption (either by an osmotic or secretory means) and generally points to an abnormal process in the small bowel or right colon. The rectosigmoid region of the colon acts as a storage reservoir. When the mucosa of this area is inflamed, it loses its compliance and ability to hold stool until defecation. Inflammation in this area results in small-volume, frequent stools. In addition to small frequent stools, inflammatory diarrhea often is associated with abdominal cramping, fever, and presence of blood in the stool from ulceration of the colonic mucosa. Box 8 includes a list of causes of diarrhea according to descriptive type.

Treatment

Supportive Care

The cardinal principle of diarrhea treatment is replacement of fluid and electrolytes. Iso-osmotic oral solutions, particularly rice-cereal-based rehydration solutions, are the oral rehydration solutions of choice. Water absorption from the gut is a passive process and is based on the absorption of sodium, glucose, or amino acids by the enterocytes. Rehydration solutions that contain these substances will enhance water absorption. Hyperosmolar solutions can increase diarrhea. Sports drinks do not contain enough sodium to improve water absorption and must be supplemented with additional sources of sodium, such as salty crackers or addition of table salt to the beverage. It is important to remember that ingestion of oral rehydration solutions does not decrease stool output and that diarrhea may even increase temporarily. The goal of rehydration is not to reduce diarrhea but to replace the net fluid loss that occurs. Patients who are unable to tolerate oral rehydration because of concomitant vomiting or who need rapid rehydration will benefit from intravenous hydration with iso-osmotic crystalloid solutions.

Medical Therapy

The decision to use antibiotic therapy in suspected infectious diarrhea is based on the clinical situation. Antibiotics often are administered empirically, even when an infectious agent has not been identified. This is a reasonable consideration in various situations; for example, when a patient has developed likely traveler’s diarrhea. Typically, rifaximin or a fluoroquinolone is given. If patients are ill enough to be hospitalized for fluid resuscitation, antibiotics can be administered while waiting for stool culture results. Often, antibiotics can shorten the course of diarrhea and decrease the duration of shedding of the organism in stool. A notable concern regarding antibiotic use and diarrhea is in eradication of Escherichia coli O157:H7 and other strains that are associated with the development of hemolytic uremic syndrome. This organism produces a toxin (a type of Shiga toxin) that produces microvascular inflammation, which leads to microvascular thrombi. This can lead to renal failure and brain edema. It presents as a triad of acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. Confusion can develop as the disease progresses. The mortality rate of hemolytic uremic syndrome is up to 5%, and 5–10% of patients can have permanent renal injury, requiring lifelong dialysis or renal transplant, or permanent neurologic sequelae 49. Many studies have shown an increased risk of the development of hemolytic uremic syndrome in patients infected with E coli O157:H7 when given antibiotics, although not all studies concur. The overall risk of developing hemolytic uremic syndrome in the presence of E coli O157:H7 infection is 15%, but it increases to as high as 50% when antibiotics are administered 50. Whether this finding represents a true association or is the result of other unidentified confounding factors is unclear. However, given the concern, antibiotics are encouraged to be avoided when suspicion for this strain is high.

Antimotility agents generally are safe to use in the treatment of acute and chronic diarrhea, even in the setting of most infections. Opiates, such as loperamide and diphenoxylate with atropine, can reduce stool frequency, improve stool form, and improve abdominal cramping. Some clinicians advise against their use in treatment of infection because these agents delay clearance of pathogens. However, no clear evidence exists to substantiate this claim. An exception is in the case of acute severe inflammatory colitis, during which anti-motility agents should be avoided. Loperamide is a preferred first-line agent because it does not cross the blood–brain barrier; therefore, potential CNS adverse effects are avoided. Loperamide also is known to increase anal sphincter tone, which can be helpful in patients prone to fecal incontinence.

Therapy for chronic diarrhea is used to accomplish one of two goals: 1) to provide relief while investigating the cause of symptoms or 2) to provide relief when no specific diagnosis is reached or if the diagnosis has no therapy. When a specific cause is found, appropriate therapy can be applied. For example, patients found to have pancreatic exocrine insufficiency are treated with oral pancreatic enzyme replacement. This resolves steatorrhea and improves fat-soluble vitamin absorption. Patients with microscopic colitis improve with bismuth subsalicylate or delayed-release budesonide, a corticosteroid with minimal systemic absorption. Patients with small-bowel bacterial overgrowth are treated with oral antibiotic therapy followed by initiation of daily oral probiotics to help reestablish a healthy gut microbiome. Those found to have a neuroendocrine tumor are referred for surgical resection, if possible, or can be treated with octreotide, a somatostatin analogue that decreases intestinal fluid secretion and motility and helps to inhibit secretion of peptide hormones. Patients who have undergone a cholecystectomy may benefit from oral bile acid binders, such as cholestyramine. When no specific cause is found, a variety of medications can be used to improve stool frequency and form Table 4 and the discussion in the section “Functional Diarrhea”).

