SUMMARIES CHRONIC CONSTIPATION: NEW THOUGHTS ABOUT AN OLD PROBLEM * Julia Pallentino, MSN, JD, ARNP-BC, and Lawrence R. Schiller, MD, FACP, FACG

CHRONIC CONSTIPATION: NEW THOUGHTS ABOUT AN OLD PROBLEM * Julia Pallentino, MSN, JD, ARNP-BC, and Lawrence R. Schiller, MD, FACP, FACG NEW THOUGHTS ABOUT AN OLD PROB- LEM: THE IMPACT AND DIAGNOSIS OF CHRONIC CONSTIPATION Based on a presentation by Pallentino J Medical Group of North Florida, Tallahassee, Florida At first glance, chronic constipation may be considered a trivial symptom, or at least not a serious one. Yet, for individuals experiencing chronic constipation, the impact is significant and often far-reaching into many aspects of quality of life and functioning. Chronic constipation is encountered frequently in many areas of healthcare beyond gastroenterology, including primary care, geriatrics, psychiatry, cardiology, neurology, pain and addiction medicine, and physical rehabilitation. In fact, with a prevalence of 12% to 19% among US adults, it ranks among the most common chronic diseases, including coronary heart disease (5.9%), asthma (6.4%), diabetes (6.7%), migraine (15.1%), and hypertension (21.6%). 1 THE BURDEN OF CHRONIC CONSTIPATION By the time a patient presents with chronic constipation, it has already become a debilitating problem. The patient may have been dealing with it for years, perhaps intermittently over his or her lifetime. In one *The following summaries are based on presentations at a symposium held at the 2006 National Conference of the American Academy of Nurse Practitioners, Grapevine, Texas, June 21, 2006. Medical Group of North Florida, Gastroenterology Practice, Tallahassee, Florida. Gastroenterology Department, Baylor University Medical Center, Dallas, Texas. Address correspondence to: Julia Pallentino, MSN, JD, ARNP-BC, Medical Group of North Florida, 2626 Care Drive, Tallahassee, FL 32308. E-mail: arnplaw@comcast.net. study, nearly 90% of patients with constipation continued to report constipation during the 12 to 20 months of follow-up. 2,3 Constipation occurs more than twice as frequently in women than men, at a ratio of 2.2:1. 2 It increases in prevalence with age, particularly after age 65 years, and with lower amounts of exercise. It is associated with well-known factors, such as depression and psychological distress, in addition to several lesser known factors, such as low socioeconomic classes (perhaps because of a diet low in fiber), lower educational level, and non- Caucasian ethnicity. 2 DIAGNOSIS WHAT EXACTLY IS CONSTIPATION? Most people (clinicians and patients) define constipation as too few stools per unit of time that is, infrequency is the primary criterion. However, for the patient, frequency is often a less pressing concern than other aspects of stool passage. Patients with self-reported constipation report many symptoms other than low stool frequency, such as straining (81%), hard or lumpy stools (72%), incomplete evacuation (54%), inability to evacuate stools (39%), abdominal bloating or fullness (37%), and a need to press around or in front of the anus for evacuation (28%); by contrast, 36% report having fewer than 3 bowel movements per week. 4 In fact, some patients are quite comfortable with once-weekly bowel movements that are easy to pass; however, they still express concern about constipation because of the general preoccupation with frequency. Therefore, when a patient reports constipation, it is important to help the patient define what he or she means by this term, because the patient may not be experiencing infrequent stools. The American College of Gastroenterology (ACG) 166 Vol. 4, No. 7 November 2006

appointed a task force to examine the current diagnosis and treatment of chronic constipation. The Task Force criteria for constipation is unsatisfactory defecation characterized by infrequent stools, difficult stool passage (including straining, a sense of difficulty passing stool, incomplete evacuation, hard or lumpy stools, prolonged time to expel stool, or need for manual maneuvers to pass stool), or both. Manual maneuvers to ease stool passage include placing pressure on the perineum to raise it, placing a finger inside the vagina to push the stool back, or in the anus itself to widen the opening. 5 A common source of confusion is the difference between chronic constipation and irritable bowel syndrome (IBS) with constipation. In fact, they may be a continuum of a single disorder. Pain often is identified as the discriminating factor between the 2 disorders with pain associated with IBS. However, practically speaking the treatment for both disorders is very similar. INITIAL WORKUP Because many patients are embarrassed about constipation, or any discussion of bowel movements, the onus is on the nurse to promote and ensure good communication between patient and healthcare practitioner. First, encourage the patient to identify specifically his or her symptoms (eg, infrequent stool or difficult passage) and then look for red flags that may signal a more serious problem. Red flags (or alarm features) are listed in Table 1. 