Etiology of Acquired Colorectal Disease: Constipation

Functional constipation is defined by the Rome II Coordinated Committees as a group of functional disorders that present with resistant, difficult, infrequent, or seemingly incomplete defecation. Previous definitions have included a regular occurrence (in more than 25% of defecations) of excessive straining, lumpy or hard stools, a sense of incomplete evacuation, a sensation of anorectal obstruction or blockage, or less than three bowel movements per week over at least 12 consecutive weeks in the preceding 2 years.

Such disorders may be congenital, as in Hirschsprung’s disease, or acquired later in life as a result of lifestyle or behavior, infection, or because of anatomic or physiologic abnormalities (Figure: Algorithm describing etiologies of various acquired constipation). The causes of constipation, even after an exhaustive evaluation, often remain unclear and, in many cases, multifactorial. This chapter discusses the etiology of acquired constipation.

Lifestyle

Diet

Western-style societies have the highest incidence of constipation as compared to less developed societies. Dietary composition, especially fiber content, may be a leading contributing cause of constipation. Inadequate dietary fiber intake produces stools that are less bulky, lower in water content, lower in volume, and more difficult to eliminate. In societies such as western Africa where the average dietary fiber intake is as much as 35 g of insoluble fiber, individuals have two to three large soft bowel movements per day on average, and reports of constipation are uncommon.

In the United States, dietary fiber intake averages less than 12 g per day, and complaints of constipation may affect 3% to 5% of the population at any given time. Insoluble dietary fiber acts by drawing water into the intestinal lumen, resulting in bulky, soft, large stools that have higher water content. Colonic peristaltic movements, in turn, are in part stimulated by colonic distention.

Frenetic Pace of Life

Strange as it may seem, a hectic schedule and lack of time to eliminate is an increasingly frequent cause of constipation, particularly in individuals trying to manage more than one job.

Medications

Numerous medications (anticholinergics, antidepressants, narcotics) may lead to iatrogenic constipation by impeding neural signaling, resulting in impaired colonic muscular coordination (Table: Pharmacologic causes of constipation). Initial treatment of constipation with an identified pharmacologic cause consists of discontinuing the offending drug or replacing the drug with a nonconstipating alternative, if available.

Psychiatric disorders such as depression, psychosis, and anorexia nervosa, as well as their pharmacologic treatments, may contribute to or worsen constipation. This has become a real clinical problem with the increasing and almost ubiquitous prescription of antidepressants and psychotropic drugs by many physicians.

Table: Pharmacologic causes of constipation

Amiodarone

Antacids (e.g., aluminum)

Anticholinergics

Anticonvulsants

Antidepressants

Antihypertensives

—      Calcium channel blockers

—      Diuretics

—      Ganglionic blockers

Antiparkinsonians

Bismuth

Bromocriptine

Bulk laxatives with inadequate hydration

Carboplatin

Cholestyramine

Erythropoietin

Filgrastim [granulocyte colony-stimulating factor (G-CSF)]

Iron

Lovastatin

Mesalamine

Narcotics/opiates

Pravachol

Sandostatin

Valproic acid

Vincristine

Weight Loss, Eating Disorders, and Laxative Abuse

Lack of oral intake, or bulimia, can be associated with reduced fecal volume. By their mechanism of action, overuse of laxatives may result in constipation due to dehydration, hypokalemia, or hypermagnesemia, altering neural transmission and function. The role of laxatives in damaging enteric neurons is uncertain. Long-term use has been associated with changes in neurons of the myenteric plexus and smooth muscle of the colon. Findings such as loss of neurons, morphologic changes of argyrophilic cells, including clubbing and shrinkage, and replacement of ganglia by Schwann cells have been histologically demonstrated. Similar morphologic findings have been discovered in patients with inflammatory bowel disease and diabetic neuropathy, and may not be specific for laxative use.

Infection

The most common infectious cause of constipation is American trypanosomiasis, or Chagas disease. Caused by the parasitic protozoan Trypanosoma cruzi, Chagas disease affects an estimated 17 to 24 million individuals throughout Central and South America and Mexico and leads to 50,000 deaths annually. The disease is endemic in South America, especially in Chile, Brazil, and Argentina. Wild and domesticated mammals harboring Trypanosoma cruzi and infected reduviid insects are found in patchy distributions from the southern United States to southern Argentina.

