One of the fundamental objectives of Clinical Updates in Women’s Health care is to provide our readers with current information on topics that affect the health care of our patients, but which are not part of the core knowledge of obstetrics and gynecology. Lower GI tract disorders certainly fit that description. There is considerable overlap between many of the signs and symptoms originating from disorders of the lower gastrointestinal tract and many of the gynecologic disorders that the practicing obstetrician–gynecologist manages every day. Many lower GI tract disorders, such as constipation, irritable bowel syndrome, and celiac disease, are also seen more commonly in women. Ob-gyns often find themselves at the forefront in the evaluation, diagnosis, and management or referral for these disorders. The authors of this monograph have done an outstanding job writing this succinct but very thorough information with the ob-gyn in mind.
Dr. Jennifer LaBundy Palagiri completed her gastroenterology and hepatology fellowship at St. Louis University School of Medicine. She remains there on faculty and is currently the gastroenterology fellowship program director. She also co-directs the gastroenterology and hepatology course for students in their second year of medical school. Additionally, she maintains a busy clinical practice. Her interests include general gastroenterology, colon cancer screening, inflammatory bowel disease, and motility disorders.
Dr. Jennifer Ray is a general gastroenterologist who completed fellowship training with a focus in motility disorders. She is currently affiliated with the University of Washington Harborview Medical Center in Seattle as an Assistant Professor of Medicine in the department of gastroenterology and hepatology. Dr. Ray specializes in esophageal and intestinal motility disorders.
The authors discuss the epidemiology, pathophysiology, diagnosis, and treatment of the major diseases of the lower GI tract, and include current recommendations for screening for colon cancer. Information specific to women, reproductive issues, and pregnancy are part of each major section. Many of the tables and boxes can serve as useful clinical resources while caring for patients in the office setting. I think you will find this monograph a valuable tool in your care of patients.
Russell R. Snyder, MD
ABSTRACT: Disorders of the lower gastrointestinal (GI) tract can be a major determinant of quality of life, particularly for women. Many women turn to their obstetrician–gynecologists for primary and preventive care or with vague GI concerns that overlap with many gynecologic disorders. As such, knowledge of current screening recommendations is essential.
Lower GI tract disorders can affect and be affected by pregnancy and fertility. Common GI tract disorders, including colorectal cancer, motility and functional disorders, and inflammatory bowel disease, are reviewed in this monograph. Because most obstetrician–gynecologists will encounter these entities in their practices, their context in women’s health will be addressed.
Lower gastrointestinal (GI) diseases and associated symptoms account for a large number of health care visits each year. According to the 2016 National Ambulatory Medical Care Survey, abdominal pain is the third most common symptom for which patients seek outpatient health care, after skin disorders 1. Many women visit their obstetrician–gynecologists more often than their primary care physicians or use them as primary health care providers. Many gynecologic and lower GI disorders share symptoms, such as lower abdominal or pelvic pain and bloating. Some diseases are more common in women compared with men, such as irritable bowel syndrome (IBS), or warrant special consideration in women, for example, for inflammatory bowel disease (IBD). This monograph outlines the major diseases that affect the lower GI tract and reviews epidemiology, pathology, presentation, and treatment of these diseases. Concerns specific to women are addressed, including reproductive issues, changes in GI physiology during pregnancy, and management of lower GI disease during pregnancy.
Basic Science Update
A thorough understanding of the anatomy and physiology of the lower GI tract is essential to understanding disorders of this organ system. Normal anatomy and physiology will be discussed within this first section of the monograph.
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.
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.
Many patients might not seek routine health care with a primary care professional, but they do see their obstetrician–gynecologists regularly. Therefore, patients often report their concerns of GI symptoms to their obstetrician–gynecologist. Additionally, a patient may choose to visit their obstetrician–gynecologist for evaluation of physical symptoms that may be the result of a lower GI tract etiology. Finally, the obstetrician–gynecologist is frequently the health care professional who discusses health maintenance and preventive medicine with patients. Breast and colon cancer screening can be addressed in the same visit. For primary care providers, the overlapping presentations of lower GI tract and gynecologic diseases can make decisions regarding patient referral and diagnosis difficult. For example, the abdominal pain of IBS can be difficult to distinguish from that caused by endometriosis. Ovarian cancer can present with vague nonspecific abdominal symptoms, such as bloating and discomfort. Many GI conditions affect women disproportionately compared with men. For example, the pooled prevalence of chronic constipation in one meta-analysis was 17% in women compared with 9% in men 2. Likewise, the prevalence of IBS is 1.5 to 2 times greater in women than in men 3.
Female biology can affect GI health. Gastrointestinal symptoms can be exacerbated around the time of menstruation, especially in patients with IBD 4. Pregnancy is associated with a multitude of GI symptoms specific to the lower GI tract, including abdominal discomfort, constipation, and hemorrhoids.
Some systemic diseases that manifest through GI symptoms occur more frequently in women than in men. Examples include rheumatologic disorders, such as scleroderma, systemic lupus erythematosus, polymyositis, and mixed connective tissue disease, which can all potentially affect colonic motility or cause other GI complications. Thyroid derangements can affect gut motility. Therefore, thyroid function studies always should be performed in patients with chronic constipation or diarrhea. Neurologic diseases, such as multiple sclerosis, can cause constipation and fecal incontinence through impaired anal sphincter function.
Colonoscopy is potentially more technically difficult in women than in men. This is likely caused by the length of the female colon and greater frequency of pelvic surgeries that contribute to adhesion formation. A technically difficult procedure is more likely to result in an incomplete examination in which right-sided or cecal lesions might be missed.
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.
As the third leading cause of cancer death in women in the United States, colorectal cancer is a prominent health concern. In 2022, the American Cancer Society estimates a total 106,180 new cases of colon cancer and 44,850 cases of rectal cancer 10. When diagnosed early, prognosis is good, with a 5-year survival rate of 90%. However, only 39% of cases are diagnosed at this stage.
Lower socioeconomic status is linked with a 40% increase risk of colorectal cancer compared to high socioeconomic status 11. The most recent data 12 illustrates that African Americans have an 11% higher incidence of colorectal cancer than their White counterparts.
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.
Risk Factors and Protective Factors Associated With Colorectal Cancer
Type 2 diabetes mellitus
Modifiable risk factors
Diet high in red or processed meat and animal fat
Lack of fruit and vegetables in diet (probable)
Family history of colorectal cancer, hereditary nonpolyposis colorectal cancer, or polyposis syndrome
Personal history of inflammatory bowel disease
Personal history of adenomatous polyps or colorectal cancer
Personal history of other types of cancer
Calcium and vitamin D intake
Use of nonsteroidal antiinflammatory drugs and aspirin
Diet high in fiber
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.
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.
Conditions Associated With Elevated Carcinoembryonic Antigen Levels
Chronic obstructive pulmonary disease
Inflammatory bowel disease
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.
The Differential Diagnosis of Colorectal Cancer
Inflammatory bowel disease
Solitary rectal ulcer syndrome
Benign mass lesions
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.
CASE NO. 1 A 45-year-old woman presents to her gynecologist for her yearly well-woman visit. During the discussion of health maintenance issues, her gynecologist discusses colorectal cancer screening. Together they review the current testing recommendations, including stool-based tests and colonoscopy. They discuss the risks and benefits of the different types of test. Although the convenience of a stool-based test is appealing, the patient opts for colonoscopy, because this test has the potential for preventing colon cancer by removal of potentially precancerous polyps. The patient subsequently undergoes colonoscopy, and three small adenomatous polyps are removed. She is then recommended to undergo repeat colonoscopy in 5 years for polyp surveillance.
Screening Guidelines and Test Options for Colorectal Cancer Screening
Colorectal cancer screening for average-risk* women should begin at age 45 years.
ACOG supports stopping routine screening at age 75 years.
ACOG recommends colonoscopy every 10 years as the most effective screening modality.
