2489 Inflammatory Bowel Disease CHAPTER 326

disease activity. The amount of glucocorticoids received by the nursing

infant is minimal. The safest antibiotics to use for CD in pregnancy for

short periods of time (weeks, not months) are ampicillin and cephalosporins. Metronidazole can be used in the second or third trimester.

Ciprofloxacin causes cartilage lesions in immature animals and should

be avoided because of the absence of data on its effects on growth and

development in humans.

MP and azathioprine pose minimal or no risk during pregnancy.

Breast milk has been shown to contain negligible levels of MP/

azathioprine when measured in a limited number of patients.

MTX is teratogenic and should be discontinued at least 3 months

before conception.

In a large prospective and multiple retrospective studies, no increased

risk of stillbirths, miscarriages, or spontaneous abortions was seen with

infliximab, ADA, or certolizumab. Infliximab and ADA are IgG1

antibodies and are actively transported across the placenta in the late

second and third trimesters. Infants can have serum levels of infliximab

and ADA up to 12 months of age, and live vaccines should be avoided

during this time. Certolizumab crosses the placenta by passive diffusion, and infant serum and cord blood levels are minimal. The antiTNF drugs are relatively safe in nursing. Miniscule levels of infliximab,

ADA, and certolizumab have been reported in breast milk. These levels

are of no clinical significance. It is recommended that drugs should not

be switched during pregnancy unless necessitated by the medical condition of the IBD. VDZ and ustekinumab appear safe during pregnancy,

although the data are limited. Tofacitinib should not be used during

pregnancy. Animal studies show teratogenic effects with tofacitinib,

and data in humans are limited. A washout period of at least 1 week is

recommended before conception. Surgery in UC should be performed

only for emergency indications, including severe hemorrhage, perforation, and megacolon refractory to medical therapy. Total colectomy

and ileostomy carry a 50% risk of postoperative spontaneous abortion.

The best time to perform surgery is in the second trimester if necessary.

Patients with IPAAs have increased nighttime stool frequency during

pregnancy that resolves postpartum. Transient small-bowel obstruction

or ileus has been noted in up to 8% of patients with ileostomies.

CANCER IN IBD

■ ULCERATIVE COLITIS

Patients with long-standing UC are at increased risk for developing

colonic epithelial dysplasia and carcinoma (Fig. 326-13).

The risk of neoplasia in chronic UC increases with duration and

extent of disease. In contrast to the relatively high risk in one large

meta-analysis (2% after 10 years, 8% after 20 years, and 18% after

30 years of disease), a decrease in the risk of colorectal cancer has been

noted over time potentially due to better control of inflammation and

better colonoscopic surveillance. The rates of colon cancer are still

about 1.5 to 2 times higher than in the general population, and colonoscopic surveillance is the standard of care.

Annual or biennial colonoscopy with multiple biopsies is recommended for patients with >8–10 years of extensive colitis (greater than

one-third of the colon involved) or 12–15 years of proctosigmoiditis

(less than one-third but more than just the rectum) and has been widely

used to screen and survey for subsequent dysplasia and carcinoma.

International guideline societies have recommended chromoendoscopy for dysplasia surveillance in IBD. Chromoendoscopy enhances

the visualization of the surface and pit pattern of the mucosa, as well as

borders of lesions, in order to better define areas of dysplasia compared

to standard-definition white light endoscopy. The evidence behind

chromoendoscopy is controversial. A systematic review of randomized

controlled trials found that chromoendoscopy had a higher likelihood

of detecting dysplasia compared to standard-definition white light

endoscopy with a relative risk of 2.12. In contrast, a retrospective study

found no significant difference in dysplasia detection rates between

chromoendoscopy and standard-definition white light endoscopy. In

real-life settings, the practice has been to use standard-definition white

light endoscopy with surveillance biopsies in patients with chronic

colitis at average risk and chromoendoscopy in higher-risk patients

including those with a history of dysplasia, PSC, or family history of

colorectal cancer.

Risk factors for cancer in UC include long-duration disease, extensive disease, family history of colon cancer, PSC, a colon stricture, and

the presence of postinflammatory pseudopolyps on colonoscopy.

■ CROHN’S DISEASE

Risk factors for developing cancer in Crohn’s colitis are long-duration

and extensive disease, bypassed colon segments, colon strictures, PSC,

and family history of colon cancer. The cancer risks in CD and UC are

probably equivalent for similar extent and duration of disease. In the

CESAME study, a prospective observational cohort of IBD patients

in France, the standardized incidence ratios of colorectal cancer were

2.2 for all IBD patients (95% CI, 1.5–3.0; p < .001) and 7.0 for patients

with long-standing extensive colitis (both Crohn’s and UC) (95% CI,

4.4–10.5; p < .001). Thus, the same endoscopic surveillance strategy

used for UC is recommended for patients with chronic Crohn’s colitis.

A pediatric colonoscope can be used to pass narrow strictures in CD

patients, but surgery should be considered in symptomatic patients

with impassable strictures.

■ MANAGEMENT OF DYSPLASIA AND CANCER

Dysplasia can be flat or polypoid. If flat high-grade dysplasia is encountered on colonoscopic surveillance, the usual treatment is colectomy

for UC and either colectomy or segmental resection for CD. If flat lowgrade dysplasia is found (Fig. 326-13), most investigators recommend

immediate colectomy. Adenomas may occur coincidently in UC and

CD patients with chronic colitis and can be removed endoscopically

provided that biopsies of the surrounding mucosa are free of dysplasia.

IBD patients are also at greater risk for other malignancies. Patients

with CD may have an increased risk of NHL, leukemia, and myelodysplastic syndromes. Severe, chronic, complicated perianal disease in CD

patients may be associated with an increased risk of cancer in the lower

rectum and anal canal (squamous cell cancers). Although the absolute

risk of small-bowel adenocarcinoma in CD is low (2.2% at 25 years in

one study), patients with long-standing, extensive, small-bowel disease

should be considered for screening.