Chagas disease is particularly a public health problem among the poor in rural areas of Central and South America. Acute Chagas disease in the United States is rare. Because enormous numbers of Central and South Americans have immigrated to the United States since the 1980s, the number of cases of chronic Chagas disease in North America will undoubtedly increase over time.

Trypanosoma cruzi is transmitted to mammalian hosts by one of several species of hematophagous triatomine insects known as reduviids. Reduviids become infected by ingesting blood from mammals that have circulating parasites. Common sites of infection include the mucous membranes, conjunctiva, and breaks in the skin. The ingested parasites multiply in the gut of reduviid insects, and infective forms are transmitted in the feces of reduviids while feeding on host blood. Trypanosomes multiply in smooth muscle, among other tissues, eventually causing destruction of these muscle cells. Migration of trypanosomes to regional lymph nodes and into systemic circulation occurs, reaching nearly all host organs.

The pathogenesis of Chagas disease is poorly understood. In its acute form, Chagas disease is generally a mild febrile illness marked by periorbital edema. Children are particularly susceptible to the disease, especially in endemic regions. Following resolution of the acute illness, the great majority of individuals remain in the indeterminate phase of Chagas disease for life, characterized by parasitemia and the absence of symptoms. In a minority of infected patients, cardiac and gastrointestinal lesions result in significant illness and death. Symptoms include abdominal pain, bloating, chronic constipation, and weight loss.

The heart is most commonly affected. As the disease progresses in the gastrointestinal tract in 7% to 11% of infected patients, parasitic infestation of the smooth muscle layers of the gut results first in myositis and then in destruction of Auerbach’s plexus. Fibrosis of the myenteric plexus occurs as ganglion cells are destroyed, leading to parasympathetic denervation. The affected segment of colon does not achieve peristalsis in a coordinated fashion. The resulting dyskinesia leads to a functional obstruction, whereby the proximal bowel becomes dilated and elongated. Uninfected areas of gut musculature hypertrophy in an attempt to overcome the functional obstruction.

The diagnosis of Chagas disease is made serologically by detecting antibodies that bind to Trypanosoma cruzi antigens (Guerro-Machado complement fixation test). Evaluation with contrast studies usually demonstrates dilation of the colon and rectum.

Anatomic Abnormalities

Anatomic alterations of the colon, rectum, and anus may also cause constipation. These problems can be divided into disorders associated with obstruction, either mechanical or functional, above the level of the pelvis or at the level of the pelvis, and disorders of transit with increased length of the colon. While functional colonic motility may be normal in the individual with constipation, the mechanical obstruction of the passage of stool by extrinsic or intrinsic causes may have an important role.

Mechanical Obstruction

Neoplasms

Neoplasms of the colon, rectum, and anus may cause gradual changes in elimination as they enlarge and obstruct the passage of stool. These lesions are usually readily identified by radiographic or colonoscopic evaluation, and the clinical suspicion of neoplasm is often aroused by the patient’s clinical status and constellation of symptoms.

Benign Strictures

Strictures of the colon, rectum, and anus may mimic symptoms of constipation. The etiology of such strictures may be due to inflammatory processes such as ulcerative colitis, Crohn’s disease, endometriosis, or diverticular disease. Adjuvant radiation therapy may also result in stricture or obstruction. Strictures may also occur at areas of prior anastomosis. The most common cause of anal stricture is previous surgery (i.e., hemorrhoidectomy) or inflammatory bowel disease.

Volvulus

Occasionally, patients who suffer from chronic constipation may, in fact, have volvulus. Volvulus may occur at the level of the sigmoid or transverse colon or cecum. Generally, the onset of volvulus is abrupt and presents with the same signs and symptoms as obstruction. On occasion, older patients may have crampy abdominal pain, nausea, and constipation that spontaneously resolves. Diagnosis is often delayed because symptoms have resolved and radiographic findings do not capture the acute event. Symptoms may be ascribed to irritable bowel syndrome or changes associated with aging. A high degree of suspicion should exist for patients who present with this constellation of symptoms and a torturous, redundant transverse or sigmoid colon.