Screening test options:
Colonoscopy (gold standard) every 10 years
CT colonography (virtual colonoscopy) every 5 years
Flexible sigmoidoscopy every 5 years
Fecal immunochemical test (FIT) annually
Guaiac-based fecal occult blood test (gFOBT) annually
Multi-targeted stool DNA test (mt-sDNA or Cologuard) every 3 years
Abnormalities found with any other screening method necessitate referral for diagnostic colonoscopy.
* A person of average risk for colorectal cancer has no personal or family history of the disease in a first-degree relative, no previous history of adenomatous polyps, no personal history of IBD, no confirmed or suspected hereditary colon cancer syndrome, and no history of abdominal or pelvic radiation to treat a previous cancer.
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 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.
CASE NO. 2 A 27-year-old woman was referred to a gastroenterologist by her obstetrician–gynecologist for new-onset rectal bleeding. A colonoscopy was performed and revealed hundreds of polyps scattered throughout the colon. Biopsy specimens of the polyps revealed them to be adenomatous. Because the patient had too many polyps to remove endoscopically, she underwent total colectomy and was found to have two small areas of invasive adenocarcinoma. She is concerned about her risk of future adenomas elsewhere in the GI tract and implications for colorectal cancer in her future children.
The patient was referred for genetic evaluation. A blood test revealed a mutation in the APC gene. Her first-degree relatives also were referred for genetic screening because of autosomal dominant inheritance of this disorder. The patient was scheduled for further evaluation, including upper-GI endoscopy to screen for adenomatous polyps of the stomach and duodenum and imaging to evaluate for other tumors, including thyroid, pancreatic, and ovarian. She will now be monitored regularly by a genetic counselor and a team of physicians to provide regular screening for extracolonic types of cancer and counseling regarding screening for her offspring.
Motility disorders of the lower GI tract cause serious morbidity in patients in the United States. Symptoms associated with these disorders can cause notable reductions in quality of life. The financial burden from medical testing, drug therapy, and loss of productivity caused by time away from work are important factors to consider.
Understanding the neurotransmitters and receptors involved in the enteric nervous system provides a foundation for understanding pharmacologic therapy for these disorders. Intestinal peristalsis is regulated by excitatory neurotransmitters (acetylcholine and substance P) and inhibitory neurotransmitters (nitric oxide, somatostatin, and vasoactive intestinal peptide), with transmission occurring along a serotonin-mediated CNS pathway.
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.
Lower Gastrointestinal Disorders Recognized by Rome IV
Functional Bowel Disorders
Irritable bowel syndrome
Functional bloating/abdominal distension
Unspecified functional bowel disorder
Functional Anorectal Disorders
Functional fecal incontinence
Functional anorectal pain
Levator ani syndrome
Unspecified functional anorectal pain
Functional defecation disorders
Inadequate defecatory propulsion
Data from: Schmulson MJ and Drossman DA, 2017 34
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.
Functional constipation can be classified into three different types:
Slow-transit constipation: characterized by slow colonic motility, which can be demonstrated with objective physiologic testing. This type responds poorly to conservative measures, such as fiber supplements.
Normal-transit constipation: Physiologic testing generally is normal. Patients may have a feeling of incomplete evacuation of stool, bloating, or abdominal discomfort.
Dyssynergic defecation or other pelvic floor disorders: Patients typically report frequent straining and incomplete evacuation. They may report the need for manual, including digital, maneuvers to evacuate stool. Defecation abnormalities can be demonstrated with anorectal manometry.
Before establishing a diagnosis of one of these forms of constipation, it is important to rule out other factors that might cause secondary constipation, such as mechanical obstruction, medications, neuromuscular disorders, or metabolic derangements. Box 6 summarizes a list of causes of secondary constipation.
Secondary Causes of Constipation
Structural or Mechanical
Extrinsic compression (tumor or adhesions)
Narcotics (opioid agonists)
Nonsteroidal antiinflammatory drugs
Antacids (calcium carbonate)
Calcium channel blockers
Anticholinergic medications (antihistamines, tricyclic antidepressants, and antipsychotics)
Metabolic or Endocrine
Neurologic or Neuromuscular
Spinal cord injury
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.
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.
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.
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.
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.
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 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.
Infectious Causes of Diarrhea
Toxigenic pathogens (release enterotoxins that cause dehydrating, watery diarrhea)
Other Vibrio species
Escherichia coli (many strains)
Toxigenic pathogens that cause a quick onset of symptoms as a result of ingestion of a preformed toxin
Invasive pathogens (cause mucosal ulceration and invade the mucosal barrier)
Enteroinvasive Escherichia coli
Other clinically important bacterial pathogens
Viral Pathogens (the major causes of acute gastroenteritis in the United States)
Enteric adeno-associated virus
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.
Causes of Diarrhea
Infection (bacteria, viruses, protozoa, and parasites)
Proton pump inhibitors
Vitamins and mineral supplements
Nonsteroidal antiinflammatory drugs
Early onset of chronic diarrhea
Carbohydrate malabsorption (eg, lactose intolerance)
Inflammatory bowel disease
Stimulant laxative abuse
Disordered gut motility
Endocrinopathies (hyperthyroidism and neuroendocrine tumors)
Neoplasia (colon cancer, lymphoma, and villous adenoma)
Inflammatory bowel disease
Malabsorption (celiac disease and short bowel syndrome after surgical resection)
Maldigestion (pancreatic exocrine insufficiency and lack of adequate luminal bile acids)
Proton pump inhibitors
Nonsteroidal antiinflammatory drugs
Vitamins and mineral supplements
A thorough medical history can be helpful in forming the differential diagnosis of diarrheal causes in a patient. The list of potential causes of diarrhea is extensive Box 8. The length of symptoms (acute or chronic) helps make infection a more or less likely diagnosis. Travel and occupational history can give clues about particular exposures. A description of the stool itself can help classify the diarrhea into one or more of the categories discussed. Small-volume bloody stools can help identify an inflammatory diarrhea, and stool with oil droplets suggests malabsorption etiology. The presence of blood or mucus (which can signify inflammation in the rectosigmoid region) is important to note. A sensation of tenesmus and inability to completely evacuate stool frequently occurs with inflammatory diarrhea. The daily timing of diarrhea also can be important. Diarrhea that ceases at night or ceases away from stressful situations might signify functional diarrhea or diarrhea-predominant IBS. Associated symptoms, such as fever, abdominal pain, arthralgia, or rash, also are important. Weight loss is an important factor.
Potential secondary causes of diarrhea should be addressed during the patient history. A diet high in caffeine or sugar substitutes will contribute to diarrhea. A thorough medication history should be obtained Box 8. An accurate assessment of other medical problems is imperative. Patients who are immunosuppressed because of human immunodeficiency virus (HIV), history of solid organ transplant, or other immune deficiencies are at risk for infections that do not tend to affect the general population, such as Cryptosporidium and Cytomegalovirus. A complete surgical history is needed to assess potential causes of diarrhea. Patients who have undergone cholecystectomy can have a bile acid diarrhea caused by elevated levels of bile salts in the colon. Those who have undergone surgical resection of the terminal ileum may have bile salt malabsorption. Patients who have had a large portion of the small intestine removed may have diarrhea secondary to short bowel syndrome, simply a result of the lack of absorptive surface area.
The physical examination is important in helping to determine the severity of illness and what type of treatment a patient may need (eg, hospitalization for intravenous [IV] fluid administration versus outpatient care). A patient who presents with diarrhea should be assessed for fever, tachycardia, and orthostatic hypotension. The abdominal examination, with attention to distension, bowel sounds, tenderness, masses, and possible hepatomegaly, is important. A rectal examination should be performed to look for evidence of perianal fistulae, as in Crohn disease, or sphincter abnormalities that might contribute to fecal incontinence.
If diarrhea has lasted more than a few days, an increasingly thorough investigation is indicated. Laboratory test results, including a complete blood count, other blood tests, and liver function tests, should be obtained. Stool studies should be obtained to evaluate for the presence of white blood cells or, more specifically, lactoferrin, which is a neutrophil protein. If results are positive, bacterial culture should be obtained. Testing for specific infections, such as Clostridioides difficile, is useful, especially in at-risk patients (see later discussion). Staining for ova and parasites also can be performed, especially in patients whose primary source of drinking water is from a well. Separate immunoassays can be performed for Giardia and Cryptosporidium. An abdominal flat plate X-ray or obstructive series can reveal ileus or toxic megacolon, as well as overflow diarrhea from fecal impaction. Flexible sigmoidoscopy with mucosal biopsies should be considered in ill patients who are not improving.
