REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY
`AND HEPATOLOGY
`
`Douglas J. Robertson and Vincent W. Yang, Section Editors
`
`Gastroenterology 2020;158:1232-1249
`
`Mechanisms, Evaluation, and Management of Chronic
`Constipation
`Adil E. Bharucha 1 and Brian E. Lacy2
`
`1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota and 2Division of Gastroenterology and
`Hepatology, Mayo Clinic, Jacksonville, Florida
`
`With a worldwide prevalence of 15%, chronic constipation
`is one of the most frequent gastrointestinal diagnoses made
`in ambulatory medicine clinics, and is a common source
`cause for referrals to gastroenterologists and colorectal
`surgeons in the United States. Symptoms vary among pa(cid:173)
`tients; straining, incomplete evacuation, and a sense of
`anorectal blockage are just as important as decreased stool
`frequency. Chronic constipation is either a primary disor(cid:173)
`der (such as normal transit, slow transit, or defecatory
`disorders) or a secondary one (due to medications or, in
`rare cases, anatomic alterations). Colonic sensorimotor
`disturbances and pelvic floor dysfunction (such as defeca(cid:173)
`tory disorders) are the most widely recognized pathogenic
`mechanisms. Guided by efficacy and cost, management of
`constipation should begin with dietary fiber supplementa(cid:173)
`tion and stimulant and/or osmotic laxatives, as appro(cid:173)
`priate, followed, if necessary, by intestinal secretagogues
`and/or prokinetic agents. Peripherally acting µ-opiate an(cid:173)
`tagonists are another option for opioid-induced con(cid:173)
`stipation. Anorectal tests to evaluate for defecatory
`disorders should be performed in patients who do not
`respond to over-the-counter agents. Colonic transit, fol(cid:173)
`lowed if necessary with assessment of colonic motility with
`manometry and/or a barostat, can identify colonic dysmo(cid:173)
`tility. Defecatory disorders often respond to biofeedback
`therapy. For specific patients, slow-transit constipation may
`necessitate a colectomy. No studies have compared inex(cid:173)
`pensive laxatives with newer drugs with different mecha(cid:173)
`nisms. We review the mechanisms, evaluation, and
`management of chronic constipation. We discuss the
`importance of meticulous analyses of patient history and
`physical examination, advantages and disadvantages of
`diagnostic testing, guidance for individualized treatment,
`and management of medically refractory patients.
`
`T he prevalence of chronic constipation (CC) among adults
`
`is approximately 15%, making it the sixth most common
`gastrointestinal symptom. CC often results in visits to ambulatory
`3 Although the preva(cid:173)
`clinics and gastroenterology referrals. 1
`-
`lence is greater in non-Caucasians than Caucasians, in women
`(median female to male ratio of 1.5:1), and in institutionalized
`rather than community-living elderly persons, symptoms can
`affect all ages, races, socioeconomic groups, and nationalities.
`
`Definition and Classification
`Chronic constipation is either primary or secondary
`(attributed to another disease), determined from patient
`
`history and results from examinations and laboratory tests
`(Table 1).4 The Rome IV criteria for primary constipation
`are based on results from anorectal tests and categorize
`(FC),
`patients
`as
`having
`functional
`constipation
`constipation-predominant irritable bowel syndrome (IBS-C),
`or defecatory disorders (ODs) (Supplementary Figure 1). 5
`FC and IBS-C are primarily defined by symptoms alone
`(Table 2). ODs are defined by symptoms (such as FC or IBS(cid:173)
`C) and results from anorectal tests that indicate impaired
`rectal evacuation. Prior American Gastroenterological As(cid:173)
`sociation reviews and this update classify patients with
`constipation based on assessments of colonic transit and
`anorectal function; the classifications are normal transit
`constipation (NTC), slow transit constipation (STC), and
`6
`pelvic floor dysfunction or ODs (Supplementary Figure 1).4
`•
`Patients with constipation have infrequent stools (fewer
`than 3 bowel movements per week) and, more importantly,
`straining at stool, a feeling of incomplete evacuation, a need
`for digital assistance to evacuate stool, bloating, and hard or
`lumpy stools.7 The Rome IV criteria are predominantly
`symptom-based and as such require that patients with a
`diagnosis of FC have 2 or more of these symptoms, which
`affect > 25% of bowel movements for at least 6 months and
`active symptoms for the past 3 months (Table 1). By
`contrast, IBS-C is defined by abdominal pain that is associ(cid:173)
`ated with 2 of 3 features: altered stool form, altered stool
`frequency, or relief of abdominal pain with defecation.