COVID-19 AND IBD

COVID-19, caused by SARS-CoV-2, was first reported in December

2019 and has rapidly spread throughout the world, leading to an international pandemic. Glucocorticoids, immunomodulators (thiopurines,

MTX), biologics, and JAK inhibitors, commonly used to treat IBD, are

associated with higher rates of serious viral and bacterial infections, and

patients with IBD using these medications are potentially at increased

risk of a serious COVID-19 infection. Yet, it is also possible that

some forms of immune suppression may blunt the excessive immune

response/cytokine storm characteristic of severe COVID-19 infection

and consequently reduce mortality. Using data from the Surveillance

FIGURE 326-13 Medium-power view of low-grade dysplasia in a patient with

chronic ulcerative colitis. Low-grade dysplastic crypts are interspersed among

regenerating crypts. (Courtesy of Dr. R. Odze, Division of Gastrointestinal Pathology,

Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts;

with permission.)

2490 PART 10 Disorders of the Gastrointestinal System

Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease, it was found that increasing age (adjusted OR

1.04; 95% CI, 1.01–1.02), two or more comorbidities (adjusted OR 2.9;

95% CI, 1.1–7.8), and systemic glucocorticoids (adjusted OR 6.9; 95%

CI, 2.3–20.5) are associated with severe COVID-19 in IBD patients.

Anti-TNF treatment was not associated with severe COVID-19

(adjusted OR 0.9; 95% CI, 0.4–2.2).

■ FURTHER READING

Alexandersson B et al: High-definition chromoendoscopy superior

to high-definition white-light endoscopy in surveillance of inflammatory bowel diseases in a randomized trial. Clin Gastroenterol

Hepatol 18:2101, 2020.

Ananthakrishnan A et al: Changing global epidemiology of inflammatory bowel disease: Sustaining health care delivery into the 21st

century. Clin Gastroenterol Hepatol. 2020;18(6):1252-1260.Bellaguarda E, Hanauer ST: Checkpoint-inhibitor-induced colitis. Am J

Gastroenterol 115:202, 2020.

Bernstein CM et al: Events within the first year of life, but not the

neonatal period, affect risk for later development of inflammatory

bowel diseases. Gastroenterology 156:2190, 2019.

Brenner E et al: Corticosteroids, but not TNF antagonists, are

associated with adverse COVID-19 outcomes in patients with

inflammatory bowel diseases: Results from an international registry.

Gastroenterology 159:481, 2020.

Graham DB, Xavier RJ: Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature 578:527, 2020.

Levine A et al: Crohn’s disease exclusion diet plus partial enteral nutrition induces sustained remission in a randomized controlled trial.

Gastroenterology 157:440, 2019.

Mahadevan U et al: Pregnancy and neonatal outcomes after fetal

exposure to biologics and thiopurines among women with inflammatory bowel disease. Gastroenterology 160:1131, 2021.

Moller FT et al: Familial risk of inflammatory bowel disease: A

population-based cohort study 1977-2011. Am J Gastroenterol

110:564, 2015.

Ng SC et al: Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: A systematic review of

population-based studies. Lancet 390:2769, 2018.

Sands BE et al: UNIFI Study Group. Ustekinumab as induction and

maintenance therapy for ulcerative colitis. N Engl J Med 381:1201,

2019.

Sands BE et al: VARSITY Study Group. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med

381:1215, 2019.

Singh S et al: AGA technical review on the management of moderate

to severe ulcerative colitis. Gastroenterology 158:1465, 2020.

327 Irritable Bowel

Syndrome

Chung Owyang

TABLE 327-1 Rome IV Diagnostic Criteria for Irritable

Bowel Syndromea

Recurrent abdominal pain, on average, at least 1 day per week in the

last 3 months, associated with ≥2 of the following criteria:

1. Related to defecation

2. Associated with a change in frequency of stool

3. Associated with a change in form (appearance) of stool

a

Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to

diagnosis.

Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain or discomfort and altered bowel habits in

the absence of detectable structural abnormalities. No clear diagnostic

markers exist for IBS; thus, the diagnosis of the disorder is based on

clinical presentation. In 2016, the Rome III criteria for the diagnosis of

IBS were updated to Rome IV (Table 327-1). Throughout the world,

~10–20% of adults and adolescents have symptoms consistent with IBS.

IBS symptoms tend to come and go over time and often overlap with

other functional disorders such as fibromyalgia, headache, backache,

and genitourinary symptoms. Severity of symptoms varies and can

significantly impair quality of life, resulting in high health care costs.

Altered gastrointestinal (GI) motility, visceral hyperalgesia, disturbance

of brain–gut interaction, abnormal central processing, autonomic and

hormonal events, genetic and environmental factors, and psychosocial

disturbances are variably involved, depending on the individual. This

progress may result in improved methods of treatment.

■ CLINICAL FEATURES

IBS is a disorder that affects all ages, although most patients have their

first symptoms before age 45. Women are diagnosed with IBS two to

three times as often as men and make up 80% of the population with

severe IBS. As indicated in Table 327-1, pain is a key symptom for the

diagnosis of IBS. This symptom should be associated with defecation

and/or have its onset associated with a change in frequency or form of

stool. In comparison to Rome III, the Rome IV criteria are more stringent, requiring abdominal pain to occur at a minimum of once a week

and eliminating “discomfort” as one of the criteria. Painless diarrhea

or constipation does not fulfill the diagnostic criteria to be classified as

IBS. Supportive symptoms that are not part of the diagnostic criteria

include defecation straining, urgency or a feeling of incomplete bowel

movement, passing mucus, and bloating.

Abdominal Pain According to the current IBS diagnostic criteria,

abdominal pain is a prerequisite clinical feature of IBS. Abdominal

pain in IBS is highly variable in intensity and location. It is frequently

episodic and crampy, but it may be superimposed on a background

of constant ache. Pain may be mild enough to be ignored, or it may

interfere with daily activities. Despite this, malnutrition due to inadequate caloric intake is exceedingly rare with IBS. Sleep deprivation is

also unusual because abdominal pain is almost uniformly present only

during waking hours. Pain is often exacerbated by eating or emotional

stress and improved by passage of flatus or stools. In addition, female

patients with IBS commonly report worsening symptoms during the

premenstrual and menstrual phases.