5 All patients with a red flag should undergo appropriate diagnostic testing. Patients without red flags will most likely have functional chronic constipation and will not likely require further testing for diagnosis. ELICITING THE PATIENT HISTORY Nurses tend to be adept at history taking, which is an essential component of managing chronic constipation. Table 2 lists some of the most pertinent questions to ask the patient presenting with symptoms of constipation, as recommended by the American Gastroenterological Association guideline on constipation. 6 The chronicity of constipation symptoms is important to define. Remember that, even in the primary care setting, patients will have suffered with these symptoms for a long time before seeing a healthcare practitioner. The patient, at this point, is in a significant amount of physical and mental discomfort, in addition to possibly being functionally impaired. The patient will most likely have tried several types of fiber supplements or over-the-counter laxatives, which were ineffective. Thus, it is important to identify the most distressing symptom(s) in addition to the type and frequency of laxative or fiber supplement the patient has used. Enemas and suppositories are used frequently by elderly patients. Herbal teas obtained at health food stores and widely advertised on the Internet are being used more frequently as laxatives. Identifying the products the patient has tried unsuccessfully often can Table 1. Alarm Features That May Suggest a Secondary Cause of Constipation Hematochezia (blood in the stool) Family history of colon cancer Family history of inflammatory bowel disease Anemia Positive fecal occult blood test Unexplained weight loss 10 lb Severe, persistent constipation that is unresponsive to treatment New-onset constipation in an elderly patient Adapted with permission from Brandt et al. Am J Gastroenterol. 2005;100:S5-S21. 5 Table 2. Eliciting the Patient History for Chronic Constipation 1. What brings you to see me? What are your concerns? 2. How long have you experienced these symptoms? 3. Does constipation limit your daily activities? 4. What is your most distressing symptom? 5. What is your approximate intake of dietary fiber? 6. What laxatives have you tried? Are you currently using laxatives? How often? What dosage? 7. Are you using enemas or suppositories? 8. Are you taking any herbal medications or teas? 9. How often do you have bowel movements? 10. What is the consistency of your stool? 11. How often do you feel the urge to defecate? Do you always attempt to have a bowel movement after this feeling? 12. What other symptoms do you experience straining, feelings of incomplete evacuation, or need for manual maneuvers? Data from Locke et al. 6 Johns Hopkins Advanced Studies in Nursing 167

Table 3. Medications That Commonly Cause Constipation Prescription Drugs Opiates Anticholinergic agents Tricyclic antidepressants Calcium channel blockers Antiparkinsonian drugs Sympathomimetics Antipsychotics Diuretics Antihistamines Nonprescription Drugs Antacids, especially calcium-containing Calcium supplements Iron supplements Antidiarrheal agents Nonsteroidal anti-inflammatory drugs Antihistamines Patients often face the choice of relieving 1 disorder (eg, pain or depression) or relieving their constipation. It is important to reassure them that treatments for constipation are available, thus they can continue to use their medications when no less constipating alternative exists. help to more completely estimate the severity of the problem. Other important features that need to be defined are stool consistency and urgency. In older patients with intermittent loose stools, for example, fecal impaction should be considered and ruled out. Among younger patients with busy schedules and lifestyles, the urge to defecate is frequently lost, particularly, in my experience, among young professionals and students, because normal urges to defecate (eg, after breakfast and coffee) are ignored. Bloating is also a very common symptom of constipation and often is cited by patients as one of the most uncomfortable. Primary causes of constipation include normaltransit constipation, defecatory disorders, IBS with constipation, and slow-transit constipation (colonic inertia). Defecatory disorders include rectocele (a common cause), megarectum, perineal descent (in which the pelvic floor cannot support the rectum, also common), and pelvic floor dyssynergia, which is greatly underdiagnosed and undertreated. 