Functional Obstruction

Rectocele

A rectocele may be an important cause of obstructive defecation that presents as constipation. A rectocele is a herniation of the anterior wall of the rectum into the lumen of the vagina. A rectovaginal septum weakened by multiple childbirths and the aging process may enable stool to become trapped in this herniation, leading to a sense of incomplete evacuation. Continued straining may further weaken the rectovaginal septum and lead to progressive enlargement of the herniation. Because patients with a rectocele believe that they cannot completely evacuate during a bowel movement, despite a normal urge to do so, digital manipulation, enemas, or suppositories are often used to assist defecation.

These patients typically have rectal fullness, bleeding, pain, and soiling. A bimanual examination discloses a defect of the anterior rectal wall above the level of the anal sphincter. Radiographically, a pocket-like protrusion of the rectovaginal septum into the vagina is noted on lateral or oblique views. This is best observed during defecating proctography by retained contrast within the rectocele at the end of defecation.

Rectoceles are a relatively common finding on physical examination, occurring in up to 81% of all women. However, only half of these patients report symptoms of constipation or difficulty with defecation. Thus, many women with rectoceles are asymptomatic, and the presence of a rectocele is not an indication for repair. Rectoceles found on defecography that measure less than 2 cm are generally considered to be clinically insignificant, whereas rectoceles larger than 3 cm are usually considered clinically significant. Interestingly, the size of a rectocele has been shown not to correlate with the severity of symptoms clinically Furthermore, the size of a rectocele as measured by the amount of barium trapped radiographically has not been proven to correlate with the success of rectocele repair.

Controversy exists as to whether rectoceles are the cause or result of excessive straining. Repeated trauma, as in obstetrical injury or repeated vaginal delivery, appears to play a role in weakening the rectovaginal septum. Typically, the sphincter is shortened and the perineal body is thinned. Beven has speculated that thinning of the rectovaginal septum and/or pelvic denervation seen following hysterectomy may contribute to rectocele formation. Johansson et al has noted that some patients have associated paradoxical sphincter contraction and elevated mean resting rectal pressures. Because rectoceles commonly present in the fourth and fifth decade of life, the postmenopausal hormonal milieu with supporting tissue laxity may play a role in the pathogenesis of rectocele.

Descending Perineum Syndrome

Weakness of pelvic floor support may result in the descending perineum syndrome. This muscular weakness is reportedly related to injury of the sacral nerves or pudendal nerves or due to damage to the musculature itself during childbirth or chronic straining while defecating. Obstruction to defecation may occur through widening of the anorectal angle, weakening of the perineal body, and a more vertical orientation of the rectum, which are all results of pelvic floor weakness. A perineal descent of greater than 4 cm on straining as identified radiographically suggests a weakened perineum.

Prolonged latency on stimulation of the pudendal nerve is characterized on electrophysiology studies. Over time, prolapsed anterior rectal wall mucosa may become irritated and bleed as it protrudes through the anal canal. Mucus secretion, soilage, and pruritus are later findings. Patients usually relate a sensation of incomplete evacuation during defecation, followed by a feeling of obstruction due to the prolapsing of the anterior rectal wall mucosa. Manual reduction with a finger in the anal canal may temporarily reduce this obstruction and allow defecation.

Nonrelaxing Puborectalis Syndrome (Anismus)

The constellation of symptoms associated with rectoceles (prolonged repeated straining at bowel movements, sensation of incomplete evacuation, and the need for digital manipulation) is also seen in puborectalis syndrome. Synonyms include nonrelaxing puborectalis syndrome,paradoxical puborectalis syndrome, spastic pelvic floor syndrome, and anismus. During normal evacuation, distention of the rectum by fecal matter induces relaxation of the internal anal sphincter, followed by contraction of the external anal sphincter mechanism. At the time of defecation, the external sphincter relaxes, as does the puborectalis muscle. This has the effect of straightening the anorectal angle, thereby facilitating elimination. The failure of the puborectalis muscle to relax (or paradoxically, to contract) in nonrelaxing puborectalis syndrome results in continued maintenance of the anorectal angle. The effect is anal outlet obstruction.