Altered Bowel Habits Alteration in bowel habits is the most

consistent clinical feature in IBS. The most common pattern is constipation alternating with diarrhea, usually with one of these symptoms

predominating. At first, constipation may be episodic, but eventually, it

becomes continuous and increasingly intractable to treatment with laxatives. Stools are usually hard with narrowed caliber, possibly reflecting excessive dehydration caused by prolonged colonic retention and

spasm. Most patients also experience a sense of incomplete evacuation,

thus leading to repeated attempts at defecation in a short time span.

Patients whose predominant symptom is constipation may have weeks

or months of constipation interrupted with brief periods of diarrhea. In

other patients, diarrhea may be the predominant symptom. Diarrhea

resulting from IBS usually consists of small volumes of loose stools.

Most patients have stool volumes of <200 mL. Nocturnal diarrhea

does not occur in IBS. Diarrhea may be aggravated by emotional stress

or eating. Stool may be accompanied by passage of large amounts of

mucus. Bleeding is not a feature of IBS unless hemorrhoids are present,

and malabsorption or weight loss does not occur.

Bowel pattern subtypes are highly unstable. In a patient population

with ~33% prevalence rates of IBS-diarrhea predominant (IBS-D),

IBS-constipation predominant (IBS-C), and IBS-mixed (IBS-M) forms,

75% of patients change subtypes, and 29% switch between IBS-C and

IBS-D over 1 year.

2491 Irritable Bowel Syndrome CHAPTER 327

Gas and Flatulence Patients with IBS frequently complain of

abdominal distention and increased belching or flatulence, all of

which they attribute to increased gas. Although some patients with

these symptoms actually may have a larger amount of gas, quantitative

measurements reveal that most patients who complain of increased

gas generate no more than a normal amount of intestinal gas. Most

IBS patients have impaired transit and tolerance of intestinal gas loads.

In addition, patients with IBS tend to reflux gas from the distal to

the more proximal intestine, which may explain the belching. Some

patients with bloating may also experience visible distention with

increase in abdominal girth.

Upper GI Symptoms Between 25 and 50% of patients with IBS

complain of dyspepsia, heartburn, nausea, and vomiting. This suggests

that other areas of the gut apart from the colon may be involved. Prolonged ambulant recordings of small-bowel motility in patients with

IBS show a high incidence of abnormalities in the small bowel during

the diurnal (waking) period; nocturnal motor patterns are not different

from those of healthy controls. The overlap between dyspepsia and IBS

is great. The prevalence of IBS is higher among patients with dyspepsia

(31.7%) than among those who reported no symptoms of dyspepsia

(7.9%). Conversely, among patients with IBS, 55.6% reported symptoms

of dyspepsia. In addition, the functional abdominal symptoms can

change over time. Those with predominant dyspepsia or IBS can flux

between the two. Thus, it is conceivable that functional dyspepsia and

IBS are two manifestations of a single, more extensive digestive system

disorder. Furthermore, IBS symptoms are prevalent in noncardiac chest

pain patients, suggesting overlap with other functional gut disorders.

■ PATHOPHYSIOLOGY

The pathogenesis of IBS is poorly understood, although roles of

abnormal gut motor and sensory activity, central neural dysfunction,

psychological disturbances, mucosal inflammation, stress, and luminal

factors such as bile acid malabsorption and gut dysbiosis have been

proposed (Fig. 327-1).

GI Motor Abnormalities Studies of colonic myoelectrical and

motor activity under unstimulated conditions have not shown consistent abnormalities in IBS. In contrast, colonic motor abnormalities are

more prominent under stimulated conditions in IBS. IBS patients may

exhibit increased rectosigmoid motor activity for up to 3 h after eating.

Similarly, inflation of rectal balloons both in IBS-D and IBS-C patients

leads to marked and prolonged distention-evoked contractile activity. Recordings from the transverse, descending, and sigmoid colon

showed that the motility index and peak amplitude of high-amplitude

propagating contractions (HAPCs) in diarrhea-prone IBS patients

were greatly increased compared to those in healthy subjects and were

associated with rapid colonic transit and accompanied by abdominal

pain.

Visceral Hypersensitivity IBS patients frequently exhibit exaggerated sensory responses to visceral stimulation. The frequency of

perceptions of food intolerance is at least twofold more common than

in the general population. Postprandial pain has been temporally

related to entry of the food bolus into the cecum in 74% of patients.

On the other hand, prolonged fasting in IBS patients is often associated

with significant improvement in symptoms. Rectal balloon inflation

produces nonpainful and painful sensations at lower volumes in IBS

patients than in healthy controls without altering rectal tension, suggestive of visceral afferent dysfunction in IBS. Similar studies show gastric

and esophageal hypersensitivity in patients with nonulcer dyspepsia

and noncardiac chest pain, raising the possibility that these conditions

have a similar pathophysiologic basis. Lipids lower the thresholds for

the first sensation of gas, discomfort, and pain in IBS patients. Hence,

postprandial symptoms in IBS patients may be explained in part by a

nutrient-dependent exaggerated sensory component of the gastrocolonic response. In contrast to enhanced gut sensitivity, IBS patients

do not exhibit heightened sensitivity elsewhere in the body. Thus, the

afferent pathway disturbances in IBS appear to be selective for visceral innervation with sparing of somatic pathways. The mechanisms

responsible for visceral hypersensitivity are still under investigation.

Central Neural Dysregulation The role of central nervous system (CNS) factors in the pathogenesis of IBS is strongly suggested by

the clinical association of emotional disorders and stress with symptom

exacerbation and the therapeutic response to therapies that act on cerebral cortical sites. Functional brain imaging studies such as magnetic

resonance imaging (MRI) have shown that in response to distal colonic

stimulation, the mid-cingulate cortex—a brain region concerned with

attention processes and response selection—shows greater activation

in IBS patients. Modulation of this region is associated with changes

in the subjective unpleasantness of pain. In addition, IBS patients also

show preferential activation of the prefrontal lobe, which contains a

vigilance network within the brain that increases alertness. These may

represent a form of cerebral dysfunction, leading to the increased perception of visceral pain.