The evaluation of chronic diarrhea is more involved because the differential diagnosis is broad. In this situation, additional stool studies can be useful. Stool sodium and potassium levels can help differentiate osmotic causes of diarrhea from secretory causes. Stool pH less than 6 can indicate carbohydrate malabsorption. Increased stool fat content can indicate malabsorption or maldigestion by pancreatic exocrine insufficiency. The diagnosis of pancreatic exocrine insufficiency, as in the case of chronic pancreatitis or pancreatic duct obstruction by a tumor, also can be supported by a low fecal elastase level. Elastase is a pancreatic protease that resists intestinal degradation and, thus, is excreted in stool. Abnormally low levels in the stool suggest a pancreatic exocrine insufficiency. Stool can also be analyzed for the presence of laxatives if a patient is suspected of self-induced diarrhea by ingestion of these compounds.
Patients with chronic diarrhea should be evaluated for small-bowel bacterial overgrowth. Normally, the propulsive forces of the intestine help to prevent bacteria from becoming stagnant and flourishing in the small intestine. In addition, the ileocecal valve helps to serve as a “flap” to help prevent backflow of bacteria from the highly populated colon to the small bowel. Bacterial overgrowth can cause malabsorption by a decrease in enterocyte disaccharidase level. Vitamin B12 deficiency can occur as a result of bacterial consumption of the vitamin. Symptoms often include diarrhea and abdominal bloating and can overlap with those of IBS. In fact, research is ongoing to evaluate whether small-bowel bacterial overgrowth may play a role in the pathogenesis of IBS. Patients can be tested for small-bowel bacterial overgrowth by obtaining a sample of duodenal aspirate during upper endoscopy and obtaining colony counts of the aspirate. A less invasive alternative to upper endoscopy is hydrogen or methane breath testing. Exhaled concentrations of hydrogen and methane are measured before and after ingestion of a sugar, such as glucose. Elevations in concentrations of these gases after ingestion indicate bacterial metabolism of the substrate, consistent with high populations of bacteria in the small intestine. Patients with altered motility or altered anatomy particularly are at risk of small-bowel bacterial overgrowth. Examples include diabetes mellitus, in which intestinal motility often is delayed, and Billroth II postsurgical anatomy, in which a blind loop of bowel easily can become overgrown with bacteria.
Colonoscopy is indicated in patients with chronic diarrhea in whom a cause has not been found. Endoscopic findings may include inflammation consistent with ulcerative colitis or Crohn disease. Conversely, the mucosa may look endoscopically normal, but biopsies may reveal evidence of microscopic colitis or eosinophilic colitis. These are conditions of mucosal inflammation characterized by lymphocytic–plasmacytic inflammation in the lamina propria in the case of microscopic colitis and eosinophil infiltration in eosinophilic colitis. Thus, biopsies always should be obtained during colonoscopy in a patient who has chronic diarrhea, even if the mucosa appears endoscopically normal. Furthermore, a large tubulovillous adenoma polyp may secrete peptides that can cause diarrhea.
Investigation for neuroendocrine tumors is in order in a patient with watery diarrhea with an unknown cause. The incidence of such tumors is low, so evaluation for these neoplasms is reserved for patients who have persistent symptoms with no explanation. Diarrhea can result in cases of carcinoid tumor, gastrinoma (associated with Zollinger–Ellison syndrome), tumors that secrete vasoactive intestinal polypeptide, and systemic mastocytosis. Assessing for elevated blood or urine levels of the associated peptides, such as 5-hydroxyindoleacetic acid, metanephrine, histamine, gastrin, vasoactive polypeptide, and tryptase, is justified in patients with obscure causes of watery diarrhea.
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.
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”).
Functional diarrhea is part of the Rome IV complex of functional bowel disorders and is characterized by the continuous or recurrent passage of loose or watery stools without abdominal pain or discomfort 36. The lack of abdominal pain or discomfort sets this diagnosis apart from diarrhea-predominant IBS. Typically, patients do not experience diarrheal symptoms at night. For some, the disorder may be associated with fecal incontinence and rectal urgency, which can be major causes of distress and frequently worsen during times of psychosocial stress. To meet specific criteria for diagnosis, stools must be loose at least 75% of the time, and the symptoms must have been present for the past 3 months, with original symptom onset beginning more than 6 months ago. Patients who have alarm features Box 9 or who are of an age when colorectal cancer screening is recommended should undergo evaluation as discussed previously, including colonoscopy, stool analysis, and evaluation for celiac disease (see discussion in the section “Celiac Disease”). Warning signs include blood in the stool, iron deficiency anemia, weight loss or other signs of malnutrition, or electrolyte disturbances. Screening for small-bowel bacterial overgrowth also is reasonable because patients often respond to specific treatment.
Alarm Features in the Presentation of Irritable Bowel Syndrome
Blood in the stool
Symptoms that awaken the patient from sleep
Iron deficiency anemia
New-onset symptoms at age 50 years or older
Family history of colon cancer, inflammatory bowel disease, or celiac disease
Therapy for functional diarrhea involves improving stool frequency and form Table 4. Loperamide and diphenoxylate with atropine are typical first-line choices. Loperamide, administered at a dosage of up to 16 mg over 24 hours, is the preferred first-choice therapy for the reasons discussed previously. Other opioids, such as codeine, can be tried when the first two fail. Opioids decrease intestinal transit time, increase the time for fluid absorption, and thus lead to decreased stool frequency and improved form. These medications also may exert an antisecretory effect. Stronger opiates, such as tincture of opium, can be used in refractory cases, but few pharmacies supply such compounds. Cholestyramine can be helpful in patients who have had a previous cholecystectomy. Alosetron is a 5-hydroxytryptamine receptor antagonist used in functional diarrhea and diarrhea-predominant IBS. Its effectiveness in relieving symptoms has been well documented, particularly in women 51. Likewise, eluxalodine is a mixed opioid receptor modulator that also is effective for diarrheal symptoms. However, it currently is approved only for diarrhea-predominant IBS 52.
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.
In 2016, IBS diagnostic criteria were revised by the Rome IV working group 36, Box 10. Patient assessment, as with any GI concern, includes obtaining a thorough history and performing a physical examination. The presence of abdominal pain sets this diagnosis apart from functional diarrhea or constipation. The pain often is poorly localized, varies in intensity, and can be exacerbated or relieved with certain factors, such as eating, defecation, and stress. This symptom can be quite disturbing to the patient. Associated changes in GI tract motility complete the diagnostic criteria. Patients can experience a predominance of diarrhea (IBS-D), predominance of constipation (IBS-C), or mixed symptoms (IBS-M). Exploring the patient’s definition of diarrhea and constipation can help the health care professional better understand the symptoms. The Bristol stool form scale Figure 1 can be helpful in standardizing these descriptions. Other symptoms, not part of the diagnostic criteria, are common, such as abdominal bloating and nausea. Symptoms of gastroesophageal reflux disease can occur in IBS patients but are considered a separate clinical entity. Irritable bowel syndrome is associated with other disorders, such as fibromyalgia and interstitial cystitis, and inquiring about such concomitant diagnoses is appropriate. The incidence of sexual abuse and other traumatic events is higher in IBS patients than in other populations. A thorough social history, perhaps unfolding in subsequent visits as doctor–patient trust is built, is important in establishing IBS diagnosis and commencing its management.