7,8 There are several secondary causes of constipation, the most common of which is medication (Table 3). 6 Other secondary causes of constipation include mechanical obstruction, metabolic and endocrine disorders (particularly hypothyroidism), neurologic disorders (eg, spinal cord injury or paralysis), collagen, vascular, and muscular disorders (eg, multiple sclerosis or myasthenia gravis), and pregnancy. 9 Many patients want to know why they are constipated. Even if a definitive cause cannot be identified, the treatments are the same. However, it is useful to be able to explain the physiology of a bowel movement. Figure 1 shows a diagram of normal anorectal anatomy. 10 Understanding the physiology of bowel movements can help to align symptoms with causes. For example, lack of urge and decreased stool frequency suggest a slow-transit disorder. Symptoms suggestive of a defecatory disorder include hard stools, impaction, need for digital maneuvers, feelings of anal blockage, severe straining, high anal sphincter tone at rest, minimal (<1 cm) or excessive (>3.5 cm) perineal descent, tender puborectalis muscle on palpation, and defect in the anterior wall of the rectum suggestive of a rectocele. 10-12 OTHER COMPONENTS OF THE CONSTIPATION WORKUP If it is difficult to ascertain from patients their constipation symptoms, it is even more difficult to encourage a discussion of stool type. However, this Figure 1. Normal Anorectal Anatomy and Physiology THE CAUSES OF CONSTIPATION The rectum sits almost at a right angle (the anorectal angle) to the anal sphincter, maintained by the puborectalis muscle, a loop of muscle that runs from the front of the pelvis around the back of the rectum and can remain contracted for long periods. This muscle is most important for preserving solid fecal continence; the anal sphincter is essential for continence with water, stools, and flatulence. For stool to pass, the rectum needs to elongate, which is accomplished by relaxation of the puborectalis muscle. A common cause of constipation is the inability to relax this muscle, so that stool remains trapped at the anorectal angle pelvic floor dyssynergia. In primary care, approximately 33% of patients may have pelvic floor disorders associated with constipation. Reprinted with permission from Lembo and Camilleri. N Engl J Med. 2003;349:1360-1368. 10 168 Vol. 4, No. 7 November 2006

Figure 2. The Bristol Stool Scale SLOW Type 1 TRANSIT Type 2 RAPID TRANSIT Type 3 Type 4 Type 5 Type 6 Type 7 Separate hard lumps, like nuts Sausage-like but lumpy Like a sausage but with cracks in the surface Like a sausage or snake, smooth and soft Soft blobs with clear-cut edges Fluffy pieces with ragged edges, a mushy stool Watery, no solid pieces Reprinted with permission from Lewis and Heaton. Scand J Gastroenterol. 1997;32:920-924. 13 information can help to determine the cause of constipation. The Bristol Stool Scale (Figure 2) is a useful graphical aid that patients can use to simply point to the stool type they pass. As shown in Figure 2, the scale also correlates well with stool transit. 13-15 Prolonged colon transit produces hard, lumpy stools whereas rapid transit produces loose, watery stools. The rectal examination is an important part of the patient examination because it can demonstrate whether the muscles in the rectal area (eg, the puborectalis) are functioning correctly. (The puborectalis feels like a bar that extends across the posterior of the rectum.) These muscles are within a finger s length of the anus. In fact, rectal examinations should be part of a complete physical examination for healthy adults. The rectal examination also should include a gross anatomical evaluation to Table 4. First-Line Treatments for Constipation ACG Task Force Treatment Mechanism Available Products Recommendation Fiber Long-chain polysaccharides and several other plant Psyllium Grade B (psyllium) components, such as cellulose, lignin, and waxes, which Methylcellulose are not digested in the human stomach or small intestine. Calcium polycarbophil Guar gum Bulking agents Poorly absorbed agents that act by absorbing liquids in the Psyllium Grade B (psyllium) intestines. The ingested bolus then swells to form a soft Most other fiber supplements bulky stool, which prompts a bowel movement. Stool softeners Minor laxative agents that modestly reduce fluid absorption Grade B and thereby prevent dry, hard stools from forming. These products decrease the need for straining and facilitate the ability to evacuate the bowel. Laxatives