Abnormal Psychological Features Abnormal psychiatric features are recorded in up to 80% of IBS patients, especially in referral

centers; however, no single psychiatric diagnosis predominates. Most

of these patients demonstrated exaggerated symptoms in response to

visceral distention, and this abnormality persists even after exclusion

of psychological factors.

Psychological factors influence pain thresholds in IBS patients, as

stress alters sensory thresholds. An association between

prior sexual or physical abuse and development of IBS

has been reported. Clinical studies suggest that IBS has

a strong developmental component that involves interactions of genetic and epigenetic factors early in life. These

may modulate brain networks related to emotional arousal

and/or central autonomic control, salience, and somatosensory integration. Abuse is associated with greater

pain reporting, psychological distress, and poor health

outcome. Brain functional MRI studies show greater activation of the posterior and middle dorsal cingulate cortex,

which is implicated in affect processing in IBS patients

with a past history of sexual abuse.

Postinfectious IBS A GI infection may predispose

a patient to IBS. In an investigation of 544 patients with

confirmed bacterial gastroenteritis, one-quarter developed IBS subsequently. Conversely, about a third of IBS

patients experienced an acute “gastroenteritis-like” illness

at the onset of their chronic IBS symptomatology. This

group of “postinfective” IBS occurs more commonly in

females and affects younger rather than older patients.

Risk factors for developing postinfectious IBS include, in

Motility

abnormalities

Brain–gut

interactions

• HPA axis

• Autonomic

 dysfunction

Genetic factors

• Twin studies

• SERT polymorphisms

Psychological

• Anxiety/panic

• Depression

• Somatization

“Leaky” gut

dysbiosis

IBS

Visceral

hypersensitivity

Bile acid

malabsorption

FIGURE 327-1 Pathophysiology of irritable bowel syndrome (IBS). The cause of IBS is likely to be

multifactorial. Patients often show evidence of visceral hypersensitivity and motility abnormalities.

Many IBS patients have increased anxiety and/or depression, and their symptoms are often

exacerbated by mental or physical stress, suggesting abnormal brain–gut interaction. Genetic

studies suggest a few IBS patients may have genetic abnormalities affecting the serotonin

transport system in the enteric nerves. Up to 30% of IBS patients may have bile acid malabsorption.

Gut dysbiosis and impaired mucosa permeability also have been reported in many IBS patients.

This may lead to subclinical mucosa inflammation.

2492 PART 10 Disorders of the Gastrointestinal System

order of importance, prolonged duration of initial illness, toxicity of

infecting bacterial strain, smoking, mucosal markers of inflammation,

female sex, depression, hypochondriasis, and adverse life events in the

preceding 3 months. Age older than 60 years might protect against

postinfectious IBS, whereas treatment with antibiotics has been associated with increased risk. The microbes involved in the initial infection

are Campylobacter, Salmonella, and Shigella. Increased rectal mucosal

enteroendocrine cells, T lymphocytes, and gut permeability are acute

changes following Campylobacter enteritis that could persist for more

than a year and may contribute to postinfective IBS.

Immune Activation and Mucosal Inflammation Some

patients with IBS display persistent signs of low-grade mucosal inflammation with activated lymphocytes, mast cells, and enhanced expression of proinflammatory cytokines. Other studies also indicate that

peripheral blood mononuclear cells (PBMCs) from IBS patients show

abnormal release of proinflammatory cytokines such as interleukin

(IL) 6, IL-1β, and tumor necrosis factor (TNF). These abnormalities

may contribute to abnormal epithelial secretion and visceral hypersensitivity. Located at the host-environment interface, mast cells are in

close proximity to sensory nerves. Electromicroscopic evidence of mast

cell activation is commonly observed in the colonic mucosa of IBS

patients. Recent studies show that the proximity of activated mast cells

to submucosal nerve fibers correlates with the frequency and severity

of abdominal pain in patients with IBS. Other studies report that the

colonic mucosa of IBS patients releases increased amounts of mast

cell mediators, including histamine, proteases, and prostaglandin E2

.

These findings, together with the observation that marked excitation of

visceral sensory nerves innervating the colon occurs after exposure to

IBS mucosal supernatant, support a prominent role for mast cells in the

pathogenesis of visceral hypersensitivity. Increasing evidence suggests

that some members of the superfamily of transient receptor potential

(TRP) cation channels such as TRPV1 (vanilloid) channels are central

to the initiation and persistence of visceral hypersensitivity. Mucosal

inflammation can lead to increased expression of TRPV1 in the enteric

nervous system. Enhanced expression of TRPV1 channels in the sensory neurons of the gut has been observed in IBS, and such expression

appears to correlate with visceral hypersensitivity and abdominal pain.

Interestingly, clinical studies have also shown increased intestinal permeability in patients with IBS-D. Psychological stress and anxiety can

increase the release of proinflammatory cytokine, and this in turn may

alter intestinal permeability. A clinical study showed that 39% of IBS-D

patients had increased intestinal permeability as measured by the

lactulose/mannitol ratio. These IBS patients also demonstrated a

higher Functional Bowel Disorder Severity Index (FBDSI) score and

increased hypersensitivity to visceral nociceptive pain stimuli. This

provides a functional link among psychological stress, immune activation, and symptom generation in patients with IBS.

Altered Gut Flora A high prevalence of small-intestinal bacterial

overgrowth in IBS patients has been noted based on positive lactulose

hydrogen breath test. This finding, however, has been challenged by a

number of other studies that found no increased incidence of bacterial

overgrowth based on jejunal aspirate culture. Abnormal H2

 breath

test can occur because of small-bowel rapid transit and may lead to

erroneous interpretation. Hence, the role of testing for small-intestinal

bacterial overgrowth in IBS patients remains unclear.