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a functional GI disorder characterized by abdominal pain or discomfort and changes in bowel habits. It is an important clinical entity because of its high prevalence and associated morbidity and economic cost. The worldwide prevalence of IBS is estimated to be 10%. The prevalence may be higher, particularly in the United States, because many patients do not seek medical attention. More than 3.5 million medical visits occur each year as a result of symptoms associated with IBS 3 53. It is important that all clinicians understand IBS, regardless of specialty, because the prevalence of this disorder is so high. At least 12% of patients of primary care physicians have a diagnosis of IBS; it is the most common diagnosis in GI clinics 54. Obstetrician–gynecologists often encounter IBS in their patients, given its increased prevalence in women, the overlapping symptoms experienced with many pelvic disorders, and the tendency of women to see their obstetric–gynecologic providers for primary care.

The prevalence of IBS is higher in young patients; however, it is being increasingly recognized in older patients. The female-to-male prevalence is approximately 2:1 55. Patients with IBS are more likely to have undergone multiple abdominal surgeries, such as appendectomy, cholecystectomy, and hysterectomy, than other patients. It is unclear whether these types of surgeries represent misdiagnosis of IBS, or if IBS is associated with a tendency of certain intra-abdominal pathologies that eventually require surgical intervention. A third possibility is that surgery, such as cholecystectomy, may be associated with an increased risk of developing IBS. The understanding of the pathophysiology of IBS is incomplete, and treatment options remain limited. No disease-specific cure exists, and symptom-targeted therapy is the mainstay of treatment. Although the disease is not associated with increased mortality or cancer rates, the effects of IBS on quality of life can be profound. Patients with IBS have been shown to score at or below those with diabetes mellitus, depression, and chronic renal disease on health-related quality of life assessments 54.

Evaluation

Irritable bowel syndrome is not a diagnosis of exclusion, but rather a distinct GI disorder that is identified by fulfilling specific diagnostic criteria established by Rome IV. In establishing a diagnosis, clinicians must decide whether additional testing is needed to help rule out other disorders that are on the list of differential diagnoses. Specific points of the patient history or physical examination help make such decisions. Warning signs should be evaluated with additional testing and are listed in Box 9. For example, a patient with abdominal discomfort and constipation, who is aged 60 years and has never undergone colorectal cancer screening, should undergo colonoscopy. Given the overlapping symptoms with celiac disease and an increased prevalence of celiac disease in IBS patients, it is reasonable to perform serologic testing to screen for celiac disease in patients with IBS. Many patients are concerned they may have inflammatory bowel disease (IBD). Table 5 summarizes symptom patterns in IBS compared with IBD. One exception to diagnostic testing is in the case of IBS-D, in which a flexible sigmoidoscopy or colonoscopy is reasonable to obtain biopsies to evaluate for microscopic colitis. Likewise, in patients with IBS-C, anorectal manometry may help identify pelvic floor disorders that could improve with physical therapy, thereby improving constipation symptoms. The American College of Gastroenterology has published guidelines regarding diagnostic testing in IBS patients 58. Instances in which diagnostic tests are warranted are listed in Table 6. It is worth mentioning that rectal bleeding, although considered an alarm symptom, can be seen commonly in IBS patients with no associated worrisome diagnoses such as IBD, infectious inflammation, or colonic neoplasia. Often internal hemorrhoids, a solitary rectal ulcer, or anal fissure may cause the bleeding. Although bleeding warrants investigation, the diagnosis of IBS in such patients should not be excluded.

Evaluation

Diagnosis of celiac disease is made by positive serologic markers with the combination of characteristic findings on duodenal biopsies obtained during upper endoscopy. Serologic testing has become an efficient way to screen for the disease and to monitor for treatment response. Levels of antibodies against tissue transglutaminase, gliadin, and endomysium can be measured in the serum. Tissue transglutaminase and endomysium immunoglobulin (Ig) A tests are the most useful because of their high sensitivity and specificity. Of note, up to 3% of patients with celiac disease have IgA deficiency, and thus total serum IgA can be considered for measurement when ordering celiac serologies 69.