Osmotic/saline Promote retention of water within the bowel lumen, Saline laxatives (eg, magnesium Grade A (polyethylene softening the stool and increasing bowel actions. hydroxide [milk of magnesia], glycol and lactulose) magnesium citrate, and sodium phosphate) Nonabsorbable sugars or sugar alcohols (eg, lactulose, sorbitol, mannitol, or lactitol) Certain polymers (eg, polyethylene glycol) Irritant/stimulant Act on the intestinal wall, stimulating secretion of water None and salt by the mucosa and increasing muscle contractions to move the stool. Lubricant Coats the bowel and is incorporated into the stool mass, Mineral oil None keeping it soft and easing passage through the digestive tract. ACG = American College of Gastroenterology. Data from Brandt et al. 5 Johns Hopkins Advanced Studies in Nursing 169

look for external and internal hemorrhoids, anal fissures, rectal prolapse, and rectocele. 7 The final part of the constipation workup is the laboratory tests. Some of the basic clinical laboratory tests that may be performed for patients with constipation include a complete blood count, thyroid function tests (thyroid-stimulating hormone, free thyroxine), and measurements of calcium and electrolytes. 10 The ACG Task Force does not recommend diagnostic testing in patients without alarm signs or symptoms (other than routine colon cancer screening for all patients aged 50 years). 5 Nonetheless, these tests can be useful as a general measure of overall health. With appropriate diagnostic skills, a thorough evaluation, and a sense of empathy and comfort from the nurse, chronic constipation can be better managed in any of the varied clinical areas in which it is so frequently encountered. NEW TREATMENTS FOR AN OLD PROBLEM: CHRONIC CONSTIPATION Based on a presentation by Schiller LR Baylor University Medical Center, Dallas, Texas Patients suffering from chronic constipation are often willing to try anything to relieve their pain and discomfort. However, first-line treatments for constipation are, in fact, very simple: increased dietary fiber, fluids, exercise, and allocating time to have a bowel movement. Patients will most likely have tried the first 3 treatments on their own. It is important to document what has been tried and the results. On the other hand, allocating a dedicated and sufficient time for a bowel movement is often not considered, but is a common remedy for chronic constipation. The best time for a bowel movement is in the morning, after breakfast, when digestive stimuli prompt the urge to evacuate the bowels. If that urge is ignored, it tends to diminish over time. With the exception of increased dietary fiber, scientific evidence showing the efficacy of these simple treatments is lacking (and they are not discussed in this article), but this has not diminished their popularity or usefulness. If the patient is not consuming sufficient fiber (>20 g daily), he or she should begin with lower doses (4 6 g daily) of dietary fiber, such as bran, or medicinal fiber, such as psyllium, and increase it gradually to avoid bloating and flatulence. There are many types of medicinal fiber supplements available (Table 4). 5 The fiber content for different foods is available on some Web sites (Table 5) and on the nutrition labeling of products. The total recommended daily intake of fiber (diet + supplementation) is 20 to 25 g, but could be increased to 30 g if necessary. 16 Bulking agents improve bowel frequency and consistency (Table 4). 5 Stool softeners (Table 4) are often the second treatment patients try after bulking agents. They may not be as effective as psyllium for increasing stool frequency, but many patients have had great success with them. 5 There are several types of laxatives (Table 4). Although there is insufficient scientific evidence to support a recommendation about using magnesium hydroxide for chronic constipation, many patients try it because it is promoted as a more gentle treatment that works overnight. The taste of milk of magnesia is an issue for many patients and some claim that it stops working after a while, although it is not clear why this occurs. Sugar alcohol laxatives have the possible disadvantage of causing excessive flatus produced by bacterial metabolism of these fermentable substrates in the colon. 5 Of note, any osmotic laxative can create fluid or electrolyte abnormalities if used inappropriately and may cause hypovolemia or diarrhea. 5,10 Stimulant (irritant) laxatives may induce cramping and discomfort associated with bowel movement and occasionally electrolyte imbalances. Allergic reactions complicate the use of some of the plant-based products. Therefore, they should be used for short-term relief rather than as a long-term solution to a chronic problem. 