Rome IV Diagnostic Criteria for Irritable Bowel Syndrome
Must have recurrent abdominal pain for at least 1 day/week in the past 3 months plus two or more of the following factors:
Pain related to defecation
Symptoms associated with a change in stool frequency
Symptoms associated with a change in stool form
Data from: Mearin F et al, 2016 36
The pathophysiology of IBS is poorly understood, but certain risk factors and associations provide some clues. For example, bacterial gastroenteritis is a risk factor for IBS, which suggests that postinfection inflammation may play a role in disordered sensory perception or gut motility. Other risk factors include recent antibiotic use, estrogen use (including postmenopausal use), food intolerance, and other associated functional disorders, such as fibromyalgia. Irritable bowel syndrome tends to affect families, which suggests there may be a genetic component to the disorder itself or its associated conditions. Generally, it is accepted that two components are involved: 1) altered gut motility and 2) visceral hypersensitivity. Additionally, altered central perception likely plays a role. Other contributing factors likely include low-grade inflammation and stress 56. Visceral hypersensitivity is present in most IBS patients and may account, at least in part, for abdominal pain or discomfort. Those with IBS have been demonstrated in multiple studies to exhibit rectal hypersensitivity in response to rectal balloon inflation tests. Patients with IBS generally are consciously aware of normal GI activities, such as intestinal contractions after meals and the movement of intestinal gas. Neurotransmitters that likely are involved in gut sensitivity and signaling are serotonin, neurokinin, and calcitonin gene-related peptide. Such substances are or have been potential targets of medical therapy.
Inflammation is a potential contributor to the development of IBS. The gut is in a continual state of smoldering inflammation because it is consistently exposed to environmental and food antigens and potential pathogens. The association between bacterial gastroenteritis and the development of IBS supports this notion. Serotonin is an important mediator of colonic inflammation and is released with increased luminal pressure, such as after a meal. It acts on afferent neurons in the enteric nervous system to initiate the peristaltic reflex. It has been proposed that symptoms in IBS patients may be caused by an abnormally high release of serotonin after a meal 57. The role of food intolerance is difficult to identify, but many patients report symptom improvement with elimination diets. The gluten sensitivity of celiac disease is a separate clinical entity, but many non-celiac patients report improved symptoms with a gluten-free diet. Overlapping conditions of lactose intolerance or fructose intolerance can confuse the clinical picture. Small-bowel bacterial overgrowth has been increasingly recognized as having a close association with IBS, with a high prevalence of this disorder in IBS patients.
Altered central perception is another focus of IBS pathophysiology. Few visceral afferent signals from the intestine reach the central cortex. Visceral afferent signals from the gut may be improperly modulated in IBS patients and can occur at many levels, including visceral, spinal, and central nerve pathways 56. Psychosocial factors, including depression, anxiety, and history of physical, emotional, or sexual abuse, are associated with IBS. Although the linking explanation is undetermined, abuse may alter the response of the CNS to pain.
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.
The first step in successful IBS therapy begins with establishing a strong, trusting patient–physician relationship. Validating the patient’s symptoms by listening to and acknowledging their concerns helps establish trust. For patients with mild symptoms, this may be the only intervention needed. Conversely, other patients may have already undergone extensive diagnostic testing and are frustrated that a diagnosis has not been previously established. Others may have been told by previous health care providers that their symptoms are “in their head” or that they have IBS and must learn to live with it. Such previous experiences may make the acceptance of the diagnosis challenging. Educating patients regarding the diagnosis of IBS and reassuring them that it is a well-characterized clinical entity can help engage them in their treatment plan. Reviewing the diagnostic criteria with patients can provide a personalized insight into the diagnosis. The next step is to begin addressing symptoms to improve the quality of life. Setting realistic treatment goals is important because symptoms cannot be completely cured. Assuring patients that treatments that work for one person do not always work for others, and that sometimes a trial-and-error approach is needed, will help to keep them from getting discouraged if particular treatments fail. Encouraging patients to take a proactive role in their care, yet have patience as treatment is initiated, is important. Patients with severe symptoms, associated anxiety, or both need frequent follow-up visits for continued encouragement and guidance.
A reasonable first step in treatment of a patient is a review of dietary habits and implementation of changes that might improve symptoms. One approach is to ask the patient to keep a food diary for 1–2 weeks, in which they would record all items ingested and symptoms. Some studies have shown a benefit in symptoms with dietary changes. Specifically, avoidance of gluten or using a low FODMAPs diet, or both, has been shown to alleviate some symptoms of IBS in a portion of patients 55. FODMAPs is an acronym for fermentable oligo-, di-, mono-saccharides, and polyols. Data from studies have been mixed and there are no long-term data regarding efficacy of dietary therapies in IBS. Although it is reasonable to assess for lactose intolerance and celiac disease, testing for food allergies with intention to alter the diet appears to offer little benefit to the patient. No clear evidence exists that food allergies cause IBS symptoms. Patients with IBS-C should increase soluble (not insoluble) fiber, such as that found in psyllium, oat bran, barley and beans, in doses of up to 25–35 g per day 58. This can improve stool viscosity and frequency, and thus can positively affect global symptoms.
Medical treatment is tailored to alleviate predominant symptoms. Medications used in the treatment of functional constipation or functional diarrhea are commonly used to control these symptoms. Treatment of the underlying motility abnormality in this fashion may relieve the abdominal pain component, but not always. Frequently, patients do not request additional therapy if the pain is minimal. However, specific medications to address abdominal pain in the patients who seek symptom relief or improvement of quality of life are warranted. In the past, antispasmodics have been recommended for IBS symptoms. Examples include hyoscyamine and dicyclomine. However, because of lack of supporting evidence and risk of adverse effects, they are no longer routinely recommended for global symptoms 58. Peppermint oil, available over-the-counter, has been found to modulate visceral sensation and can be helpful in improving abdominal pain or discomfort. It is generally well tolerated, although it can contribute to heartburn symptoms. These symptoms can be alleviated with use of enteric-coated formulations 58.
It is now widely recognized that nonabsorbable antibiotics can improve IBS-D symptoms 55. Patients treated with rifaximin for 10–14 days note improvement in abdominal discomfort, bloating, and diarrhea. This observation may be a clue that small-bowel bacterial overgrowth or other derangements in intestinal flora may play a role in IBS pathogenesis, but further studies are needed. However, the effect of rifaximin is short lived, with symptom recurrence evident in 2–3 months. Given the chronic nature of IBS, symptom recurrence after cessation of antibiotics, and the uncertainty of potential adverse effects with long-term antibiotic use, treatment of IBS with antimicrobials warrants investigation. Additionally, unfortunately the cost of some nonabsorbable antibiotics can be cost-prohibitive for patients.
As mentioned in the section “Functional Diarrhea,” alosetron and eluxadoline are FDA-approved therapies for the treatment of diarrhea-predominant IBS. They have been shown to improve diarrhea, abdominal pain, and overall quality of life scores 59 60 61. Constipation is the most commonly reported adverse effect and can be severe. Therefore, these medications are generally reserved for patients in whom first-line therapy has failed. Of note, it is recommended that these medications be prescribed under the direction of a gastroenterologist because of reports of ischemic colitis associated with alosetron and pancreatitis with eluxadoline.
When medications that are taken on an as-needed basis fail, neuromodulation agents should be considered to control pain. Antidepressants afford some symptom improvement, likely by their modulatory effects on visceral hypersensitivity and central pain perception. The most highly studied group of centrally acting medications is the tricyclic antidepressants. Studies of mixed quality produced varied results, but short-term randomized, double-blind trials do show symptom improvement. One study noted an improvement in global symptom scores in IBS patients treated with imipramine for 12 weeks compared with placebo (80.6% versus 48.0%, P=.01) 62. These medications have anticholinergic adverse effects that limit their use in some patients. These adverse effects include constipation, dry mouth, urinary retention, and tachycardia. The adverse effect of constipation can be useful in patients with IBS-D. Initial dosage usually is low, at 10–25 mg daily and increased by 10–25 mg weekly. Patients typically require lower doses for IBS symptoms than are required to treat depression. It is best to advise patients that tricyclic antidepressant dosages used for IBS therapy are not aimed to treat any concomitant depressive symptoms. Given the adverse effects of tricyclic antidepressants that sometimes limit their use (especially in patients who have IBS with severe constipation), selective serotonin reuptake inhibitors (SSRIs) are a reasonable alternative with fewer adverse effects. However, the data for the efficacy of SSRIs in IBS are not as strong as those for tricyclic antidepressants 58.