Celiac disease can present with a variety of symptoms. The previous notion that patients with celiac disease typically present with diarrhea and weight loss has been rebuked because many patients present with constipation and are overweight. The disease can be clinically silent, with no symptoms. Because symptoms often are vague and overlap with IBS, the disease often is not diagnosed or is diagnosed after prolonged symptoms. Many patients present with disordered bowel habits, including diarrhea, steatorrhea (fatty stool), flatulence, constipation, and bloating because of malabsorption. These symptoms tend to occur intermittently and are not consistent. Frequently, patients report morning and postprandial diarrhea and, unlike patients with IBS, often experience bowel movements at night. Weight loss can occur secondary to malabsorption, but often patients keep up with caloric intake through diet, and weight loss may be minimal. In severely malnourished patients, weight loss may not be recognized because of edema associated with hypoproteinemia. Regardless of nutritional status, fatigue and general malaise are common symptoms. Other GI symptoms, such as nausea and vomiting or severe abdominal pain, are rare. Aphthous stomatitis can occur frequently and, in many patients, may be the only presenting sign.

Celiac disease can present with a host of extraintestinal signs and symptoms. When other symptoms occur in the absence of GI symptoms, the diagnosis can be difficult. Dermatitis herpetiformis is a pruritic vesiculopapular rash that involves the extensor surfaces of the upper and lower extremities and buttocks bilaterally, as well as the trunk, neck, and scalp. It occurs in approximately 2–15% of patients with celiac disease, depending on the study 70 71 72, and may occur in the absence of intestinal pathology. For some, it can be the only presenting symptom. Apart from this distinct clinical entity, most extraintestinal manifestations, however, are the result of malabsorption. For example, anemia caused by iron, folate, vitamin D, or vitamin B₁₂ deficiencies can occur. Menstrual irregularities can be present as well. Vitamin B₁₂ and thiamine deficiencies can lead to neurologic sequelae, such as peripheral neuropathy and ataxia. Osteopenia caused by calcium and vitamin D malabsorption is an important concern for patients with celiac disease. These patients have been shown to have lower bone mineral density measurements than controls 73. Women with celiac disease are at an increased risk of osteopenia or osteoporosis because of the potential for early menopause and amenorrhea, which are themselves risk factors for decreased bone mineral density (BMD) 74. These derangements in menstrual regularity also can lead to fertility problems. Celiac disease has been associated with difficulty becoming pregnant and with spontaneous abortion 75. Infertility may be the presenting sign of the disease. Once on a gluten-free diet, such patients often can become pregnant. Silent celiac disease has been reported with spontaneous abortion and fetal growth restriction. Male fertility also can be affected by celiac disease, with low sperm counts or impotence in patients with untreated disease. Also, it is important to note that celiac disease is associated with a host of other autoimmune disorders. These include diabetes mellitus type I, thyroid derangements, IgA deficiency, microscopic colitis, and IBD.

Findings on physical examination vary widely. A physical examination can yield completely normal results, or patients may show signs of malnutrition. Such signs include emaciation, edema from hypoproteinemia, finger clubbing caused by iron deficiency anemia, and dry skin. Aphthous stomatitis and cheilosis at the angles of the mouth may be appreciated. The enamel of the teeth may be affected. Abdominal tenderness is uncommon, but the abdomen can be distended and tympanic because of distended bowel loops. Neurologic examination may reveal sensory deficits in the extremities that result from neuropathy. Skin lesions suggestive of dermatitis herpetiformis might be observed. Patients with celiac disease also can be found to have abnormal hepatic transaminase findings that normalize with treatment.

Given the relatively high prevalence in the population and symptom overlap with IBS, which is very common, clinicians should have a low threshold for screening for the disease. The following patients should be considered for testing:

• those with chronic GI symptoms of diarrhea, abdominal discomfort or bloating, and weight loss, including those with symptoms that meet the criteria for IBS

• those who have signs or symptoms that can be explained by malabsorption, without clear explanations for the findings, including patients with iron deficiency anemia, folate deficiency, vitamin B₁₂ deficiency, neurologic sequelae (including peripheral neuropathy or ataxia), fertility problems, aphthous stomatitis, dental enamel abnormalities, and abnormal liver transaminase levels

• patients with dermatitis herpetiformis or high-risk factors, including concomitant autoimmune diseases and family history of celiac disease

