- Email: [email protected]
Diagnostic approach to suspected irritable bowel syndrome
Best Practice & Research Clinical Gastroenterology Vol. 18, No. 4, pp. 735–746, 2004 doi:10.1016/j.bpg.2004.04.001 available online at http://www.sciencedirect.com
9 Diagnostic approach to suspected irritable bowel syndrome J. G. Hatlebakk*
MD, PhD
Associate Professor
M. V. Hatlebakk
MD, MHA
Researcher Institute of Medicine, Haukeland University Hospital, University of Bergen, Bergen, Norway
Diagnostic activity in patients with suspected irritable bowel syndrome (IBS) should be brief and focussed, limited to investigations that are likely to exclude serious alternative diagnoses and when negative support a positive diagnosis of IBS. The diagnosis of IBS is clinical, and is robust over time, although other symptoms may add to the clinical picture and other symptoms of functional disorders are common. The most important differential diagnoses are celiac disease, colorectal carcinoma and colitis. ‘Red Flag’ symptoms and signs should be considered indications for full colonoscopy, which should be performed with a low threshold in patients above 50 years of age. Serologic markers are useful to exclude celiac disease, but positive tests must be confirmed with duodenal biopsies. Key words: irritable bowel syndrome; celiac disease.
The prevalence of irritable bowel syndrome (IBS) is high in all populations/regions of the world in which epidemiological studies have been performed, which includes several European, North American, but also Asian and African countries. Prevalence rates in the order of 9 to 25% are most often cited, always highest in women. Differences in cultural factors, including reporting of symptoms and health care seeking behaviour, extent of urbanisation and diet, are likely to explain the modest differences that are found between studies and between countries. For the medical profession and health care systems, the group of patients with IBS is resource-demanding and requires a structured approach to diagnostic management, for several reasons. First and foremost should potentially serious disease not be overlooked in the setting of common and often non-specific symptoms. Secondly, care should be taken to avoid overuse of often limited diagnostic resources. A prolonged and unfocussed diagnostic workup is likely to create anxiety and confusion with the patient, whereas a more brief and evidence-based approach will create more confidence and be a better basis for * Corresponding author. Tel.: þ47-55-97-70; Fax: þ 47-55-97-29-50. E-mail address: [email protected] (J.G. Hatlebakk). 1521-6918/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
736 J. G. Hatlebakk and M. V. Hatlebakk
a future therapeutic relationship. At least in primary care, subjects with symptoms of IBS often demand primarily reassurance and simple lifestyle advice.
THE DIAGNOSIS OF IBS The diagnosis of IBS is and must be clinical, since any objective confirmative diagnostic test for the disorder is lacking. For practical purposes, the history most often gives all necessary information for a positive working diagnosis: a symptom complex compatible with IBS and absence of alarm or ‘Red Flag’ symptoms. This may be supplemented with a limited number of diagnostic tests, designed to exclude alternative and more serious disease, depending on symptoms as well as age and clinical findings. The clinical setting of the consultation is all-important, since we know that only a minority of subjects with IBS-like symptoms consult at the primary care level and less than 3% are referred to the secondary level of medical care. Those who are seen at the secondary care level are much more likely to have organic disease and may need a somewhat more sophisticated diagnostic workup and follow-up. Whenever diagnostic tests are used to exclude organic disease, it is important to let this information lead to a conclusion and explanation for symptoms within a limited period of time, to avoid confusion and create insight and a platform for future therapy of IBS. How reliable is a clinically based diagnosis of IBS over time? This has been studied in at least two studies. Vanner and coworkers1 retrospectively identified 98 patients and prospectively 95 patients with IBS according to Rome criteria, with no red flags fulfilled. The positive predictive value was 100% with no patient requiring a revision of the diagnosis within an observational period of 2 years.1 Harvey and coworkers studied 101 patients who fulfilled the Manning criteria for IBS, again with no patient proving to be incorrectly diagnosed after an observational period of 5 years.2
DIAGNOSTIC CRITERIA IN A CLINICAL SETTING Classically, IBS was defined as altered bowel habits with abdominal pain, with no structural or biochemical abnormalities present. This left much to subjective theories of what were the essential components of the clinical picture and required for the diagnosis. More practically, in 1978 Manning and coworkers3 published a list of symptoms and observations that were found to distinguish between patients with organic disease of the abdomen and patients ultimately diagnosed with IBS. The Manning criteria are given in Table 1. They have been confirmed as useful in Table 1. The Manning criteria for irritable bowel syndrome3. Visible abdominal distension Relief of pain with bowel movement More frequent bowel movement with the onset of pain Loose stools at the onset of pain Passage of mucus per rectum Feeling of incomplete evacuation
Diagnostic approach to suspected irritable bowel syndrome 737