Studies using culture-independent approaches such as 16S rRNA

gene-based analysis found significant differences between the molecular profile of the fecal microbiota of IBS patients and that of healthy

subjects. A review of 24 studies involving 827 IBS patients showed

extensive variability in bacterial flora among IBS patients and healthy

subjects. However, a few general observations were made: (1) an

increase in the ratio of fecal Firmicutes to fecal Bacteroidetes was

noted in IBS; (2) the diversity of the microbiota was decreased; and

(3) these changes were accompanied by an increase in instability of the

bacteria flora in IBS. Despite a lack of consensus on the exact microbial

difference between IBS patients and controls, IBS patients generally

had decreased proportions of the genera Bifidobacterium and Faecalibacterium and increased abundance of family Enterobacteriaceae

(phylum Proteobacteria), family Lactobacillaceae, and genus Bacteroides (phylum Bacteroidetes) (Fig. 327-2). Many members of the

genus Faecalibacterium are butyrate-producing and anti-inflammatory

organisms and may reduce IBS symptoms via mediation of IL-17

expression. Similarly, members of the genus Bifidobacterium are also

anti-inflammatory organisms and may reduce mucosal inflammation

in IBS patients in clinical trials. On the other hand, the three groups

of bacteria that were increased were potentially harmful commensal

microbiota. The gram-negative Enterobacteriaceae family is capable

of injuring epithelium lining and inducing mucosal inflammation

via a lipopolysaccharide-dependent pathway. Members of the genus

Bacteroides such as Bacteroides fragilis produces toxin to dissolve glycoproteins and induce mucosal inflammation. Lastly, in the family of

Lactobacillaceae, Lactobacillus can produce gas and organic acids from

glucose and fructose fermentation, resulting in bloating and abdominal

pain. It is conceivable that gut dysbiosis acting in concert with genetic

susceptibility and environmental insults may alter mucosal permeability and increase antigen presentation to the immune cells in the lamina

propria. This may result in mast cell activation and altered enteric neuronal and smooth-muscle function causing IBS symptoms. In addition,

release of cytokines and chemokines from mucosal inflammation may

generate extra-GI symptoms such as chronic fatigue, muscle pain, and

anxiety (Fig. 327-3).

Abnormal Serotonin Pathways The serotonin-containing

enterochromaffin cells in the colon are increased in a subset of IBS-D

patients compared to healthy individuals or patients with ulcerative

colitis. Furthermore, postprandial plasma serotonin levels were significantly higher in this group of patients compared to healthy controls.

Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme in

enterochromaffin cell serotonin biosynthesis, and functional TPH1

polymorphism has been shown to be associated with IBS habit subtypes. In addition, gut microbes promote colonic serotonin production

through an effect of short-chain fatty acids on enterochromaffin cells.

In IBS patients, the expression of mucosal serotonin reuptake transporter (SERT) is downregulated due to gram negative gut dysbiosis.

Thus, gut and reuptake dysbiosis in IBS may contribute to abnormal

serotonin synthesis in this disorder. Because serotonin plays an important role in the regulation of GI motility and visceral perception, the

increased release of serotonin may contribute to the postprandial

symptoms of these patients and provides a rationale for the use of serotonin antagonists in the treatment of this disorder.

APPROACH TO THE PATIENT

Irritable Bowel Syndrome

Because IBS is a disorder for which no pathognomonic abnormalities have been identified, its diagnosis relies on recognition of

positive clinical features and elimination of other organic diseases.

Symptom-based criteria have been developed for the purpose of

differentiating patients with IBS from those with organic diseases.

These include the Manning, Rome I, Rome II, Rome III, and Rome

IV criteria. Rome IV criteria for the diagnosis of IBS were published

in 2016 (Table 327-1) and defined IBS on the basis of abdominal

Lactobacillaceae

Healthy controls IBS

IBS vs Controls

Bacteroides

Bifidobacterium

Faecalibacterium

Enterobacteriaceae

FIGURE 327-2 Changes in gut microbiota among patients with irritable bowel

syndrome. (Adapted from R Pittayanon et al: Gastroenterology 157:97, 2019.)

2493 Irritable Bowel Syndrome CHAPTER 327

pain and altered bowel habits that occur with sufficient frequency

in affected patients. A careful history and physical examination

are frequently helpful in establishing the diagnosis. Clinical features suggestive of IBS include recurrence of lower abdominal

pain with altered bowel habits over a period of time without

progressive deterioration, onset of symptoms during periods of

stress or emotional upset, absence of other systemic symptoms

such as fever and weight loss, and small-volume stool without any

evidence of blood.

On the other hand, the appearance of the disorder for the first

time in old age, progressive course from time of onset, persistent

diarrhea after a 48-h fast, and presence of nocturnal diarrhea or

steatorrheal stools argue against the diagnosis of IBS.

Because the major symptoms of IBS—abdominal pain, abdominal

bloating, and alteration in bowel habits—are common complaints

of many GI organic disorders, the list of differential diagnoses is a

long one. The quality, location, and timing of pain may be helpful

to suggest specific disorders. Pain due to IBS that occurs in the

epigastric or periumbilical area must be differentiated from biliary tract disease, peptic ulcer disorders, intestinal ischemia, and

carcinoma of the stomach and pancreas. If pain occurs mainly in

the lower abdomen, the possibility of diverticular disease of the

colon, inflammatory bowel disease (including ulcerative colitis and

Crohn’s disease), and carcinoma of the colon must be considered.

Postprandial pain accompanied by bloating, nausea, and vomiting

suggests gastroparesis or partial intestinal obstruction. Patients with

small intestinal bacteria overgrowth can present with abdominal

pain, nausea, and bloating, and this possibility should be ruled

out before making a diagnosis of IBS. Intestinal infestation with

Giardia lamblia or other parasites may cause similar symptoms.