Probiotics are increasingly advertised as therapy for GI symptoms, including those of IBS. Although several different strains exist, Bifidobacterium infantis has been shown in randomized controlled trials to improve pain, bloating, bowel dysmotility, and overall global symptoms. Previously studied species, such as Lactobacillus, have not shown substantial symptom improvement over placebo 63. Robust trials on the effectiveness of probiotics for IBS symptoms are lacking. Additionally, the large choice of commercial preparations makes the ability to assess products and make recommendations difficult. Therefore, probiotics are not recommended for IBS therapy in the 2021 American College of Gastroenterology Clinical Guideline 58. However, given their relative safety, it is reasonable to consider a trial in patients who are interested. Probiotics may be helpful in the treatment of postinfectious IBS.
When dietary or medical therapies alone are inadequate or poorly tolerated, behavioral treatments can provide global symptom improvement. Examples include cognitive behavioral therapy, dynamic psychotherapy, and gut-directed hypnotherapy. The American College of Gastroenterology IBS Task Force reviewed 20 randomized controlled trials that addressed these forms of treatment and included 1,278 IBS patients. A benefit of psychologic therapy over usual care was observed (risk ratio of IBS not improving with therapy, 0.67; 95% CI, 0.57–0.79), with a number needed to treat of four 54. Psychologic treatment is unlikely to improve GI symptoms, such as disordered motility and abdominal pain; however, global improvement may be gained by the ability to cope with IBS. When referring patients for psychologic therapy, it is important to validate their diagnosis and the reality of their symptoms. Psychologists can be beneficial in helping patients work through their chronic IBS symptoms, especially because the disorder is lifelong.
CASE NO. 3 A 19-year-old college student presents to her obstetrician–gynecologist for a well-woman examination. She expresses concern that since she moved to college, she has been experiencing multiple GI issues. When she eats a meal, frequently she feels the urge to have a bowel movement. She also reports abdominal cramping and diarrhea, especially after eating. She does not have problems at night and noticed symptoms were less pronounced when she was back home. The abdominal cramping and sense of urgency of bowel movements have been causing her anxiety.
This patient is referred to a gastroenterologist for evaluation and management of symptoms. The patient reports her weight has been stable, and she had recent blood work as part of an internship physical examination that revealed normal hemoglobin levels. She has not had other symptoms, such as nausea, vomiting, or blood in her stool. She has no family history of colorectal cancer or IBD. Serologic tests yield negative results for celiac disease. The gastroenterologist then discusses with the patient that she meets the following two criteria for the diagnosis of IBS: 1) a change in stool frequency or form and 2) abdominal pain or discomfort, often associated with defecation and relieved after a bowel movement. The gastroenterologist reassures the patient that the diagnosis of IBS does not place her at an increased risk of other diseases, such as IBD or colorectal cancer. Together they discuss dietary changes, such as low-fat and high-fiber diet and avoidance of caffeine. Upon follow-up 3 months later, the patient reports that she simply feels better knowing her symptoms are not indicators of more serious or debilitating disease. She notes that since she has become more settled in her routine in college, the symptoms do not seem as severe as they initially were.
Clostridioides difficile Colitis
Clostridioides difficile colitis deserves special mention because it is an important source of morbidity and mortality in hospitalized patients, and its incidence as a community-acquired infection is increasing. The Centers for Disease Control and Prevention (CDC) estimates that 13,000 deaths per year are caused by C difficile 64. Specific risk factors include disruption of normal intestinal microflora, patients over 65 years old, women, and immune-compromised patients.
The infection readily spreads through spores. Even asymptomatic individuals shed spores, and these exist on surfaces for long periods, thus easily spreading to other individuals through hand contact from affected surfaces. The spores are resistant and can remain viable on inanimate surfaces for up to 5 months 65. Infection is frequently associated with watery diarrhea, abdominal pain, and leukocytosis. It can manifest as a range of symptoms from bothersome diarrhea to a life-threatening colitis. In a hospitalized patient with increasing white blood cell count and no clear source of infection, C difficile infection should be considered. The infection is diagnosed by detection in the stool. An enzyme-linked immunosorbent assay is available to detect both toxins of C difficile (A and B). Testing for the antigen also is frequently performed. Real-time polymerase chain reaction is gaining popularity. Stool can remain positive for 3–6 weeks after cessation of symptoms. Ileus and toxic megacolon can be appreciated on abdominal imaging. Endoscopy can be helpful for unclear diagnosis and assessment of disease severity. A finding of pseudomembranous colitis is not specific for C difficile, so biopsies are needed to confirm the diagnosis.
The best treatment is cessation of all concomitant antibiotics, which is difficult in hospitalized patients. Either oral vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of C difficile 66. In severe cases or fulminant C difficile infection, vancomycin is given orally and per rectum with intravenous metronidazole. Colectomy may be required if the patient is not responding to antimicrobials. Up to 20–30% of patients will have recurrent C difficile infections. For recurrent episodes, tapered oral vancomycin or fidaxomicin is recommended. Probiotics like Saccharomyces boulardii are recommended as the antibiotic is tapered to protect against recurrent C difficile infection 67 and help reestablish healthy gut flora. However, not all studies clearly demonstrate this benefit. If multiple episodes recur, the patient should be referred for fecal microbiota transplantation.
CASE NO. 4 A 66-year-old woman is hospitalized for community-acquired pneumonia. Her past medical history includes hypertension and diabetes mellitus type 2. On presentation, she has a low-grade fever to 100.6°F, blood pressure 140/90, heart rate 90 with normal oxygen saturation. Her laboratory test results reveal leukocytosis of 12,000 white blood cells per microliter with normal electrolytes and renal function. The patient is started on ceftriaxone and azithromycin. While she is hospitalized, the patient begins to develop generalized abdominal pain.
Soon after the pain starts, she develops 6 to 8 episodes of loose, foul-smelling stools. She develops rebound fevers to 105°F, hypotension, worsening leukocytosis of 20,000 white blood cells per microliter, and new acute renal failure with creatinine of 3 mg/dL. The patient has stool studies performed and is found to have Clostridioides difficile infection. A CT scan of her abdomen is negative for toxic megacolon. Because of the severity of her clinical presentation, with worsening hemodynamics and laboratory values, she is started on a combination of oral and rectal vancomycin with intravenous metronidazole. Her cephalosporin is stopped. After 5 days, she slowly recovers with cessation of diarrhea. She is discharged to a rehabilitation facility.
Celiac disease is an autoimmune disorder of the small intestine, which generally is not considered part of the lower GI tract. However, it is high on the differential list for any patient who presents with lower GI symptoms given that often it causes malabsorptive diarrhea and other lower GI tract symptoms. Celiac disease, also called gluten-sensitive enteropathy or nontropical sprue, is characterized by small-bowel malabsorption caused by inflammation and villous atrophy. These abnormalities are caused by the ingestion of gluten, which is a protein in wheat, rye, and barley. Generally, intestinal mucosal abnormalities and clinical symptoms improve with avoiding gluten. Predictably, the malady recurs when gluten is ingested again. The prevalence of celiac disease is highest in North America and Western Europe, approaching nearly 1% of the population 68, with a slight female preponderance. The mean age at diagnosis is 45 years, but the disease can present in a spectrum of ages, from early childhood to over 60 years 68. Incidence is increased among first-degree relatives.
The disease affects the mucosa of the small intestine. The deeper layers are spared. A spectrum of severity of histologic changes and clinical symptoms exists. Biopsy samples of the duodenum obtained during upper endoscopy can reveal these changes. Atrophy of intestinal villi, increased presence of inflammatory cells, and reduced thickness of the mucosa lead to a markedly reduced surface area available for digestion and absorption. Tight junctions between the enterocytes are compromised, and the gut epithelium becomes leaky, which causes unregulated exchange of fluids and antigens that incite inflammation. Additionally, the loss of integrity of the small-bowel mucosa can cause a secretory diarrhea. Malabsorption results, because of small-bowel mucosal damage as well as loss of digestive enzymes. Such changes can cause abdominal pain and bloating.