5,10 Mineral oil is sometimes used as an acute Table 5. Web Sites Listing the Fiber Content of Common Foods Harvard University Health Services, Nutrition Know How http://huhs.harvard.edu/pdf/fibercontentnutritiionfall2004a.pdf Continuum Health Partners, Dietary Fiber Chart http://www.wehealnewyork.org/healthinfo/dietaryfiber/fibercontentchart.html The Mayo Clinic http://www.mayoclinic.com/health/fiber/nu00033 University of Arizona, College of Agriculture and Life Sciences http://cals.arizona.edu/pubs/health/az1127.html American Dietetic Association, Fiber Facts http://www.eatright.org/cps/rde/xchg/ada/hs.xsl/nutrition_5440_e NU_HTML.htm 170 Vol. 4, No. 7 November 2006

treatment for children, less so with adults. Aspiration of mineral oil produces a lipoid pneumonia that may be difficult to treat. In general, regular intake of currently available laxatives is considered unlikely to be harmful to the colon and data do not support a potential for addiction. 5 However, although laxative preparations are effective for short-term relief, they tend to cause unpleasant side effects that preclude their long-term use. 5,10 The ACG Task Force specifically recommended psyllium, stool softeners, polyethylene glycol, and lactulose for use as laxatives, citing insufficient data to make recommendations for any other laxative treatments. 5 NEWER TREATMENTS FOR CONSTIPATION TEGASEROD Tegaserod is indicated for IBS with constipation in women and for chronic constipation in men and women under age 65. The ACG Task Force gave tegaserod a grade A recommendation for the treatment of chronic constipation. 5 Tegaserod acts by enhancing the peristaltic reflex (and thus moving the fecal bolus through the gastrointestinal [GI] tract) by mimicking serotonin. Tegaserod also may decrease visceral sensitivity, thus decreasing the amount of pain associated with IBS with constipation. 17-19 Two published, large, placebo-controlled clinical trials show the efficacy of tegaserod in chronic constipation, increasing the number of complete spontaneous bowel movements per week by at least 1 over the first 4 weeks of treatment (Figure 3). 20,21 Tegaserod produced statistically significant improvement over placebo for the full 12 weeks of treatment and when treatment is extended to 13 months beyond the initial 12-week treatment period. 20-22 Tegaserod is well tolerated. 20,21 The most frequent side effect is diarrhea that typically lasts from 1 to 2 days when first starting the medication. There are no clinically relevant drug-drug interactions with tegaserod, and no prolongation of QT intervals on electrocardiography. 20-22 Also, there is no apparent rebound effect when tegaserod was discontinued over a 4-week withdrawal period. 20,21 There is a precaution noted in the labeling for tegaserod regarding recently reported cases of ischemic colitis with tegaserod use: [tegaserod] should be discontinued immediately in patients who develop symptoms of ischemic colitis, such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. 23 However, a causal association has not been established, and the occurrence of ischemic colitis may be no higher with the drug than with the underlying condition alone. LUBIPROSTONE Lubiprostone is indicated for the treatment of chronic constipation in adults. 24 It selectively activates a specific subset of chloride channels (ClC-2 channels) on the cells lining the GI tract, thus enhancing fluid secretion into the intestine. This promotes spontaneous bowel movements, softens the stool, and reduces abdominal discomfort/pain and bloating. 25,26 It does not have detectable systemic absorption. 27,28 Lubiprostone has been studied in 2 large clinical trials, producing significantly more spontaneous bowel movements per week than placebo (Figure 4). 28-30 Lubiprostone is equally effective in men and women and, importantly, is effective in elderly patients. 31,32 The most common side effects with lubiprostone were nausea, diarrhea, and headache. 28,33-37 Nausea can be minimized by taking lubiprostone with food or by reducing the dose. Most study subjects tolerated the nausea in order to relieve their constipation; however, approximately 10% of patients discontinued lubipros- Figure 3. Responder Rate During the First 4 Weeks of 12-Week Studies of Tegaserod vs Placebo 50 40 30 20 10 0 25 41* 43* Responder rates, % 27 Placebo Tegaserod 2 mg BID Tegaserod 6 mg BID 36 40* 0 n = 447 n = 450 n = 451 n = 416 n = 417 n = 431 50 40 30 20 10 Responders had an increase of 1 spontaneous complete bowel movement/wk and completed 7 days of treatment. Responder rates were significantly higher than placebo for the primary study endpoint (weeks 1 4) and the secondary endpoint (weeks 1 12, not shown). BID = twice a day. *P <.0001; P <.01. Adapted with permission from Johanson et al. Clin Gastroenterol Hepatol. 2004;2:796-805 20 and Kamm et al. Am J Gastroenterol. 2005;100:362-372. 21 Johns Hopkins Advanced Studies in Nursing 171