`Although patients with CC also have abdominal pain, the
`pain is not, in contrast to the definition for IBS-C, associated
`with the symptoms mentioned. In (real-world) clinical
`practice, it is more useful to conceptualize FC and IBS-C
`along a spectrum; it is sometimes difficult to distinguish
`FC from IBS-C and to determine which patients are true
`
`Abbreviations used in this paper: BET, balloon expulsion test; CC, chronic
`constipation; DD, defecatory disorder; DRE, digital rectal examination; FC,
`functional constipation; FDA, US Food and Drug Administration; HAPC,
`high-amplitude propagated contraction; HAM, high-resolution anorectal
`manometry; IBS, irritable bowel syndrome; IBS-C, constipation-predominant
`irritable bowel syndrome; MR, magnetic resonance; NTC, normal
`transit constipation; PEG, polyethylene glycol; STC, slow transit
`constipation.
`
`~ Most current article
`
`© 2020 by the AGA Institute
`0016-5085/$36.00
`https://doi.org/10.1053/j.gastro.2019.12.034
`
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`Chronic Constipation 1233
`
`Table 1. Common Medical Conditions Associated With Constipation
`
`Cause
`
`Comments
`
`Drug effects
`Mechanical obstruction : colon cancer, external compression from
`malignant lesion, strictures (diverticular or post ischemic),
`rectocele (if large), megacolon, anal fissure
`Metabolic conditions: diabetes mellitus, hypothyroidism,
`hypercalcemia, hypokalemia, hypomagnesemia, uremia, heavy
`metal poisoning, uremia, heavy metal poisoning
`Myopathies: amyloidosis, scleroderma
`Neuropathies: Parkinson 's disease, spinal cord injury or tumor,
`cerebrovascular disease, and multiple sclerosis
`Other conditions: depression, degenerative joint disease, autonomic
`neuropathy, cognitive impairment, immobility, cardiac disease
`
`See Supplementary Table 1
`Often associated with alarm clinical features or laboratory tests,
`apparent on digital rectal examination (fissure) or x-ray image of
`the abdomen, or preceded by the primary event (diverticulitis)
`All are associated with/can be diagnosed by abnormal results from
`laboratory tests, which should be performed only when there is a
`high index of suspicion (such as in patients on diuretics)
`Typically associated with other clinical features of these conditions
`Constipation, either due to slow colon transit and/or DD, is common
`in patients with these disorders, which have many other features
`The disorder and/or medications may contribute to constipation
`
`medication responders using the definitions used in clinical
`trials (see Table 2). IBS-C patients are more likely to pre(cid:173)
`dominantly have abdominal pain, heightened rectal sensa(cid:173)
`tion, 8 upper gastrointestinal symptoms (eg, heartburn,
`dyspepsia), anxiety and depression, and urinary symp(cid:173)
`toms.9'10 However, blurring the distinction between FC and
`IBS-C, 1 study found that approximately 90% of patients
`with IBS-C also met criteria for FC and 44% of the FC
`patients also met criteria for IBS-C.11 In approximately one(cid:173)
`third of patients, symptoms shift over time between FC and
`IBS-C. 11 In individual patients, a diagnosis of either FC or
`IBS-C is possible only because the Rome criteria specify that
`patients with symptoms of IBS-C and FC be designated as
`IBS-C not FC.