Management

It is important to establish a diagnosis before attempting empiric treatment with a gluten-free diet. The levels of tissue transglutaminase and endomysial antibodies begin to normalize within the first few months of gluten elimination. Diagnostic testing after a patient has made dietary changes may lead to a false negative result. It is important to affirm or rule out the diagnosis accurately because lifelong adherence to a gluten-free diet is not easy. Gluten-free diets are expensive, and adherence when eating in social situations can be difficult. Once a diagnosis is established, patients are instructed to totally eliminate gluten from their diet. This includes all wheat, rye, barley, and, initially, oats (because of potential cross-contamination in processing). Malt also is to be avoided, unless it is derived from corn. Patients are instructed to scrutinize food labels for items marked “gluten-free.” In order to attain this distinction, the food product must contain less than 20 ppm of gluten. Beer, unless clearly marked as gluten-free, also needs to be avoided. Medications, herbal supplements, and vitamin supplements can contain gluten, so patients should check with their pharmacists and pharmaceutical makers to verify the gluten content. It is best to limit milk and other dairy products initially to avoid overlapping symptoms with lactose intolerance. Once GI symptoms improve, lactose can be added back to the diet.

Consultation with a nutritionist skilled in celiac disease is ideal. Patient education regarding gluten avoidance, especially hidden gluten, is essential. Nutritional deficiencies should be assessed and treated. Patients should undergo iron, vitamin D, vitamin B₁₂, and folate studies. If a patient has vitamin D deficiency, it is reasonable to measure the levels of other fat-soluble vitamins—vitamin A, vitamin E, and vitamin K. Once in remission, most patients tolerate addition of moderate amounts of oats back into the diet, up to 2 ounces per day. However, one must carefully consider where the oats are obtained. Oats and oat products in grocery stores often are processed alongside wheat products, which may cause cross-contamination. Part of thorough nutritional counseling involves not only gluten avoidance but ensuring adequate intake of nutrients because the gluten-free diet often is low in iron, vitamin D, vitamin B₁₂, calcium, and dietary fiber. Given the association with decreased BMD, all patients are recommended to undergo BMD testing within a year after diagnosis. Bone mineral density should then be monitored every 1–2 years. Patients with progressive bone loss despite adequate calcium and vitamin D supplementation should be considered for bisphosphonate therapy. Patients must be counseled regarding the weight gain that is likely to follow resolution of histologic inflammation and encouraged to avoid high-fat, high-calorie processed food alternatives.

The rate of improvement in GI symptoms after initiation of the diet varies, but patients can experience relief within the first week. Up to 70% of patients notice improvement within 2 weeks 69 76. Patients whose signs, symptoms, or laboratory results do not improve by 6 months of diet modification are said to have refractory disease, and warrant re-evaluation.

Adherence to a gluten-free diet is difficult, and surreptitious ingestion of gluten is common. Therefore, much research is underway to identify alternative therapies to induce remission and perhaps cure the disease. Mechanisms of potential treatment include enzyme supplementation for gluten digestion, modulation of the immune system, and induction of tolerance to gluten with immunotherapy 69 77.

Crohn Disease

Crohn disease differs from ulcerative colitis in that it can affect areas along the entire length of the GI tract, from the mouth to the anus. Inflammation typically is not continuous; “skip” areas of unaffected mucosa are common. The most common sites of involvement are the terminal ileum, ileocecal valve, and cecum. Thirty percent of patients have isolated colonic disease, known as Crohn colitis 86. Isolated upper GI Crohn disease is rare. Endoscopically, aphthous ulcers are seen. They are small superficial ulcers, up to 3 mm in size, surrounded by a ring of erythema. They are an early sign of disease and also can occur in the mouths of affected patients. At the tissue level, Crohn disease exhibits transmural inflammation, which penetrates all layers of the bowel wall. Because of this, fistulas can form between affected bowel loops or other structures, such as the skin, bladder, uterus, vagina, and even the stomach. Perianal fistulization is common. Continued inflammation can lead to intestinal strictures, which can be inflammatory, fibrotic, or both. Histologically, mucosal inflammation is seen, with cryptitis and crypt abscesses. Signs of chronic relapsing injury, such as crypt architectural distortion, are observed in prolonged disease and are identified by branching of the epithelial crypts. Noncaseating granulomas can be seen on biopsy specimens of patients with Crohn disease. This is not observed in ulcerative colitis and can be helpful, when identified, in distinguishing the two forms of IBD.