Figure 4. Efficacy of Lubiprostone vs Placebo in 4- Week Studies SBMs per week SBMs per week 7 6 5 4 3 2 1 0 (B) 7 6 5 4 3 2 1 0 (A) Baseline Wk 1 Wk 2 Wk 3 Wk 4 tone because of nausea. 24 Lubiprostone does not cause any electrolyte imbalances or renal dysfunction, and systemic drug-drug interactions have not been a problem. 38 Finally, the prescribing information suggests that lubiprostone be used in women only if they are not pregnant (verified by a negative pregnancy test) because of the potential for fetal loss observed in guinea pigs who received lubiprostone. 24 WHEN TO REFER TO A GASTROENTEROLOGIST An accurate history, careful physical examination, * LUB PL In these studies, 237 patients (A) or 242 patients (B) received oral lubiprostone 24 µg or placebo BID for 4 weeks, preceded by a 2-week drug-free washout period. BID = twice a day; LUB = lubiprostone; PL = placebo; SBM = spontaneous bowel movement. *P <.05 vs placebo; P <.007 vs placebo; P.0004 vs placebo. Reprinted with permission from McKeage et al. Drugs. 2006;66:873-879. 28 and appropriate specialized investigations are essential for the diagnosis and selection of appropriate treatment for chronic constipation. Patients should be referred to a gastroenterologist if they present with new-onset constipation with any alarm symptoms, if they require high doses of medication to adequately treat the constipation, or if constipation is not alleviated with any of the recommended treatments. Patients also should be referred if they are thought to Table 6. Tests to Determine Cause of Constipation Test Use Anorectal Assesses the internal and external anal sphincters (volmanometry 10,40 untary relaxation and contraction), rectal sensation, pelvic floor, and associated nerves Screening test of choice for outlet obstruction Especially useful for detecting pelvic floor dyssynergia Balloon Simple, office-based test expulsion 10,40 Detects defecatory disorders Method: Involves placing and inflating a balloon (50 ml) inside rectum; most individuals can expel the balloon within 60 sec Defecography 10,40 Detects structural abnormalities of the rectum, assesses degree of bowel evacuation, and measures the anorectal angle Operator dependent, can cause performance anxiety in patient, poor reliability, not widely available Method: Balloon is inserted into the rectum and inflated to simulate stool, prompting the urge to evacuate the bowels. Patients are asked to note how this feels and to relax the sphincter muscles and pelvic floor while contracting the diaphragm and abdominal wall muscles to increase intra-abdominal pressure Colonic transit Measures rate at which fecal mass moves through colon study 10,40 Essential for diagnosis of slow-transit constipation Should always be performed before considering surgery for chronic constipation Method: Patient ingests radio-opaque markers in a gelatin capsule; abdominal radiography performed 120 h later Biofeedback 10,39,41 Emphasizes coordination of appropriate muscles during defecation Rapport with therapist is crucial to success Approximately 70% success rate; effects appear to be long lasting (up to 1 year) Only 12 major motility centers in the United States Method: Patient views pressure signals of the anal sphincter on a monitor during relaxing and squeezing to train pelvic floor muscles Data from Lembo and Camilleri 10 ; Rao et al 39 ; Rao et al 40 ; and Chiarioni et al. 41 172 Vol. 4, No. 7 November 2006

have pelvic floor dyssynergia (also known as functional outlet obstruction or anismus). When patients are referred, the gastroenterologist may perform colonoscopy to exclude causes of secondary constipation, such as obstructing lesions, or they may perform any of several tests to discern the pathophysiology of constipation. In clinical practice, the most useful pathophysiologic tests are anorectal manometry, balloon expulsion, defecography, and colonic marker transit study (Table 6). 10,39-41 REFERENCES 1. Lethbridge-Cejku M, Schiller JS, Bernadel L. Summary health statistics for US adults: National Health Interview Survey, 2002. Vital Health Stat 10. 2004;222:1-151. 2. Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol. 2004;99:750-759. 3. Talley NJ, Weaver AJ, Zinsmeister AR, et al. Onset and disappearance of gastrointestinal symptoms and functional gastrointestinal disorders. Am J Epidemiol. 1992;136:165-177. 4. 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