`This limitation can be overcome by classifying consti(cid:173)
`pated patients, based on the presence or absence of mod(cid:173)
`erate to severe abdominal pain, into 1 of 2 categories, such
`(Supplementary
`as painful or painless constipation
`Figure 2).9'10 In contrast to the Rome IV criteria for IBS-C,
`these definitions do not specify the temporal relationship,
`or lack thereof, between abdominal pain and bowel habits.
`Similar to the differences for FC and IBS-C, compared to
`mild pain constipation, patients with painful constipation
`have more prominent bowel, upper gastrointestinal (such as
`dyspepsia), anorectal, urinary and sexual symptoms, anxiety
`and depression, and slower rectosigmoid transit. The
`widespread symptoms in painful constipation could partly
`reflect
`increased perception of visceral
`sensations.
`Symptom-based criteria for discriminating between painful
`and mild-pain constipation have been proposed but require
`finalization.
`
`segment and mix intraluminal contents. By comparison,
`newer high-resolution catheters have sensors separated by
`1-2.5 cm and are more accurate for detecting propagated
`motor events (Supplementary Figure 3).15 Colonic motor
`patterns are diverse, and include individual or rhythmic
`events, which may be simultaneous or propagated (ante(cid:173)
`grade or retrograde), and have low or high amplitude.13 Of
`these patterns, the gastrocolonic response to a meal and
`high-amplitude propagated contractions are arguably the
`most physiologically important. The gastrocolonic response
`begins shortly, often within a few seconds, after eating and
`may last for up to 21/z hours.16 Although a 1000-kcal meal
`invariably elicits a response, 600 kcal is probably equiva(cid:173)
`lent.17 Propagated contractions, categorized as low (5-40
`mmHg) or high-amplitude propagated contractions (HAPCs,
`> 75 mmHg), occur an average of 6 times per day, originate
`predominantly in the cecum or ascending colon, cause mass
`movement of colon contents, and often precede defeca(cid:173)
`tion.18 HAPCs occur more frequently after awakening and
`after meals and can account for the urge to defecate in
`healthy subjects and in patients with IBS. HAPCs occur
`spontaneously, occasionally in response to luminal disten(cid:173)
`tion, or can be induced by glycerol, bisacodyl, oleic acid, and
`the cholinesterase inhibitor neostigmine.
`
`Pathophysiology
`Colonic sensorimotor disturbances and pelvic floor
`dysfunction are the most widely recognized causes. Other
`factors, such as reduced caloric intake, disturbances of the
`microbiome, anatomical issues, or medications, can also
`contribute.
`
`Physiology of Colonic Motor Functions
`The right colon is a reservoir that mixes and stores
`contents.12-14 The
`left colon functions primarily as a
`conduit. The rectum and anal canal enable defecation and
`maintain fecal continence. Our understanding of motor
`activity, which is derived mostly from studies with non(cid:173)
`high-resolution manometry catheters in which sensors were
`separated by 7.5 cm or more,13 suggest that most colonic
`motor activity is irregular and nonpropagated and serves to
`
`Colonic Sensorimotor Dysfunctions and the
`Microbiome
`Isolated slow-transit constipation (eg, no DD) is used as
`a marker of colonic motor dysfunction(s), perhaps due to
`reductions in colonic intrinsic nerves and interstitial cells of
`Cajal.19,20 Manometry can reveal colonic motor distur(cid:173)
`bances, such as reduced propagated and nonpropagated
`activity and reduced phasic contractile responses to a meal
`
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`1234 Bharucha and Lacy
`
`Gastroenterology Vol. 158, No. 5
`
`en c
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`23
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`and/or to bisacodyl or neostigmine, in patients with STc.21
`-
`Manometry catheters only measure phasic pressure activity.