Patients with Crohn disease can have subtle or severe symptoms and signs. Often, patients report intermittent attacks of diarrhea, fever, and abdominal pain and will note intervening asymptomatic periods. They may describe flares that are exacerbated by stress or NSAID use. Prolonged disease is associated with weight loss caused by malabsorption from intestinal inflammation and a chronic inflammatory state. Patients can have iron deficiency anemia; vitamin B₁₂ deficiency, folate deficiency, or both; and hypoproteinemia. They can present with obstruction caused by intestinal strictures or intestinal perforation caused by penetrating inflammation. Esophageal and gastroduodenal Crohn disease can cause upper GI symptoms of heartburn, odynophagia, dyspepsia, and epigastric pain. Upper GI disease usually indicates a complicated form and warrants aggressive therapy.

Crohn disease tends to take on one of three phenotypes: 1) aggressive fistulizing disease, 2) fibrostenotic disease from relapsing and healing, and 3) indolent inflammatory disease. The three are not mutually exclusive and the disease in a patient can change forms over time. The first form is very distressing for patients because intra-abdominal fistulae, perianal fistulae, and intra-abdominal abscesses are difficult to manage. Severe inflammation in the rectum can lead to a rectovaginal fistula. Patients who have had a hysterectomy are at an increased risk of rectovaginal fistulae. Approximately one fourth of patients with Crohn disease will develop an intra-abdominal abscess at some point in their lives 86. Typically, these abscesses result from inflamed serosa that adheres to an adjacent unaffected serosal surface or a small perforation with abscess formation around the site of a previous anastomosis.

Strictures can occur anywhere along the GI tract where inflammation has been present. Typically, they recur at anastomosis sites and at the terminal ileum. Generally, they do not cause symptoms until the luminal diameter becomes small enough to cause obstruction. Strictures can be caused by intraluminal narrowing from inflammation or by fibrostenosis. Inflammation may respond to medical therapy, but fibrostenosis requires surgical resection.

In addition to the GI symptoms, extraintestinal manifestations are common and occur in up to 25% of patients with Crohn disease 87. Many complications are related to the pathophysiology of the disease itself. Bile salts are absorbed in the terminal ileum for recycling into the enterohepatic bile salt circulation. Disrupted bile salt circulation can lead to derangements in calcium absorption and cholesterol metabolism. As a result, patients have an increased incidence of nephrolithiasis caused by oxalate malabsorption and cholelithiasis with cholesterol stones. Osteopenia and osteoporosis are common in patients with Crohn disease. Malabsorption of calcium and vitamin D and the effects of proinflammatory cytokines on osteoclasts contribute to bone loss. Treatment with corticosteroids increases this risk further. Other common extraintestinal manifestations are rheumatologic symptoms. Commonly, joint and musculoskeletal pain waxes and wanes with disease flares. Ankylosing spondylitis and sacroiliitis can occur. Other autoimmune conditions, such as erythema nodosum and uveitis, can develop. Pyoderma gangrenosum can occur in patients with Crohn disease and is often present without an associated intestinal flare. Patients with Crohn disease also are at risk for vascular thrombosis.

Ulcerative Colitis

Ulcerative colitis is limited to the colon, and inflammation affects only the mucosa and submucosa. The key features that differentiate ulcerative colitis from Crohn disease are summarized in Table 7. In ulcerative colitis, involvement always begins at the rectum and moves proximally. No skip lesions or isolated areas spared of the disease are present. The small intestine is normal, but the terminal ileum can be inflamed in 10% of patients as a result of what is termed “backwash ileitis.” Continued superficial ulceration with healing leads to raised lesions in the colonic mucosa known as inflammatory pseudopolyps. Histologically, the appearance is similar to Crohn disease, with cryptitis, crypt abscesses, and architectural distortion. Granulomas are not seen, but their absence does not differentiate between ulcerative colitis and Crohn disease. Submucosal fibrosis and mucosal atrophy occur and, on endoscopy, the colon may take on a “lead pipe” appearance over time as a result.

Patients with ulcerative colitis generally present with diarrhea, lower abdominal pain and cramping, and bloody mucoid diarrhea. Initially, infection usually is suspected, but when symptoms last more than 4 weeks, ulcerative colitis should be high on the differential diagnosis list. Some patients with isolated rectal inflammation (known as proctitis) will present with constipation. In cases of severe inflammation, toxic megacolon can develop in which the colon becomes abnormally dilated, colitis is present, and the patient appears toxic. A concern for perforation exists in this case, and therefore surgical resection is indicated 95. Strictures can occur in patients with ulcerative colitis because of prolonged inflammation but rarely cause complications. If a stricture is found in a patient, a high index of suspicion for underlying malignancy should prompt further evaluation with endoscopic biopsy and radiologic imaging.