When diarrhea is the major complaint, the possibility of lactase

deficiency, laxative abuse, malabsorption, celiac sprue, hyperthyroidism, inflammatory bowel disease, and infectious diarrhea must

be ruled out. On the other hand, constipation may be a side effect

of many different drugs, such as anticholinergic, antihypertensive,

and antidepressant medications. Endocrinopathies such as hypothyroidism and hypoparathyroidism must also be considered in the

differential diagnosis of constipation. In addition, acute intermittent porphyria and lead poisoning may present in a fashion similar

to IBS, with painful constipation as the major complaint. These

possibilities are suspected on the basis of their clinical presentations

and are confirmed by appropriate serum and urine tests.

Few tests are required for patients who have typical IBS symptoms and no alarm features. Unnecessary investigations may be

costly and even harmful. The American Gastroenterological Association has delineated factors to be considered when determining

the aggressiveness of the diagnostic evaluation. These include the

duration of symptoms, the change in symptoms over time, the

age and sex of the patient, the referral status of the patient, prior

diagnostic studies, a family history of colorectal malignancy, and

the degree of psychosocial dysfunction. Thus, a younger individual

with mild symptoms requires a minimal diagnostic evaluation,

while an older person or an individual with rapidly progressive

symptoms should undergo a more thorough exclusion of organic

disease. Most patients should have a complete blood count and

sigmoidoscopic examination; in addition, stool specimens should

be examined for ova and parasites in those who have diarrhea. In

patients with persistent diarrhea not responding to simple antidiarrheal agents, a sigmoid colon biopsy should be performed to

rule out microscopic colitis. In those age >40 years, an air-contrast

barium enema or colonoscopy should also be performed. If the

main symptoms are diarrhea and increased gas, the possibility of

lactase deficiency should be ruled out with a hydrogen breath test

or with evaluation after a 3-week lactose-free diet. Excessive gas

with bloating also raises the possibility of small-bowel bacteria

overgrowth and should be ruled out with a glucose hydrogen breath

test. Some patients with IBS-D may have undiagnosed celiac sprue.

Because the symptoms of celiac sprue respond to a gluten-free diet,

testing for celiac sprue in IBS may prevent years of morbidity and

attendant expense. Decision-analysis studies show that serology

testing for celiac sprue in patients with IBS-D has an acceptable

cost when the prevalence of celiac sprue is >1% and is the dominant

strategy when the prevalence is >8%. In patients with concurrent

symptoms of dyspepsia, upper GI radiographs or esophagogastroduodenoscopy may be advisable. In patients with postprandial right

upper quadrant pain, an ultrasonogram of the gallbladder should

be obtained. Laboratory features that argue against IBS include

evidence of anemia, elevated sedimentation rate, presence of leukocytes or blood in stool, and stool volume >200–300 mL/d. These

findings would necessitate other diagnostic considerations.

TREATMENT

Irritable Bowel Syndrome

PATIENT COUNSELING AND DIETARY ALTERATIONS

Reassurance and careful explanation of the functional nature of

the disorder and of how to avoid obvious food precipitants are

important first steps in patient counseling and dietary change.

Occasionally, a meticulous dietary history may reveal substances

(such as coffee, disaccharides, legumes, and cabbage) that aggravate

symptoms. Excessive fructose and artificial sweeteners, such as

Altered

permeability

Increased

antigen

presentation

Mast cell

activation

Extra-GI

symptoms

Systemic

cytokines

& chemokines

IBS

Altered

enteric

neuronal &

smooth

muscle

function

-Dysbiosis

-Genetic

 susceptibility

-Environmental

 insults

FIGURE 327-3 Gut dysbiosis and irritable bowel syndrome (IBS). Gut dysbiosis acting in concert with genetic and environmental factors may alter intestinal permeability

and increase antigen presentation, resulting in mast cell activation. Products of mast cell degranulation may alter neuronal and smooth-muscle function causing IBS

symptoms. The cytokines and chemokines generated from mucosal inflammation may cause symptoms such as fibromyalgia, chronic fatigue, and mood changes. GI,

gastrointestinal. (Adapted from NJ Talley, AA Fodor: Gastroenterology 141:1555, 2011.)

2494 PART 10 Disorders of the Gastrointestinal System

sorbitol or mannitol, may cause diarrhea, bloating, cramping, or

flatulence. As a therapeutic trial, patients should be encouraged to

eliminate any foodstuffs that appear to produce symptoms. However, patients should avoid nutritionally depleted diets. A diet low in

fermentable oligosaccharides, disaccharides, monosaccharides, and

polyols (FODMAPs) (Table 327-2) has been shown to be helpful in

IBS patients (see “Low FODMAP Diet”).

STOOL-BULKING AGENTS

High-fiber diets and bulking agents, such as bran or hydrophilic

colloid, are frequently used in treating IBS. The water-holding

action of fibers may contribute to increased stool bulk because of

the ability of fiber to increase fecal output of bacteria. Fiber also

speeds up colonic transit in most people. In diarrhea-prone patients,

whole-colonic transit is faster than average; however, dietary fiber

can also delay transit. Furthermore, because of their hydrophilic

properties, stool-bulking agents bind water and thus prevent both

excessive hydration and dehydration of stool. The latter observation

may explain the clinical experience that a high-fiber diet relieves

diarrhea in some IBS patients. Fiber supplementation with psyllium

has been shown to reduce perception of rectal distention, indicating

that fiber may have a positive effect on visceral afferent function.

Controlled trials of dietary fiber in IBS patients have produced

variable results. This is not surprising since IBS is a heterogeneous

disorder, with some patients being constipated and other having

predominant diarrhea. Most investigations report increases in stool

weight, decreases in colonic transit times, and improvement in

constipation. Others have noted benefits in patients with alternating diarrhea and constipation, pain, and bloating. However,

most studies observe no response in patients with diarrhea- or

pain-predominant IBS. Compared to insoluble dietary fiber such

as wheat bran, soluble fibers such as psyllium preparations tend

to produce less bloating and distention. Fiber should be started at

a nominal dose and slowly titrated up as tolerated over the course

of several weeks to a targeted dose of 20–30 g of total dietary and

supplementary fiber per day. Even when used judiciously, fiber can

exacerbate bloating, flatulence, constipation, and diarrhea. Patients

with drug-induced or slow colonic transit constipation usually do

not respond to fiber supplementation.