`A barostat balloon device also records colonic tone; fasting
`tone and tonic contractile responses to a meal and/or
`neostigmine are reduced in STC (Figure 1).21
`23 Colonic
`-
`inertia, which represents profound motor dysfunction, can
`only be identified by manometry or a barostat and is defined
`by reduced or absent contractile response to a meal and to
`24
`pharmacologic stimuli (such as bisacodyl or neostigmine).23
`•
`Unfortunately, NTC and STC are imperfect markers of
`normal and impaired colonic motor function, respectively.
`For example, fasting and/or postprandial colonic tone
`and/or compliance were reduced in 40% of patients with
`NTC, 47% in patients with STC, 53% in patients with DD
`and normal transit, and 42% in patients with DD and
`slow transit. 23 Similarly, 43% of patients with STC had
`normal fasting colonic motility and motor responses to a
`meal and bisacodyl. 25 Patients with NTC might have
`symptoms of FC or IBS-C; 23% of patients with FC or IBS(cid:173)
`C had delayed colonic transit. 26
`27 Some patients have
`•
`increased perception of rapid distention and reduced
`perception of slow distention. 28 Increased rectal sensi(cid:173)
`tivity is associated with abdominal pain and bloating,
`31
`suggestive of IBS. 29
`-
`Germ-free mice colonized with the fecal microbiome
`from patients with constipation developed slow colonic
`transit. 32
`33 Slow colon transit correlates inversely with
`•
`colonic serotonin content, associates with a decreased
`relative abundance of Firmicutes and increased Bacter(cid:173)
`oidetes, and associates with altered fecal content of
`short-chain fatty acids and bile acids. 32 In humans, CC
`is associated with alterations
`in colonic mucosa!
`microbiota, especially more plentiful phylum Bacter(cid:173)
`oidetes, resulting from a greater abundance of Fla(cid:173)
`vobacterium. 34 Adjusted for colonic transit, the colonic
`mucosa! microbiome
`discriminated
`patients with
`constipation from controls with 94% accuracy, even
`after adjusting for diet and colonic transit. By contrast,
`fecal microbiomes were associated with colonic transit
`and increased methane in breath samples, but not with
`constipation.
`
`Defecatory Disorders
`ODs (also called functional outlet obstruction, anorectal
`dyssynergia, or pelvic floor dysfunction) are caused by
`reduced rectal propulsive forces and/or increased resistance
`to evacuation (Figure 2). 35 Increased resistance results from
`resting pressure (anismus) or paradoxical
`high anal
`contraction or incomplete relaxation 36 of the pelvic floor and
`external anal sphincters ( dyssynergia). 37 These patterns are
`not associated with specific clinical patterns or the response
`to pelvic floor retraining.38 ODs primarily develop via mal(cid:173)
`adaptive pelvic floor contraction during defecation. 39 Other
`abnormalities, especially reduced rectal sensation and
`structural deformities (such as rectoceles and excessive
`perinea! descent), can coexist and be primary or secondary to
`40
`constipation. 14
`44 Reduced rectal sensation could reduce
`·
`-
`desire to defecate40.4 5
`; as many as 50% of patients with
`
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`
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`Chronic Constipation 1235
`
`4 hours
`
`24 hours
`(GC=1.1)
`
`48 hours
`(GC = 1.8)
`
`Gastric
`emptying
`baseline (0%)
`
`Gastric
`emptying
`4h (86%)
`
`24 hours
`(GC = 1.1)
`
`Figure 1. Patterns of colonic motor dysfunctions in patients with CC. The pronounced reduction in sigmoid colonic balloon
`volume indicates a normal tonic response to a meal (0) in a patient with excess colonic stool burden (A). Anorectal tests (not
`shown) identified a DD. During scintigraphy, colonic transit is usually measured using an isotope 111 coated with a pH-sensitive
`methacrylate that dissolves in the terminal ileum. In (B), the isotope is in an intact capsule ifett) observed in the ascending colon at
`24 hours (center pane~ and then in the transverse colon at 48 hours (right pane~. The geometric center (GC), which is the weighted
`distribution of the isotope throughout the colon, indicates slow colon transit; normal values are 1.4-3.6 at 24 hours and 2.1-4.9 at
`48 hours. In this patient, the colonic manometry (E) depicts considerable phasic pressure activity during the fasting period,
`increased phasic activity after a meal, and more so after intravenous neostigmine. However, the tonic contractile response to the
`meal was reduced. (C) shows a patient with delayed colonic transit with normal gastric emptying. In this patient, the colonic
`manometry (F) reveals sparse phasic pressure activity and tonic or phasic contractile responses to a meal.