Management

As with Crohn disease, the goal of therapy is to induce and maintain remission. Table 8 reviews medical therapy for IBD, indicating agents that are specific to ulcerative colitis versus Crohn disease. As in Crohn disease, treatment decisions are based on the needs of the individual patient in the setting of professional society guidelines 95. In patients with disease limited to the sigmoid colon and rectum, topical 5-aminosalicylates can be effective. Likewise, topical steroid suppositories or foam enemas can have the same effect. Also, they can be used in conjunction with systemic therapy in patients with bothersome symptoms of proctitis, such as rectal bleeding and tenesmus. Suppositories with 5-aminosalicylates are available for rectal disease up to 20 cm from the anal verge; enemas can be used and are able to deliver medication up to the level of the splenic flexure when used properly. Patients with ulcerative colitis respond to corticosteroids and immune modulators, such as azathioprine and 6-mercaptopurine. Methotrexate monotherapy is not effective against ulcerative colitis. Additionally, an oral delayed-release formulation of budesonide is available for mild to moderate ulcerative colitis. Cyclosporine is indicated in hospitalized patients with severe disease who do not respond to IV steroids. However, it cannot be used for long periods and generally is considered a bridge before initiation of other medical therapy or colectomy. Its use must be monitored closely, given the associated risk of nephrotoxicity and neurologic sequelae. Several biologic agents, including TNF-α inhibitors, an anti-integrin antibody, and an anti-IL 12/23 agent, have been approved for the treatment of patients with ulcerative colitis. Most recently, in 2018 the FDA approved an oral Janus kinase inhibitor, tofacitinib, for induction and maintenance of remission. See Table 8 for a summary.

Patients with ulcerative colitis should be referred for surgery when they have uncontrollable colonic hemorrhaging, perforation, severe medically refractory disease, or suspected or documented colonic carcinoma. Unlike in Crohn disease, surgery is technically curative because complete colectomy is performed. Multiple surgical options exist, and they need to be discussed in detail with patients before surgery. If surgery is emergent or urgent because of perforation or hemorrhage, usually the rectum is left in place with formation of an ileostomy so that future bowel restoration remains an option. Frequently, either a total proctocolectomy with permanent ileostomy or ileal pouch–anal anastomosis is performed. In the latter, a “neorectum” is constructed out of a J-shaped ileal pouch and anastomosed to the anus. Ileal pouch–anal anastomosis is the most frequent colectomy procedure performed for ulcerative colitis. However, complications, such as inflammation of the pouch, arise in approximately 50% of patients at some point and may require long-term medical therapy 98. These complications include acute and chronic pouchitis, abscess, or anastomotic stricture. The pouch also can be inflamed as a result of Crohn disease, which may have been misdiagnosed as ulcerative colitis initially.

Implications for Colorectal Cancer

The increased risk of colorectal cancer in patients with ulcerative colitis is well established. Patients with Crohn disease also are at an increased risk if the disease affects the colon. Additional factors increase the risk even further. These include a family history of colon cancer, early age at diagnosis, severity of inflammation, and a personal history of primary sclerosing cholangitis, an autoimmune liver disease that is frequently associated with ulcerative colitis. The incidence of colorectal cancer increases with duration of disease. The risk of colorectal cancer is up to 20% after 20 years of disease 95. The risk begins to increase after 8–10 years of colitis, and increased colorectal screening is recommended. Screening colonoscopy is performed every 1–3 years after 8 years of colitis. During the procedure, multiple biopsy samples are obtained in systematic fashion to evaluate for dysplastic changes in colonic mucosa. Abnormal lesions are biopsied separately. New endoscopic imaging techniques allow targeted biopsies of mucosa that appears subtly abnormal and that might harbor dysplasia. Any discrete area of dysplasia should be completely resected endoscopically, and more frequent surveillance should be performed thereafter. Dysplasia that cannot be resected endoscopically, or that is multifocal, is indication for colectomy. The challenge arises in differentiating typical sporadic adenomatous polyps from IBD-associated dysplasia. Endoscopic polyp removal and mucosal resection techniques are being continually revised to help patients avoid colectomy in cases of dysplasia.