The relationship between the ingestion of gluten and celiac disease has been well characterized. Celiac disease is the only autoimmune disorder with a single clearly identified environmental trigger. Although the exact mechanism of the disease development is unknown, celiac disease appears to form from a complex interplay of environmental, immune, and genetic factors.
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
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.
Like celiac disease, lactose intolerance is a disorder of the small intestine. It can cause an osmotic diarrhea and other lower GI tract symptoms, such as bloating and flatulence. The most common cause of lactose intolerance is lactase deficiency. Lactose is a disaccharide that is broken down by lactase, an enzyme present on the surface of the small bowel (known as the brush border). In most individuals, lactase function is intact in infancy. Later in childhood and in adulthood, primary lactase deficiency causes a loss of function of lactase. The frequency of primary lactase deficiency varies across ethnicities. For example, lactose intolerance is prevalent in Middle Eastern and Asian individuals, but much less common in northern European individuals 78.
Reports of abdominal bloating and distension and flatulence are common in patients with lactose intolerance. Because lactase is not functional, undigested lactose reaches the colon, where it is processed by colonic bacteria, producing the aforementioned symptoms. A food and symptom diary with entries that demonstrate a correlation between dairy intake and symptoms can be helpful in supporting the diagnosis. An empiric trial of a dairy holiday for 5–7 days also may provide some insight if an individual’s symptoms improve during this time. A definitive diagnosis is made with a lactose breath test. During this test, baseline levels of methane and hydrogen in exhaled breath are obtained. A patient then ingests a specified amount of lactose. The concentrations of methane and hydrogen in exhaled breath are obtained at several time points. An increase in the concentration of these gases in the presence of typical GI symptoms is characteristic of lactose intolerance caused by lactase deficiency. The changes in gas concentrations occur as the lactose that escaped digestion in the small bowel is processed by colonic bacteria. Treatment includes lactose avoidance or oral lactase supplementation, reminding the patient to take the lactase immediately before ingesting lactose-containing foods.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a collective term for chronic inflammatory conditions of the GI tract and includes Crohn disease and ulcerative colitis. When the disease cannot be clearly classified as Crohn disease or ulcerative colitis, it is labeled as indeterminate colitis until such time as the disease clearly becomes one or the other. Crohn disease and ulcerative colitis involve chronic or relapsing–remitting immune activation and inflammation. The conditions differ in their anatomic involvement, mucosal depth of invasion, and disease behavior (such as formation of strictures and fistulae). Both conditions are associated with extraintestinal manifestations that include skin, musculoskeletal, and ocular abnormalities. The mainstay of treatment for moderate to severe disease in both cases is chronic immunosuppression, with or without surgical intervention for refractory disease. Inflammatory bowel disease is lifelong, with implications on a patient’s overall quality of life, risks associated with immunosuppression and surgery, risk of colorectal cancer, associated comorbidities, and fertility and pregnancy outcomes. The following general discussion of the disease will be supplemented by a review of reproductive concerns. The behavior and treatment of ulcerative colitis and Crohn disease will be discussed separately.
The incidence of IBD is increasing over time and is highest in North America and northern Europe 79. Currently, approximately 1.6 million Americans have IBD, with up to 70,000 new cases being diagnosed each year 80. In North America, the incidence of ulcerative colitis is estimated at 19.2 individuals per 100,000 and that of Crohn disease at 20.2 individuals per 100,000. Overall, it is estimated that approximately 1.3% of the U.S. population has been diagnosed with inflammatory bowel disease 81. In general, IBD affects adult men and women equally in terms of incidence 80 82. Studies examining racial and ethnic variances in the United States are mixed, but some have found a slight increased prevalence among Hispanic people and non-Hispanic White people compared to non-Hispanic Black people 81. Inflammatory bowel disease can affect any age group but tends to peak in the second and third decades of life. A second, smaller peak is seen in the seventh and eighth decades. The incidence of Crohn disease is higher in smokers than in nonsmokers, but the observation is not consistent in ulcerative colitis. In fact, smoking seems to have a protective effect in ulcerative colitis. Many patients will note onset of symptom development with smoking cessation 83.
It has been well established that the pathogenesis of Crohn disease and ulcerative colitis involves a sustained immune response. A complex interaction of genetic susceptibility and environmental exposures is thought to be responsible for initiating IBD development, and research continues in this area. Family history is a major risk factor for the disease. Individuals with a first-degree relative with IBD have a 14-fold to 15-fold increased risk of disease development compared with the general population 84. Many experts have suggested that the demographic and geographic patterns of IBD demonstrate that the disease is greatly influenced by environmental factors. Even on a smaller geographic scale, the incidence of IBD is higher in urban areas than in rural areas 85. The differences in exposures to environmental antigens through different microbial exposures, occupations, sanitation, diet, pollutants, and medications have all been implicated as potential risk factors for IBD development 83. In particular, intestinal microflora, personal history of GI infection, and antibiotic use are increasingly being investigated as important factors for IBD development.
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.
Proper evaluation of a patient with potential Crohn disease involves the appropriate diagnosis and documentation of disease activity. When Crohn disease is suspected, laboratory investigations (complete blood count and assessment of iron, vitamin B12, and folate levels) and measurement of inflammatory markers (C-reactive protein or erythrocyte sedimentation rate) should be completed. Serum inflammatory markers are not specific for IBD but can be helpful in deciding whether further investigation is warranted. Stool studies should be performed to assess for bacterial infection, ova and parasites, and Clostridioides difficile toxin. Assessment for Giardia species and Entamoeba histolytica should be considered in certain cases. Fecal leukocytes or lactoferrin can indicate intestinal inflammation. The level of fecal calprotectin, a cytosolic neutrophil protein that is resistant to intestinal degradation, is elevated in intestinal inflammation. It is useful for IBD assessment because it is measured quantitatively; thus, response to treatment over time can be monitored. Small-bowel barium follow-through is being replaced by CT or MRI with enterography to identify potential intestinal inflammation, areas of stricture, and anatomical distribution of inflammation. Narrowed areas with proximal bowel dilatation are suggestive of stricture, obstruction, or both. CT and MRI are preferred because abscesses and fistulae are more readily identifiable. Endoscopy with biopsy provides a necessary complement to radiographic imaging to assess disease distribution and severity and to obtain tissue for histopathologic verification and exclusion of other etiologies, such as infection. Serologic studies can be helpful when trying to differentiate between Crohn disease and ulcerative colitis but are not recommended as part of the routine evaluation. Antibodies against Saccharomyces cerevisiae (also known as ASCA or baker’s yeast) occur in up to 76% of patients with Crohn disease 88. The presence of S cerevisiae has an 87% specificity in Crohn disease 89. In contrast, approximately 60% of patients with ulcerative colitis possess perinuclear antineutrophil cytoplasmic antibody.
Treatment of patients with Crohn disease is a lifelong endeavor because no surgical or medical cure exists. The goal of therapy is to induce and maintain disease remission. In doing so, symptoms and quality of life improve. Therapy also involves managing complications, such as fistulae and extraintestinal manifestations. A multidisciplinary approach with the involvement of the gastroenterologist, surgeon, primary care physician, and gynecologist is needed. Frequently, dermatologists, rheumatologists, and even infectious disease physicians are involved in the setting of complex therapy. Continued health maintenance assessment, including correction of nutritional deficiencies, cancer screenings, vaccinations, and bone density testing, is an important component of ongoing therapy. Treating reproductive-aged patients introduces additional specific considerations to disease management.