`
`constipation have delayed colonic transit.23·37'46 Beside
`colonic motor dysfunction unrelated to DD,22 retained stool
`can physically obstruct passage of contents or evoke rec(cid:173)
`tocolonic inhibitory reflexes.47 Over time, excessive straining
`can weaken the pelvic floor, increasing risk for excessive
`perinea! descent, rectal intussusception, solitary rectal ulcer
`syndrome, and pudenda! neuropathy. Pudenda! neuropathy
`can weaken anal sphincters, increasing risk for fecal incon(cid:173)
`tinence.45.4s-so
`The precise contribution of dyssynergia to impaired
`evacuation is unclear because dyssynergia has been re(cid:173)
`ported in asymptomatic people as well as patients with
`rectal pain.38'51'52 This might be because it is a challenge
`to simulate defecation in the laboratory. When dyssy(cid:173)
`nergia and structural abnormalities (such as large rec(cid:173)
`it
`is difficult
`to determine
`the
`toceles) overlap,
`contributions of each to the symptoms (Figure 2). Some
`features (such as delayed colonic transit) are conse(cid:173)
`quences of DD and improve after biofeedback therapy.53
`Other factors , particularly stool form, affect development
`of symptoms in patients with DD.54'55 The pathogenesis of
`DD is unclear. ODs are believed to result from maladap(cid:173)
`tive learning of sphincter contraction, possibly initiated by
`avoidance of pain, or trauma, 56 or even neglecting the call
`to defecate. One-third of children with constipation
`continued to have severe symptoms beyond puberty.57
`There is no evidence for an association between obstet(cid:173)
`ric trauma and DD.58
`
`Clinical Evaluation
`
`The bowel symptom questionnaire is a quick and effec(cid:173)
`tive tool for evaluating symptoms of constipation (Table 1).
`Questionnaires provide a snapshot of symptoms, whereas a
`2-week bowel diary provides a more refined assessment of
`day-to-day variations and the relationship between stool
`form and other symptoms.54 Analyses of bowel diaries
`recorded by patients when they are off laxatives can help
`determine contribution of laxatives to symptoms (such as
`bloating). It is also important to collect information on prior
`bowel habits, when bowel habits changed, and what pa(cid:173)
`tients consider as normal, because perceptions, influenced
`by societal and cultural norms, influence symptom report(cid:173)
`ing. Some patients report constipation because they do not,
`perhaps in contrast to a spouse, pass a daily bowel move(cid:173)
`ment. Other patients, in retrospect, have had mild and/or
`intermittent symptoms for longer than initially acknowl(cid:173)
`edged (such as since childhood). Inadvertent withholding,
`perhaps secondary to an aversion to using public toilets, or
`constipation after recent surgery, medication changes, or
`coexistent urinary
`symptoms,
`are not uncommon.