The symptoms of these two syndromes are so similar that the history alone cannot discriminate between the two. While paradoxical contraction of the puborectalis muscle during the Valsalva maneuver can be evaluated on physical examination, electromyography (EMG), balloon expulsion studies, and defecography are typically more reliable and reproducible means for diagnosing this condition. Diagnosis may require the use of several modalities, and each test has its limitations. Patient inhibition may lead to nonrelaxation of the pelvic floor on defecography. Pain during EMG due to probe placement may also result in nonrelaxation during testing, resulting in a false-positive finding. Prospective studies suggest that EMG has a sensitivity of 67%, positive predictive value of 70%, and specificity of 83%, whereas these values for defecography are 70%, 67%, and 80%, respectively.

Whether paradoxical contraction of the puborectalis muscle during defecation is a cause of constipation or a coincidental finding is unclear. A study by Jorge et al evaluated 112 constipated patients with EMG and defecography. One third of these patients displayed findings consistent with paradoxical puborectalis contraction as measured by these techniques. However, the correlation between EMG and defecography was poor: 33% of patients displaying findings of anismus on defecography had a normal EMG, and 30% of patients with an EMG suggesting anismus had normal defecography. Treatments directed at inhibiting contraction of the puborectalis muscle, such as injection of botulinum toxin or division of the puborectalis muscle, have yielded mixed results.

It may be that the isolated finding of contraction of the puborectalis muscle represents an abnormal learned response that has been hypothesized to result in some patients from sexual assault or abuse. The passage of large painful bowel movements in children is also thought to contribute to the development of paradoxical puborectalis contraction.

Rectal Prolapse

Internal rectal intussusception is an early stage of rectal prolapse, where the proximal rectum has prolapsed into the ampulla but has not progressed through the anal canal. Symptoms include constipation and an incomplete sense of evacuation. Less commonly reported are incontinence, pain, and soiling. Endoscopy may reveal a solitary rectal ulcer on the anterior rectal wall 8 to 10 cm above the anal verge. Defecography is the diagnostic test of choice and shows the rectum intussuscepting several centimeters above the level of the levators. Classically, a funnel-shaped pattern is seen reflecting circular prolapse of the rectal wall.

Rectal intussusception previously had been thought to be a common cause of obstructed defecation. However, because operative repair of rectal intussusception has met with little success, current thought suggests that intussusception may be the result of, and not the cause of, obstructed defecation. Full-thickness rectal prolapse is the protrusion of the full thickness of the wall of the rectum through the anal canal. Symptoms correlate with the degree of prolapse through the anal canal. With complete prolapse through the anal canal, the extruded rectum becomes excoriated, resulting in ulceration, bleeding, and mucous discharge. In this latter stage, fecal incontinence is the rule. A history of constipation is a common finding.

Physical examination discloses a protruding mass of reddened friable tissue. Digital rectal examination may easily reduce the prolapse, and a widely patent, poorly contractile, anal canal is noted. Concentric folds of colonic mucosa are observed in contrast to the radial folds seen in patients with prolapsed internal hemorrhoids. Uterine prolapse or cystocele may be identified concomitantly

Slow-Transit Constipation Without Megacolon

Patients with slow-transit constipation are almost always women, usually presenting in their second or third decade. They have two or fewer bowel movements per week. Malaise, bloating, nausea, and abdominal cramping are frequent complaints. Symptoms are typically unresponsive to bulk laxatives and stool softeners. There is often a strong association with gynecologic complaints such as irregular menstrual cycles, ovarian cysts, and galactorrhea. Many patients have delayed gastric emptying, biliary dyskinesia, and delays in small bowel transit, suggesting the presence of a panenteric motility disorder. A diagnosis of colonic inertia is made only after excluding systemic neurologic processes such as diabetes mellitus or multiple sclerosis, or a pelvic floor abnormality as a cause.

Investigation typically reveals a normal-caliber but often very redundant colon on barium enema. Defecography and manometry are essential to exclude pelvic floor dysfunction as an etiology of constipation. Colonic transit studies show markedly delayed transit of ingested radiopaque markers. Interestingly, there are two categories of transit studies. The first displays pancolonic inertia, as markers have delayed transit beginning in the cecum and continuing throughout the remainder of the colon. The second shows passage of markers without delay through the ascending and transverse colon and a slowing of transit through the left colon and rectosigmoid.