Special Concerns for Women

The female patient with IBD warrants special consideration because of multiple factors. Many individuals receive the diagnosis in their high school or college years, when social interaction and body image are important. Inflammatory bowel disease can affect sexual health at all ages because increased stool frequency, fecal incontinence, perianal involvement of Crohn disease, and dyspareunia from regional inflammation can affect sexual activity. The hormonal fluctuations associated with menstrual cycles can affect GI symptoms, most notably diarrhea, abdominal discomfort, and weight gain. Contraception must be addressed in patients of childbearing age. Unintended pregnancy during disease flares can have deleterious consequences for the patient and the fetus. Family planning, as discussed later, is very important because pregnancy outcomes are better when IBD is in remission than when it is active.

The use of oral contraceptives (OCs) is a concern for patients and must be addressed with their gynecologist and gastroenterologist. Generally, OCs are absorbed in the small bowel; this can be compromised in a small bowel affected by Crohn disease. Additionally, patients with IBD have a twofold risk of vascular thrombosis, and this raises a concern for patients taking combined hormonal OCs. It is unknown whether the increased risks of vascular thrombosis associated with combined hormonal OCs and the increase associated with IBD is cumulative in patients with IBD on this therapy. In patients with marked active disease, recent surgery, or evidence of malnutrition, it is thought that the risks of OC therapy (and contraceptive patches and rings) might outweigh the benefits. However, in patients with IBD with controlled or mild disease, the benefits of OC therapy may prevail. In addition to birth control, OCs can help regulate GI symptom fluctuations related to the menstrual cycle 99.

The immunosuppressants used for IBD treatment have been associated with increased rates of solid tumors, although no increased risk of gynecologic types of cancer has been clearly established. Nonetheless, physicians who provide care to patients with IBD must ensure their patients have had all recommended health maintenance screening tests, including HPV vaccination. Cervical cancer screening and breast cancer screening at regularly recommended intervals are important aspects of continued care in patients with IBD. Data have been mixed regarding whether IBD patients have a higher incidence of abnormal Pap test results 100. Because of this, it is recommended that IBD patients should be screened for cervical cancer per the current recommendations for the general population, with special attention to patients who smoke or receive considerable immunosuppressive therapy. In addition, given the known association with human papillomavirus, vaccination for this virus should be discussed with patients who meet the criteria for vaccination 100. Patients who take immunosuppressant therapy should undergo yearly skin examinations for mole surveillance, given an increased risk of nonmelanoma skin cancer. As mentioned previously, the potential for osteoporosis must receive continued and diligent attention. Derangements in calcium and vitamin D absorption, a chronic inflammatory state, and use of corticosteroids all contribute to the development of osteopenia and osteoporosis. Patients with IBD are recommended to undergo BMD assessment in accordance with recommendations for the general population, with special considerations for earlier screening in patients with exposure to glucocorticoids for 3 consecutive months at a dosage of 7.5 mg or greater per day of prednisone or equivalent 101. Given the increasing array of medications available to treat osteoporosis, the concerns of adverse effects of bisphosphonates (such as esophagitis and osteonecrosis of the jaw), and the concerns of nephrolithiasis, it is reasonable to involve an endocrinologist in managing patients with IBD with bone disease.

Fertility and pregnancy present many concerns to female patients with IBD. Inflammatory bowel disease itself has not been shown to decrease fertility. However, some treatments require careful consideration. Male fertility can be reduced by treatment with sulfasalazine. Sulfasalazine has been associated with reduced sperm counts and decreased sperm motility in male patients with IBD. This finding reverses within approximately 2 months with cessation of the medication. The other 5-aminosalicylates, such as mesalamine, do not appear to have this effect 99. Colectomy for ulcerative colitis has been shown to affect fertility rates. Ileal pouch–anal anastomosis has been associated with a threefold increase in infertility rates 99. This surgery may cause scarring that prevents proper release of the egg from the fallopian tube into the uterus. Decrease in fertility is lessened with laparoscopic surgery, but still a concern. This effect is not seen with total colectomy with end ileostomy. However, most patients with a history of ileal pouch–anal anastomosis are able to achieve pregnancy by in vitro fertilization. The success rate of in vitro fertilization in patients with IBD is similar to that of the general population 99.

Fecal incontinence is another potential adverse effect of ileal pouch–anal anastomosis, especially in the first year after surgery. One study revealed that 20% of women experienced dyspareunia or fecal incontinence during intercourse during a 3-year follow-up after surgery 102.