`Addressing the most bothersome symptoms of constipation
`can increase patients' quality of life.59
`Colonic transit affects fecal form, which is assessed using
`the Bristol Stool Form Scale and ranges from liquid, to semi(cid:173)
`formed, to pellet-like stools.60-62 Abdominal pain and its
`relationship to bowel movements can differentiate patients
`
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`1236 Bharucha and Lacy
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`Gastroenterology Vol. 158, No. 5
`
`Rest
`
`Evacuation
`
`Paradoxical
`contraction
`
`Excessive
`descent
`
`Rest
`
`Normal
`pattern
`
`Evacuation
`Decreased
`propulsive
`force
`
`Paradoxical
`contraction
`
`Decreased propulsive
`force with paradoxical
`contraction
`
`Pressure
`(mmHg)
`
`I
`I
`220
`150
`0
`50
`Figure 2. Normal and abnormal anorectal evacuation. Evacuation was recorded by MR imaging (top row) and high-resolution
`manometry (bottom row). MR imaging shows anorectum filled with gel at rest (A), increased puborectalis indentation during
`squeeze (B, arrow) and normal relaxation of the puborectalis, perinea! descent, opening of the anal canal, and evacuation of
`ultrasound gel during evacuation (C). In patients with constipation, during evacuation, there is paradoxical contraction of the
`puborectalis (0, arrow) and exaggerated perinea! descent with an enterocele (E, arrow). High-resolution manometry shows anal
`pressure at rest (F) and increased anal pressure during squeeze (G) compared to rest (F). The white rectangle demarcates the
`duration of squeeze (G) and evacuation (H-K). Note the increased rectal pressure with anal relaxation during evacuation in a
`healthy person (H). By contrast during evacuation in constipated patients, note increased rectal pressure with paradoxical anal
`contraction (~, no change in rectal pressure vs rest (J), and no change in rectal pressure with paradoxical anal contraction (K).
`Reproduced from Bharucha and Wald, 72 with permission.
`
`with CC from patients with 18S-C. Co-existing gastrointes(cid:173)
`tinal symptoms should be identified; constipated patients
`frequently have bloating, which can be due to the underly(cid:173)
`ing disorder and/or medications-especially fiber and os(cid:173)
`motic
`laxatives. The
`presence
`of multiple other
`gastrointestinal symptoms (such as dyspepsia), especially in
`a younger patient without warning signs, supports a func(cid:173)
`tional cause of symptoms.63 However, distinct mechanisms
`can cause dyspepsia (such as impaired gastric accommo(cid:173)
`dation) and constipation in the same patients. 64 In consti(cid:173)
`pated patients, fecal impaction, perhaps compounded by
`laxative-induced overflow diarrhea, increases the risk for
`fecal incontinence. 65 It is important to ask patients about
`diet (for adequate fiber intake, intake of calories, and poorly
`absorbed carbohydrates that contribute to bloating), 66 life(cid:173)
`style (such as level of activity), toileting habits, medical
`conditions, obstetric history, and surgery (Table 1). At the
`appropriate time, patients should be asked whether they
`have a history of abuse, which is common in patients with
`DD. 67 Medications and supplements should be reviewed
`(Supplementary Table 1). Warning
`signs,
`such as
`
`unintentional weight loss > 10% of body weight, anemia,
`rectal bleeding, a family history of colorectal cancer, and
`polyposis syndromes should be identified, which have low
`predictive values in patients with CC. 68
`A meticulous and directed physical examination is
`essential for several reasons. Considered
`in
`isolation,
`symptoms (such as straining vs infrequent bowel move(cid:173)
`ments) do not discriminate between DD and other causes of
`CC. 38
`69 Examinations can identify an organic cause for
`•
`constipation, such as an abdominal mass, whereas dry skin
`is associated with hypothyroidism. Examinations also reas(cid:173)
`sure patients that their concerns are taken seriously.
`Digital rectal examinations (DREs) identify not only
`structural disorders ( such as anal fissures, hemorrhoids,
`fecal impactions, descending perineum syndrome, or ano(cid:173)
`rectal cancer), but also pelvic floor dyssynergia, which is
`treated differently. 70 Although DREs are recommended by
`many different societies, many providers do not perform
`them for constipated patients. 71 DREs identified patients
`with dyssynergia with 75% sensitivity and 87% specificity
`when manometry was used as the reference standard. 70
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`Chronic Constipation 1237
`
`Compared with the rectal balloon expulsion test (BET), the
`sensitivity and specificity of a DRE were 80% and 56%,
`respectively. For some people with normal pelvic floor
`function, it is a challenge to simulate defecation during a
`DRE. This might account for the lower specificity compared
`with a BET. A normal result from a DRE is more useful than
`an abnormal result from an examination.70 Nonetheless,
`patients with persistent symptoms and a normal finding
`from DRE should be referred for anorectal testing to exclude
`ODs.