ANTISPASMODICS

Clinicians have observed that anticholinergic drugs may provide

temporary relief for symptoms such as painful cramps related to

intestinal spasm. Although controlled clinical trials have produced

mixed results, evidence generally supports the beneficial effects

of anticholinergic drugs for pain. Physiologic studies demonstrate

that anticholinergic drugs inhibit the gastrocolic reflex; hence,

postprandial pain is best managed by giving antispasmodics

30 min before meals so that effective blood levels are achieved

shortly before the anticipated onset of pain. Most anticholinergics

contain natural belladonna alkaloids, which may cause xerostomia,

urinary hesitancy and retention, blurred vision, and drowsiness.

They should be used in the elderly with caution. Some physicians

prefer to use synthetic anticholinergics such as dicyclomine that

have less effect on mucous membrane secretion and produce fewer

undesirable side effects. Peppermint oil appears to reduce abdominal cramps by some undefined mechanism. In a meta-analysis of

nine double-blind randomized controlled trials evaluating 726 IBS

patients, peppermint oil was found to be significantly superior to

placebo for global improvement of IBS symptoms and reduction in

abdominal pain. The most commonly reported adverse event was

heartburn, which was mild and transient.

ANTIDIARRHEAL AGENTS

Peripherally acting opiate-based agents are the initial therapy of

choice for IBS-D. Physiologic studies demonstrate increases in

segmenting colonic contractions, delays in fecal transit, increases

in anal pressures, and reductions in rectal perception with these

drugs. When diarrhea is severe, especially in the painless diarrhea

variant of IBS, small doses of loperamide, 2–4 mg every 4–6 h up

to a maximum of 12 mg/d, can be prescribed. These agents are less

addictive than paregoric, codeine, or tincture of opium. In general,

the intestines do not become tolerant of the antidiarrheal effect of

opiates, and increasing doses are not required to maintain antidiarrheal potency. These agents are most useful if taken before anticipated stressful events that are known to cause diarrhea. However,

not infrequently, a high dose of loperamide may cause cramping

because of increases in segmenting colonic contractions. Another

antidiarrheal agent that may be used in IBS patients is the bile acid

binder cholestyramine resin because up to 30% of IBS-D patients

may have bile acid malabsorption.

ANTIDEPRESSANT DRUGS

In addition to their mood-elevating effects, antidepressant medications have several physiologic effects that suggest they may be

beneficial in IBS. In IBS-D patients, the tricyclic antidepressant imipramine slows jejunal migrating motor complex transit propagation

and delays orocecal and whole-gut transit, indicative of a motor

inhibitory effect. Some studies also suggest that tricyclic agents may

alter visceral afferent neural function.

TABLE 327-2 Some Common Food Sources of FODMAPs

FOOD TYPE FREE FRUCTOSE LACTOSE FRUCTANS

GALACTOOLIGOSACCHARIDES POLYOLS

Fruits Apple, cherry, mango,

pear, watermelon

Peach, persimmon,

watermelon

Apple, apricot, pear,

avocado, blackberries,

cherry, nectarine, plum,

prune

Vegetables Asparagus, artichokes,

sugar snap peas

Artichokes, beetroot, Brussels

sprout, chicory, fennel, garlic,

leek, onion, peas

Cauliflower, mushroom,

snow peas

Grains and cereals Wheat, rye, barley

Nuts and seeds Pistachios

Milk and milk products Milk, yogurt, ice

cream, custard, soft

cheeses

Legumes Legumes, lentils, chickpeas Legumes, chickpeas,

lentils

Other Honey, high-fructose corn

syrup

Chicory drinks

Food additives Inulin, FOS Sorbitol, mannitol,

maltitol, xylitol, isomalt

Abbreviations: FODMAPs, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; FOS, fructo-oligosaccharides.

Source: Reproduced with permission from PR Gibson et al: Food choice as a key management strategy for functional gastrointestinal symptoms. Am J Gastroenterol 107:657, 2012.

2495 Irritable Bowel Syndrome CHAPTER 327

A number of studies indicate that tricyclic antidepressants may

be effective in some IBS patients. When stratified according to the

predominant symptoms, improvements were observed in IBS-D

patients, with no improvement being noted in IBS-C patients. The

beneficial effects of the tricyclic compounds in the treatment of IBS

appear to be independent of their effects on depression. The therapeutic benefits for the bowel symptoms occur faster and at a lower

dosage. The efficacy of antidepressant agents from other chemical

classes in the management of IBS is less well evaluated. In contrast

to tricyclic agents, the selective serotonin reuptake inhibitor (SSRI)

paroxetine accelerates orocecal transit, raising the possibility that

this drug class may be useful in IBS-C patients. The SSRI citalopram

blunts perception of rectal distention and reduces the magnitude of

the gastrocolonic response in healthy volunteers. A small placebocontrolled study of citalopram in IBS patients reported reductions

in pain. However, these findings could not be confirmed in another

randomized controlled trial. Hence, the efficacy of SSRIs in the

treatment of IBS needs further confirmation.

ANTIFLATULENCE THERAPY

The management of excessive gas is seldom satisfactory, except

when there is obvious aerophagia or disaccharidase deficiency.

Patients should be advised to eat slowly and not chew gum or drink

carbonated beverages. Bloating may decrease if an associated gut

syndrome such as IBS or constipation is improved. If bloating is

accompanied by diarrhea and worsens after ingesting dairy products, fresh fruits, vegetables, or juices, further investigation or a

dietary exclusion trial may be worthwhile. Avoiding flatogenic

foods, exercising, losing excess weight, and taking activated charcoal are safe but unproven remedies. A low FODMAP diet has been

shown to be quite effective to reduce gas and bloating (see “Low

FODMAP Diet”). Data regarding the use of surfactants such as simethicone are conflicting. Antibiotics may help in a subgroup of IBS

patients with predominant symptoms of bloating. Beano, an overthe-counter oral β-glycosidase solution, may reduce rectal passage

of gas without decreasing bloating and pain. Pancreatic enzymes

reduce bloating, gas, and fullness during and after high-calorie,

high-fat meal ingestion.