Numerous treatment options exist for patients with Crohn disease and typically are chosen based on disease severity and location. Mild disease can be treated with antiinflammatory medications, such as 5-aminosalicylates, which include sulfasalazine and the sulfa-free 5-aminosalicylates, such as mesalamine, olsalazine, and balsalazide. These oral medications are useful in mild disease that is mostly limited to the colon because the medication is released in a delayed or pH-dependent manner into the distal ileum and colon. Antibiotics have a limited role and are not recommended for the purpose of inflammation control. However, metronidazole is indicated to aid in prevention of postoperative recurrence 90. For moderate or severe disease, corticosteroids, such as prednisone or controlled ileal-release budesonide, are short-term options. They are not indicated for maintenance therapy because of risks of adverse effects 90. Severely ill patients are treated with IV methylprednisolone sodium succinate until they can take oral prednisone or prednisolone. Steroid-sparing agents or immune modulators, such as azathioprine, 6-mercaptopurine, and methotrexate, are useful in maintaining steroid-free remission. Azathioprine and 6-mercaptopurine have a slow onset of action, so they are administered after a patient has attained remission (usually with steroids) to avoid relapse once a patient stops taking steroids. Biologic therapies are recommended to induce remission for patients with moderate to severe Crohn disease 91. These include monoclonal antibodies that are directed against specific inflammatory mediators. Such targets include antibodies engineered against tumor necrosis factor alpha (anti-TNF-α), molecules involved in leukocyte trafficking (anti-integrin/anti-adhesin antibodies), and interleukin 12/23 (anti-IL 12/23 antibodies).
The decision to use one therapy over another should be based on standard of care guidelines 90, individual patient and disease characteristics, and safety concerns. All medications have associated adverse effects and potential adverse reactions. The long-term risk of immunosuppression with corticosteroids, immune modulators, and biologic agents in terms of infection and malignancy risk is a consideration for clinicians and their patients. A patient’s age, comorbidities, childbearing plans, and environmental exposures must all be considered when choosing therapy. Often, combinations of therapies are used. Those who develop the disease at a young age or those with perianal or other fistulizing disease are likely to have a more aggressive course, and consideration of more aggressive therapy is reasonable.
Surgical therapy is an important component of treatment. Although the advent of biologic therapy has reduced the need for surgical intervention in many patients, overall 40–70% of patients with Crohn disease will require surgical intervention at some point in their lives for complication such as stricture, abscess, or fistula 92, with one half requiring bowel resection within the first 10 years of disease 93. Disease recurrence after surgical resection of affected bowel is high. On average, one fourth of patients require a second surgery within 5 years of the first surgery, with clinical or endoscopic evidence of disease recurrence present in 90% of patients at 1 year post first surgery 93. Surgery is used to treat medically refractory disease by resecting affected bowel segments, performing stricturoplasty, or draining abscesses. Repair of fistulas that do not heal with medical therapy also is an indication. Patients with Crohn disease are treated with limited surgical resection to preserve as much bowel length as possible, given the high prevalence of recurrent surgical procedures. It also is worth noting that the use of corticosteroids at the time of surgery increases the risk of postsurgical complications.
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.
Evaluation of the patient with suspected ulcerative colitis, as with Crohn disease, involves establishing the appropriate diagnosis and assessing disease severity and distribution. Patients with ulcerative colitis may have iron deficiency anemia and elevated levels of serum inflammatory markers but typically do not have the associated malabsorptive signs of Crohn disease, such as vitamin and protein deficiencies. Because the small intestine is not involved and ulcerative colitis is not associated with fistula and abscess formation, abdominal imaging is not used frequently. Abdominal imaging can be helpful in assessing ileus or toxic megacolon, strictures, or malignancy. Stool studies also are important to evaluate for infection. Endoscopy is essential in evaluating patients with ulcerative colitis to determine the proximal extent of inflammation, obtain tissue samples for diagnostic confirmation, and rule out other etiologies such as infection, including colitis caused by Cytomegalovirus. Measurement of fecal calprotectin level also is useful, and this, in conjunction with clinical symptoms, can be helpful for following response to therapy.
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.
CASE NO. 5 A 29-year-old woman with ulcerative colitis reports frequent loose stools and occasional rectal bleeding. Colonoscopy reveals mild to moderate inflammation throughout the colon (pancolitis). She has been taking oral 5-aminosalicylates since the diagnosis 2 years ago, which initially seemed to control her symptoms. However, she required two short courses of prednisone to treat flares and put the disease back into remission. Now, she is concerned the symptoms have returned. She is concerned about the effect her disease and potential treatment will have on her health, potential future pregnancy, and the health of the child.
The patient is aware of the deleterious effects of steroids and is concerned that she has required more than one course to treat disease flares despite maintenance therapy. She plans to become pregnant in the next few years. A gastroenterologist explains that successful control of the disease before and during pregnancy offers the best chance of avoiding adverse pregnancy outcomes, such as low birth weight or preterm delivery, and discusses treatment options with the patient. After discussing steroid-sparing agents, such as azathioprine and TNF-α inhibitors, the patient decides to proceed with therapy with the latter. During a follow-up 6 months later, the patient reports that she is feeling well and has no signs or symptoms of active disease.
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.
Diverticulosis is a common condition, with an estimated prevalence of 12–50% in the United States 108. Anatomically, diverticula are small herniations that occur along any portion of the colonic wall. The incidence increases with age; 10% of patients are younger than 40 years, but as patients approach age 80 years, 50–65% of patients have diverticulosis 108. The incidence rates are equal in women and men, although women are more likely to experience complications of stricture or obstruction 109.
The cause of diverticulosis is uncertain, but theories suggest a multifactorial etiology of constipation or altered motility, structural weakness of the colonic wall, and abnormal colon microbiota 110. Patients with these findings are encouraged to eat a high-fiber diet to help prevent symptom development. Symptomatic uncomplicated disease is characterized by intermittent left lower-quadrant abdominal pain (exacerbated by eating and improved with defecation), bloating, constipation, or diarrhea. Symptoms overlap with IBS, and the prognosis and treatment are similar. Antispasmodics can be helpful for abdominal discomfort. The old theory that nuts and seeds should be avoided in patients with uncomplicated diverticulosis is not supported by any data.
Diverticulitis occurs in approximately 10–25% of patients with diverticulosis 109. Inflammation can range from a localized phlegmon, an intra-abdominal abscess, perforation with peritonitis, fistula formation, or obstruction. The preferred diagnostic procedure is abdominal CT. Endoscopy is avoided during acute diverticulitis because of perforation risk but should be considered 6–8 weeks after symptoms resolve to rule out neoplasm as an inciting agent. Patients are treated with bowel rest and antibiotics. An abscess requires percutaneous drainage or surgical intervention. Perforation is a surgical emergency. Surgery often is performed in one step or a two-stage Hartman procedure in which a colostomy is created, and a subsequent re-anastomosis is performed. Recurrent attacks of diverticulitis can lead to colonic strictures. Once malignancy is ruled out, symptomatic strictures can be dilated with balloon endoscopy. Patients with recurrent diverticulitis can be considered for surgical resection.
Diverticular bleeding is the most common cause of lower GI tract bleeding. It occurs in 3–15% of patients with diverticulosis 111. Diverticular bleeding presents as abrupt, painless hematochezia. Bleeding spontaneously ceases in 75–80% of cases but can recur in 25–33% of cases 111. When bleeding occurs, urgent intervention by colonoscopy or angiogram can localize the bleeding. Endoscopic therapy or vascular embolization by an interventional radiologist can be effective. If bleeding continues or recurs, segmental colectomy is performed if the bleeding has been localized. In cases of recurrent bleeding in patients with pan-diverticulosis, subtotal colectomy is considered.
CASE NO. 6 A 60-year-old woman presents to the emergency department with a recurrent episode of left lower-quadrant abdominal pain. The pain had acute onset, is nonradiating and constant, and is associated with fever and constipation. This is her fifth episode of this clinical presentation in the last 2 years. She is otherwise healthy and has no relevant past medical history. In the emergency department, the patient has a low-grade fever to 100.0°F, normal blood pressure, and elevated heart rate to 110. She has a CT scan of her abdomen and pelvis, which shows fat stranding of the mid sigmoid colon with associated segmental diverticulosis with diverticulitis and micro-abscess without perforation. The patient is hospitalized and treated with bowel rest and intravenous ciprofloxacin and metronidazole. The surgery staff are consulted and they recommend nonoperative management.