`Thereafter, in the absence of warning signs, patients
`should receive a diagnosis of CC. A complete blood count is
`helpful in making a diagnosis, but other laboratory studies
`are unnecessary.4·5·72 Colonoscopies are only necessary for
`patients with alarm symptoms, or as required for age(cid:173)
`appropriate screening. Physicians and
`their patients
`should discuss the benign nature of CCs, treatment options,
`and their efficacy, safety, and cost; questions about special
`tests should be answered.
`
`on the type of rectal balloon used for the test.76-78 Most
`centers use a party or commercial balloon, for which the
`upper limit of normal is 1 minute. For a Foley catheter
`inflated to 50 mL, which is above the manufacturer(cid:173)
`recommended limit of 30 mL, the upper limit of normal is
`2 minutes. 76 Even with the 2-minute cutoff, 25% of healthy
`people would be misclassified as abnormal because they
`require more than 2 minutes.79
`Among 106 patients with FC and 24 patients with DD,
`the BET identified those with DD, documented with defe(cid:173)
`cography, with 88% sensitivity and 89% specificity; positive
`and negative predictive values were 64% and 97% for
`diagnosis of DD, respectively.80 However, this uncontrolled
`study excluded patients with
`secondary
`(such as
`medication-induced) CC. The rectal balloon was inflated not
`to a fixed volume but until patients experienced the desire
`to defecate, averaging 183 mL, which may compensate for
`reduced rectal sensation identified in some patients with
`DD.41
`
`Diagnostic Tests
`Anorectal testing with manometry and BET are recom(cid:173)
`mended for patients who have not responded to a high-fiber
`diet and/or simple laxatives.4·73·74 Because access to ano(cid:173)
`rectal testing is not universal, some practitioners treat pa(cid:173)
`tients empirically with prescription
`laxatives before
`anorectal testing. However, < 25% of patients with 18S-C
`report being very satisfied with prescription laxatives,
`perhaps partly because they have a DD. This observation
`supports the need for anorectal testing.75
`During anorectal tests, maintenance of privacy will
`facilitate cooperation and reduce embarrassment, which
`can account for
`false-positive
`results
`from
`tests
`in
`asymptomatic and constipated patients.52 Results should
`be interpreted along with clinical features. There is no
`criterion standard diagnostic test, or symptom, for a
`diagnosis of DD. Although different tests provide different
`information about individual patients, 14·44 overall, the re(cid:173)
`sults of anorectal high-resolution anorectal manometry
`(HRM), BET, and magnetic resonance (MR) imaging are
`significantly correlated with each other, which sub(cid:173)
`stantiates the criterion validity of these tests,44 even
`though these tests are performed in different positions,
`with or without rectal filling. Therefore, the Rome IV
`criteria propose that a diagnosis of DD be confirmed by
`abnormal findings from 2 of 4 tests (such as manometry,
`rectal BET, surface electromyography, or barium or MR
`defecography). Taking all factors (such as diagnostic utility,
`usability, availability, risk, and expense) into consideration,
`the rectal BET is the most useful test to make a diagnosis
`of DD.