Studies in animal models suggest that colonic transit can be accelerated by serotonin, serotonin analogues, or both. Zhao et al evaluated the distribution, density, and staining intensity of enterochromaffin and serotonin cells in the colonic mucosa of patients with colonic inertia compared to controls. The number of enterochromaffin cells and serotonin-producing cells was increased in the group with colonic inertia, with a greater number found in the left colon. Compared with controls, these cells contained fewer hormones as measured by the intensity of staining but were present in greater numbers. It is unknown whether an increased level of serotonin is the cause of motility impairment or a consequence.

The mechanism by which serotonin exerts an effect on colonic motility is not completely understood. Work by Haga et al indicates that serotonin, both endogenously produced and exogenously applied, stimulated acetylcholine release via 5-hydroxytryptamine (5-HT₃) receptors, resulting in increased colonic transit.

Alterations of hormones at the enteric level also may play a role in the etiology of idiopathic slow-transit constipation. Substance P levels have been found to be decreased in the mucosa and submucosa of patients with slow-transit constipation. Altomare et al and others have suggested that slow-transit constipation is a manifestation of autonomic nervous system dysfunction, pointing out that such disorders are characterized by abnormalities in diverse systems such as cardiovascular, urinary, sexual, and digestive.

A recent review found that more than 70% of patients suffering from slow-transit constipation also showed some degree of autonomic dysfunction, such as biliary dyskinesia and delayed small bowel transit. This group has also shown that women with slow-transit constipation exhibit impaired sweat production after acetylcholine application. Impaired extrinsic autonomic control of mechanisms controlling colonic motility via acetylcholine and serotonin-regulated pathways may result in multisystem dysregulation and subsequent clinical symptoms. Pharmacologic treatment of such patients will be a rapidly expanding field in the future.

Slow-Transit Constipation with Megarectum/Megacolon

In contrast to the condition previously described, some patients with constipation present with a markedly dilated colon and rectum. Males and females are affected equally. This condition usually presents in childhood or adolescence. Patients often require chronic laxative use to maintain bowel function. The symptoms of chronic constipation with abdominal pain, bloating, and often fecal incontinence can have a significant adverse affect on lifestyle.

Radiographic evaluation shows dilatation of the colon and rectum to the pelvic floor. Although any part of the colon may be affected, the process usually begins in the rectum or involves the rectum. A rectal diameter of 6.5 cm at the pelvic rim on lateral view defines megarectum. Colonic transit studies are abnormal, with marked delay in the dilated segment of affected bowel. Small bowel transit studies are generally normal. The diagnosis of idiopathic megacolon and megarectum is a diagnosis of exclusion, made only after other causes of constipation such as Hirschsprung’s disease have been ruled out.

This syndrome can be distinguished from Hirschsprung’s disease by the presence of anorectal inhibitory reflex, the absence of a normal caliber or stenotic length of distal bowel, and the presence of ganglion cells on rectal biopsy. Subtle histologic abnormalities have been identified in both smooth muscle and intrinsic innervation. There is thickening of the bowel wall due to smooth muscle hypertrophy and fibrosis of the muscularis mucosa, circular muscle, and longitudinal muscle layers. These findings, however, are not specific to this syndrome.

Several investigators have found decreased vasoactive intestinal peptide levels in the muscularis externa in patients with idiopathic megacolon, suggesting a loss of inhibitory nerves that normally innervate colonic smooth muscle. Other researchers have noted reduced numbers of argyrophilic neurons and structural abnormalities in these neurons, such as decreased neuronal processes and variable-size nuclei in the ganglia.

Physiologic Abnormalities

Other than the anatomic and functional causes of constipation described above, a host of other, less common medical problems may present with constipation. Systemic illness such as diabetes mellitus, multiple sclerosis, hypothyroidism, hypopituitarism, and porphyria may cause or exacerbate constipation. Neurologic disorders, including brain and spinal cord neoplasms, central nervous system trauma, and Parkinson’s disease, are known to be associated with constipation, significantly altering the quality of life.

Conclusion

There are many causes of acquired constipation, and unfortunately, many patients have constipation due to a combination of these. A careful patient history and evaluation is necessary in order to determine the etiology, which is outlined in succeeding chapters. It is wise to begin with the least invasive and safest treatment and then proceed with further treatment, only if this initial treatment fails. The next few years will likely see the development of more effective pharmacotherapy for slow-transit colonic constipation, and thereby greatly facilitate the treatment of affected individuals.