Three issues arise during pregnancy in patients: 1) the effect of IBD on pregnancy, 2) the effect of pregnancy on IBD, and 3) the safety of IBD medications in pregnancy and lactation. The status of IBD at the beginning of the pregnancy determines IBD-related outcomes of pregnancy. Patients in remission at the beginning of pregnancy generally have the same rates of spontaneous abortion, pregnancy-related complications, and adverse outcomes as do individuals of the general population. People who become pregnant during active disease are more likely to experience preterm birth, low birth weight, and fetal loss 103. In regard to pregnancy effects on disease activity, the general pattern is that the status of disease at the beginning of pregnancy tends to remain constant throughout pregnancy. If the disease is in remission at the beginning of pregnancy, it tends to stay in remission, with a rate of relapse similar to nonpregnant patients, especially if therapy is continued during pregnancy. Active disease at the beginning of pregnancy can be resistant to treatment. The presence of ileal pouch–anal anastomosis should not alter the decision to undergo vaginal delivery versus cesarean delivery. Likewise, the presence of a colostomy or ileostomy should not influence delivery decision. Pouch function in ileal pouch–anal anastomosis, fecal continence, and quality of life have not been shown to be adversely affected by uncomplicated vaginal delivery.

The American Gastroenterological Association has published a detailed clinical care pathway for management of the pregnant patient with IBD, including prepregnancy planning and care of the postpartum patient and infant 104. These guidelines are a valuable resource for the obstetrician and gastroenterologist who are navigating the complex care of the pregnant IBD patient. The guidelines include specific recommendations regarding assessment of disease activity before a pregnancy, monitoring nutrition status, medication management before, during, and after pregnancy, and considerations for delivery methods.

Much attention has been drawn to the safety of IBD medications in pregnancy. The general consensus is that risks of active disease in pregnancy outweigh adverse effects of medications. Although mesalamine crosses the placental barrier, generally, 5-aminosalisylates are considered safe in pregnancy. One formulation of delayed-release mesalamine contained a compound in its coating found to be associated with urogenital defects in male offspring born to exposed rats 105. This formulation was removed from the market in 2013. Patients who take sulfasalazine should take 800–1,000 micrograms of folic acid daily because sulfasalazine can cause folate deficiency through inhibition of dihydrofolate reductase. Corticosteroids, including budesonide, are considered safe in pregnancy and can be used acutely in disease flares. Prednisolone does not cross the placental barrier as readily as prednisone, so it should be considered instead. The risk of adverse events is low, but a mild increase in cleft lip or cleft palate risk in newborns has been reported when corticosteroids were used in the first trimester 106.

In contrast to the general safety of IBD medications in pregnancy and lactation, methotrexate has been classified by the FDA as pregnancy category X because of its teratogenicity. It should be used cautiously with two forms of contraception in all reproductive-aged women and should be stopped at least 6 months before attempting pregnancy. It can be excreted in breast milk and should not be used during breastfeeding. Methotrexate also has been associated with oligospermia and potential risks of mutation in sperm. Methotrexate use in men should be stopped 3–4 months before pregnancy is attempted. Additionally, because of the lack of long-term data, it is recommended to avoid initiating therapy with tofacitinib during pregnancy, as well as to avoid breastfeeding on this medication 104.

In 2007, the Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes registry was established to monitor pregnant patients with IBD prospectively over time. The objective of the registry is to evaluate whether increased rates of adverse events occur in people with IBD who are being treated with azathioprine/6-mercaptopurine or anti–tumor necrosis factor agents. By 2019, 1,490 pregnancies had become registered with the study, with 1-year outcomes available for 1,010 infants. The rates of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections in the first year of life were not increased in patients exposed to thiopurines, biologics, or both during pregnancy. Of note, higher disease severity was associated with adverse outcomes including spontaneous abortion and preterm birth 107. These data demonstrate the utility of controlling IBD and continuing these medications during pregnancy.

Many biologic therapies cross the placental barrier, and these drug antibodies are detectable in infant serum (except for certolizumab). Although the above data have shown the medication is safe to continue in pregnancy, often the administration of the last dose of biologic is attempted to be scheduled such that serum levels of the drug in the fetus will be low at delivery. Nonetheless, because of the presence of biologic medication in infant serum at birth, these infants are recommended not to undergo live-virus vaccines within the first 6 months of life. Breastfeeding while taking biologic or thiopurine therapy has been shown to be safe 104.