`
`Balloon Expulsion Test
`The BET is a simple procedure generally performed in
`conjunction with anorectal manometry to evaluate the time
`required to evacuate a 5O-mL water-filled balloon (warm
`tap water) in the seated position. The normal values depend
`
`Anorectal Manometry
`Conventional catheters that incorporate water-perfused,
`air-charged, or solid-state sensors, HRM, or high-definition
`manometry can be used.81-83 HRM and high-definition
`anorectal manometry catheters have more closely spaced
`sensors that straddle the entire anal canal. They provide
`better spatial resolution, and allow pressures to be assessed
`without a pull-through maneuver (Figure 2). Although
`conventional and HRM catheters measure anal pressures
`with comparable levels of precision, pressures are much
`higher with HRM or high-definition anorectal manometry
`than conventional catheters.84 Anorectal pressures vary
`among techniques, so they must be compared with normal
`values measured by the same technique. Compared with
`healthy individuals, patients with DD have lower rectoanal
`pressure gradients (rectal-anal pressure) during evacua(cid:173)
`tion. The rectoanal pressure pattern can also indicate causes
`of DD, such as decreased propulsive force, paradoxical
`contraction, or both.69 However, the rectoanal gradient
`measured by HRM is negative in many asymptomatic peo(cid:173)
`ple, which limits the utility of this parameter for making a
`diagnosis of DD. 52·82·85 Anorectal manometry is best per(cid:173)
`formed in a seated rather than a left lateral, recumbent
`position.86 Other features of DD include a higher anal
`resting pressure (anismus) and/or reduced voluntary
`augmentation during pelvic floor contraction.
`
`Barium and Magnetic Resonance Defecography
`Some practitioners prefer defecography to the BET.
`Others use defecography as a backup method, when
`the other anorectal tests produce results that are inconsis(cid:173)
`tent with clinical findings, to identify anatomic abnormal(cid:173)
`ities, or for patients with persistent symptoms after
`biofeedback therapy.87-90 Abnormalities include inadequate
`(such as a spastic disorder) or excessive (such as in
`descending perineum syndrome) widening of the anorectal
`angle and/or perinea! descent during defecation. Internal
`
`Bausch Health Ireland Exhibit 2058, Page 6 of 21
`Mylan v. Bausch Health Ireland - IPR2022-00722
`
`

`

`1238 Bharucha and Lacy
`
`Gastroenterology Vol. 158, No. 5
`
`Patient with chronic constipation
`
`Laboratory tests and structural
`evaluation as appropriate
`
`Supplement dietary fiber intake
`and/or use OTC laxatives;
`education, routine toileting
`
`Treat with secretagogue or prokinetic agent
`
`Continue
`therapy
`
`No
`
`Did symptoms
`improve?
`
`Continue
`Yes
`1--------1► 1 treatment plan
`
`No
`
`Anorectal manometry
`
`Balloon expulsion test ~
`
`Defecatory
`disorder
`
`Assess colonic transit ~
`Abnormal
`
`Slow
`
`Normal
`
`No
`
`Slow transit
`constipation
`
`Prokinetic agents,
`colectomy,
`loop lleostomy
`
`Consider
`
`• Alternative
`medications
`• Colonic motility
`study
`
`Continue
`treatment plan
`
`Consider
`• Defecography if not performed
`• Suppositories or enemas
`• Loop ileostomy
`• Rectal suspension or
`rectovaginal repair for rectal
`prolapse or rectocele
`
`Figure 3. Treatment algo(cid:173)
`rithm for CC.
`
`intussusception, solitary rectal ulcers, rectoceles, and rectal
`prolapse are also observed.91 Enteroceles, bladder, and
`uterovaginal prolapse can be visualized when the vagina
`and small intestine are opacified.
`The techniques for barium defecography are incom(cid:173)
`pletely standardized; some
`radiologists have
`limited
`enthusiasm for the test.88 Asymptomatic subjects have
`features of DD. Methodological limitations to barium defe(cid:173)
`cography (such as limited reproducibility of anorectal angle
`measurements) can be minimized by using standardized
`techniques. 14
`92 In contrast to barium defecography, MR
`·
`defecography is performed in the supine position but avoids
`radiation exposure and can is better for visualizing pelvic
`organ prolapse and the bony landmarks, which are neces(cid:173)
`74
`93
`sary to measure pelvic floor motion.40
`94 MR defecog(cid:173)
`·
`·
`•
`raphy is especially useful for patients who are believed to
`have ODs with a normal BET; this group includes > 90% of
`patients with a large rectocele, enterocele, peritoneocele,
`and/or p