SEROTONIN RECEPTOR MODULATORS

Serotonin 5-HT3

 and 5-HT4

 receptors are found throughout the GI

tract. Prucalopride, a dihydrobenzo-furancarboxamide derivative,

is a new selective agonist of 5-HT4

. In six of seven multicenter,

double-blind, randomized trials of prucalopride in patients with

chronic constipation, the drug was more effective that placebo. The

most frequently encountered side effects were headache, nausea,

and diarrhea, which were mostly transient. Unlike with the older

5-HT4

 agonist tegaserod, there were no significant cardiovascular

side effects. Prucalopride was approved by the European Medicines

Agency and the U.S. Food and Drug Administration (FDA) for

treatment of chronic constipation.

Another 5-HT4

 receptor agonist, tegaserod, also exhibits prokinetic activity by stimulating peristalsis. Clinical studies involving

>4000 IBS-C patients reported reduction in abdominal discomfort

and improvements in constipation and bloating compared to placebo. Diarrhea is the only major side effect. In 2007, the drug was

voluntarily withdrawn from the market after a greater number of

cardiovascular complications were observed in a database of 18,000

patients receiving tegaserod (0.11 vs 0.01% in placebo). In 2019, the

FDA reviewed additional data and approved the use of tegaserod

in women younger than 65 years old who do not have a history of

ischemic cardiovascular disease and who have no more than one

risk factor for cardiovascular disease.

SECRETAGOGUES

Lubiprostone, linaclotide, and plecanatide are secretagogues that

stimulate net efflux of ions and water into the intestinal lumen and

thus enhance transit and facilitate ease of defecation. By activating

channels on the apical (luminal) enterocyte surface, these secretagogues increase intestinal chloride secretion. Other ion channels

and transporters secrete sodium into the intestine to maintain electroneutrality, followed by the secretion of water. Lubiprostone is a

bicyclic fatty acid derived from prostaglandin E1

 that activates type

3 chloride channels in the apical membrane of intestinal epithelial

cells. Oral lubiprostone was effective in the treatment of patients

with IBS-C in large phase 3, randomized, double-blind, placebocontrolled multicenter trials. The recommended daily dose is

24 mg twice daily. In general, the drug is quite well tolerated. The

major side effects are nausea and diarrhea. Linaclotide and plecanatide are minimally absorbed 14-amino-acid peptide guanylate

cyclase-C (GC-C) agonists that bind to and activate GC-C on the

luminal surface of intestinal epithelium. The subsequent increase in

cyclic guanosine monophosphate activates the cyclic fibrosis transmembrane regulator and induces fluid secretion into the GI tract.

These drugs are similar to endogenous peptides secreted by the

small intestine (uroguanylin) or colon (guanylin). In two 12-week,

double-blind, randomized, controlled trials, linaclotide (290 or 145 μg,

once daily) reduced constipation and pain. A lower dose (72 μg

once daily) was also more effective than placebo. Linaclotide has

been approved by the FDA for treatment of constipation in IBS-C

patients. Plecanatide (3- and 6-mg doses) also has been shown to

be more effective than placebo in two phase 3 trials. The 3-mg

once-daily dose has been approved by the FDA. The only significant

side effect was diarrhea, which occurred in <5% of patients. Linaclotide and plecanatide are of similar efficacy and tolerability for

the treatment of chronic constipation. Tenapanor, a small-molecule

inhibitor of GI sodium-hydrogen exchange-3, has been shown to

be more effective than placebo when given at 50 mg twice daily in

patients with IBS-C.

OSMOTIC LAXATIVES

Osmotic agents such as magnesium citrate–based products, sodium

phosphate–based products, and nonabsorbable carbohydrates are

hypertonic products that, through osmosis, extract fluid into the

intestinal lumen to soften stool and enhance colonic transit. In

contrast, polyethylene glycol (PEG)–based solution is iso-osmotic

and induces bowel movement by high-volume lavage. The osmotic

laxatives were better than placebo in improving symptoms of

chronic constipation in clinical trials. However, chronic use of

magnesium hydroxide may result in severe hypermagnesemia in

patients with renal impairment. Frequent sodium phosphate–based

bowel cleansing should be avoided as this is associated with hyperphosphatasemia, hypocalcemia, and hypokalemia. In 19 trials,

PEG consistently induced more bowel movements than placebo.

A Cochrane review of 10 randomized trials showed that PEG was

superior to lactulose for improving stool frequency and abdominal pain. Among the nonabsorbable carbohydrates, lactulose and

sorbitol had similar laxative effects. However, bacterial metabolism

of unabsorbed carbohydrates often leads to gas production and

abdominal pain, which can limit long-term use.

MODULATION OF GUT FLORA

Because altered colonic flora (gut dysbiosis) may contribute to the

pathogenesis of IBS, this has led to great interest in using antibiotics, prebiotics, probiotics, and dietary measures to treat IBS.

Antibiotics Antibiotic treatment benefits a subset of IBS patients.

In a double-blind, randomized, placebo-controlled study, neomycin

dosed at 500 mg twice daily for 10 days was more effective than

placebo at improving symptom scores among IBS patients. The

nonabsorbed oral antibiotic rifaximin is the most thoroughly studied antibiotic for the treatment of IBS. In a double-blind, placebocontrolled study, patients receiving rifaximin at a dose of 550 mg

two times daily for 2 weeks experienced substantial improvement

of global IBS symptoms over placebo. Rifaximin is the only antibiotic with demonstrated sustained benefit beyond therapy cessation

in IBS patients. The drug has a favorable safety and tolerability

profile compared with systemic antibiotics. A systemic review and

meta-analysis of five studies of IBS patients found that rifaximin

is more effective than placebo for global symptoms and bloating