On discharge, the patient is seen in clinic for follow-up. A month after her hospitalization, she undergoes a diagnostic colonoscopy to evaluate the area of diverticulitis observed on recent imaging. Her colonoscopy shows left-sided diverticulosis and is otherwise negative for neoplasms. After discussion with her primary care physician, the patient is referred for surgical evaluation. After discussion of risks versus benefits of a left hemicolectomy, the patient decides to pursue surgical resection of her affected colon. On postoperative follow-up, the patient is doing well and has had no recurrent episodes of diverticulitis.
Complementary and Alternative Medicine
Many people use complementary and alternative medicine (CAM) therapies for many of the disorders discussed, including colon cancer. For the purposes of this monograph, complementary and alternative medicine is defined as therapy that is not widely taught or endorsed in U.S. medical schools and is not widely available in hospitals. The use of CAM has increased dramatically over time, and an increasing number of studies are being conducted that address its effectiveness. Complementary and alternative medicine frequently is used to help ameliorate GI symptoms, especially functional bowel disorders. One survey revealed that more than 40% of GI patients use some form of CAM therapy, with women more likely than men to report its use 112. Examples include herbal medicines, homeopathy, acupuncture, colonic irrigation therapy, and meditation and relaxation therapy. Some sources include hypnotherapy as CAM therapy, but that has been discussed previously in the context of psychologic therapy in the section “Irritable Bowel Syndrome.” Table 9 summarizes common CAM therapies, their uses, and specific concerns. Although some studies demonstrate benefit and relative safety with the use of such therapies, the safety of other modalities is either not known or has been shown to have concerning effects. Inquiring about the use of CAM is important and provides a counseling opportunity regarding benefits and safety of CAM therapies. Resources listed at the end of this monograph can provide additional information to practitioners about particular forms of therapy.
Outside the realm of vitamin and nutrient supplementation, a paucity of data exists regarding CAM therapies and their utility for colorectal cancer prevention. However, studies have focused on the use of CAM in colorectal cancer patients and survivors. Therapies associated with colorectal cancer treatment, including surgery, chemotherapy, and radiation, all can reduce quality of life, especially during the treatment period, with some additional long-term effects (particularly in the case of radiation for rectal cancer). A survey of more than 500 cancer patients revealed frequent use of CAM therapies, including special diets, nutritional or herbal supplements, acupuncture, massage, and meditation and relaxation techniques 114. In this study, women were more likely to have used any form of CAM therapy (86%) compared with men (70%). One study of 193 patients did show an increased survival rate when Chinese herbal medications with vitamins were used in combination with conventional therapy, compared with conventional therapy alone 115.
Conclusions and Future Directions
Future research is directed at 1) decreasing the morbidity and mortality of patients with lower GI tract disease by improving prevention, early diagnosis, and treatment and 2) improving quality of life in those with chronic disease. Although the incidence of colorectal cancer has decreased since implementation of screening guidelines, it remains the third leading cause of cancer death in women in the United States 13. Identifying and closing gaps in screening, improving screening test accuracy, and developing acceptable and accessible screening methods are current areas of research. Treatment of colorectal cancer continues to evolve, because genetic testing can help predict tumor response to specific therapies.
Increasing understanding of the pathophysiology of GI motility disorders has led to an implementation of a wide range of therapies. Although no cure exists for functional bowel disorders, symptom management and a trusting patient–physician relationship remain paramount to the well-being of the patient. Continual assessment of the Rome guidelines helps to better characterize patients with functional disorders. New therapies continue to be introduced to improve motility disturbances. An improved understanding of the complex interplay of visceral hypersensitivity and central perception in IBS has led to increased use of nonpharmacologic therapies, such as cognitive–behavioral therapy and gut-directed hypnotherapy.
Physicians have witnessed great progress in IBD treatment over the past three decades with the introduction of biologic agents that have helped avoid surgery in many patients. Research is currently underway to evaluate additional monoclonal antibodies and inflammatory mediators as targets for potential therapy. Clues to the causes of IBD, including environmental factors and genetic mutations, continue to unfold through diligent research. Pregnancy and fertility are frequent concerns for many patients with IBD, given that the disease is often diagnosed in early adult life. Data from the Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes registry and other studies continue to help physicians manage patients in all stages of family planning.
In conclusion, obstetrician–gynecologists evaluate or treat many patients with lower GI tract disorders. Often, they are the first physicians to elicit lower GI tract concerns in patients. Patients with lower GI tract disease often require a multidisciplinary management team, including obstetrician–gynecologists, internists or family practitioners, gastroenterologists, oncologists, and psychiatrists or psychologists. Such management can improve their well-being and outcomes.
The future of colorectal cancer screening is focused on many avenues, such as improving screening rates and increasing the accuracy of screening tests. Screening rates in the United States are still less than optimal but have improved over the years. The CDC estimates that colon cancer screening rates increased from 67.4% in 2016 to 68.8% in 2018, which includes an additional 3.5 million adults undergoing screening 116. This is a substantial improvement compared with 2005 and 2010, in which rates were 50.8% and 64.8%, respectively 117 118. Although screening rates have improved, potential for further improvement remains. Screening rates are lowest among those individuals without health insurance, those who do not have a usual source of health care, and those who have not visited a health care professional within the past year. Moreover, racial disparities in screening rates persist. In 2015, over 65% of non-Hispanic White patients reported some form of screening, compared to 60% of non-Hispanic Black patients and only 47% of Hispanic patients 119. Access to primary care, patient awareness of the disease, its prevalence, and knowledge of available screening tests are all limiting factors. Eliminating barriers to screening and, thus, improving screening rates is expected to decrease mortality from colorectal cancer further. One example is the implementation of the Affordable Care Act of 2010, which requires Medicare and most private insurance companies to provide screening colonoscopy as a covered test for patients without out-of-pocket cost to the patient, including a deductible or copayment fee 120.
In addition to improving access of patients to screening tests, improving the accuracy of the tests themselves is thought to decrease mortality from colorectal cancer. The American Society for Gastrointestinal Endoscopy quotes miss rates for colonoscopy of up to 6% for cancer and up to 12–17% for adenomatous polyps 121. Numerous quality indicators have been identified by the U.S. Multi-Society Task Force on Colorectal Cancer as areas of focus for improving adenoma detection during colonoscopy 122. Examples include cecal intubation rate (verifying that an examination was complete), withdrawal time (increased withdrawal times have been associated with increased polyp detection rates), and removal of all polyps less than 2 cm or explicit documentation of polyp unresectability. Quality of bowel preparation also is documented. Poor preparation of the bowel is associated with missed lesions because retained stool can obscure polyps and even advanced neoplasms.
Improving the sensitivity and specificity of the tests is another area of focus. Advancements in endoscopic technologies, such as improvements in optical imaging and complete polyp removal, have improved adenoma detection rates. Improvements that could make screening modalities such as stool DNA testing and CT colonography more cost-effective may increase screening rates by offering a variety of testing modalities to patients.
The following list is for information purposes only. Many of these sources contain links for helpful patient information. Referral to these sources and websites does not imply the endorsement of the American College of Obstetricians and Gynecologists. This list is not meant to be comprehensive. The exclusion of a source or website does not reflect the quality of that source or website. Please note that websites are subject to change without notice.
The American College of Gastroenterology: gi.org
The American Gastroenterological Association: www.gastro.org
The Rome Foundation: theromefoundation.org
Celiac Disease Foundation: www.celiac.org
Centers for Disease Control and Prevention: www.cdc.gov
The Cochrane Collaboration: www.cochrane.org
Crohn Colitis Foundation of America: www.ccfa.org
International Foundation for Functional Gastrointestinal Disorders: www.aboutibs.org
National Center for Complementary and Alternative Medicine: www.nccam.nih.gov
National Institute on Diabetes and Digestive and Kidney Diseases: www2.niddk.nih.gov
Natural Medicines Comprehensive Database: www.naturaldatabase.com
U.S. Food and Drug Administration: www.fda.gov
Studies were reviewed and evaluated for quality according to the method outlined by the U.S. Preventive Services Task Force:
I Evidence obtained from at least one properly designed randomized controlled trial.
II-1 Evidence obtained from well-designed controlled trials without randomization.
II-2 Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group.
II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this type of evidence.
III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.