Table 2. The Rome II criteria for irritable bowel syndrome.4 At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two of three features: 1. Relieved with defecation; and/or 2. Onset associated with a change in frequency of stool; and/or 3. Onset associated with a change in form (appearance) of stool Supportive (non-essential) symptoms of the irritable bowel syndrome: 1. Fewer than three bowel movements a week 2. More than three bowel movements a day 3. Hard or lumpy stools 4. Loose or watery stools 5. Straining during a bowel movement 6. Urgency 7. Feeling of incomplete emptying 8. Passing mucus during a bowel movement 9. Abdominal fullness, bloating or swelling
several later publications and have been used for patient selection in epidemiological and clinical studies. The later Rome criteria were created for clinical research and may be perceived as too restrictive for everyday clinical use.4 This is particularly the case for the Rome II criteria5, which require symptoms (pain or pain-related discomfort) to have been present for at least 12 weeks out of the preceding 12 months, whereas the earlier Rome I criteria had no such time window defined. The great emphasis on pain may also be unsatisfactory, since most patients have a complex pattern of symptoms. There will always be patients in whom Rome I and II criteria are not fulfilled, but who clearly suffer from IBS as judged by clinical perception and experience. The Rome II consensus report defines several other groups of functional gastrointestinal disorders giving symptoms localized to the lower abdomen, and these can be important differential diagnoses. It is also very common for patients to suffer from more than one functional gastrointestinal disorder, as evidenced by reports that suggest that up to 30% of IBS patients suffer from functional dyspepsia. Still it is the opinion of the authors that the clinician should be familiar with the main and non-essential criteria for IBS in the Rome II classification, since this will facilitate a systematic and rational history taking and interpretation of symptoms. The Rome II criteria are shown in Table 2.
PSYCHOPATHOLOGIC FACTORS In a subgroup of IBS patients, particularly so in secondary care, psychopathology plays a more extensive role and questions need to be addressed in a sympathetic manner, allowing adequate time for identification of worries and discussion. There is often a paradoxical discrepancy between subjective symptom burden, and objective clinical findings. In all patients it is useful to identify any ‘hidden agenda’,
738 J. G. Hatlebakk and M. V. Hatlebakk
including why he or she decided to consult just now. There are often health worries (cancer) within the family, anxiety for marital life, unemployment, economic problems etc. It is also important to ask for symptoms of other functional disorders, including sleep disorders, pelvic pain and fibromyalgia, conditions that coexist with IBS more often than by sheer chance. Indeed, it is known that patients with functional gastrointestinal disorders rank their bowel symptoms on average fourth, after back pain, headache and anxiety/depression.6
THE HISTORY IN IBS Some important elements of the history are shown in Table 3: time and type of onset of disease, course and pattern of symptoms, predominant and less prominent symptoms, aggravating and relieving factors. As an important element in the definition of IBS, according to the Rome criteria, it is important to ask about the relationship of symptoms to bowel movements. The severity of symptoms may vary in each patient over time and between patients. It is useful to chart major consequences of symptoms, including absence from work or school. If symptoms started acutely with a (febrile) gastroenteritis, which instead of subsiding spontaneously continued with pain and diarrhoea over months, this may indicate infection-induced IBS (or colitis). Negative lifetime events preceding the onset of a period with pain may also be worth noting.
CLINICAL EXAMINATION AND SIMPLE LABORATORY TESTS Clinical examination is important to not overlook easily identifiable pathology, but usually contributes little toward a diagnosis in this patient group. A mild tenderness in the lower left abdomen, or even some resistance corresponding to a spastic sigmoid colon is not uncommon, but certainly not diagnostic, as other causes for this must be ruled out. Simple blood tests, such as erythrocyte sedimentation rate (ESR), haemoglobin, leucocyte count and albumin are useful to screen for inflammation and other pathology. Thyroid-stimulating hormone (TSH) and free thyroxin in plasma (FT4) are often analyzed and should be recommended, but in our experience clinically important abnormalities are infrequent. Faecal occult
Table 3. Important elements of the history in patients suspected of suffering from IBS. Acute, subacute or gradual onset of symptoms Predominant symptom (Pain? Discomfort?) Improvement in symptoms after bowel movements? Chronic course of disease? Variation over time? Presence of blood or mucus on stools? Associated symptoms?
Diagnostic approach to suspected irritable bowel syndrome 739
Table 4. Observations that may indicate an organic cause for abdominal symptoms. Complaints over less than 24 months Elderly patient Diarrhoea is persistent Nighttime diarrhoea Sudden onset Weight loss of 5 kg or more Abnormal ESR, Hb and / or albumin Mean faecal mass .225 g/24 h
blood test, from three to six separate stool samples, and taken with adequate exclusion of meats from the diet, is clearly important to detect bleeding lesions in the gastrointestinal tract, and decide on the indication for colonoscopy.
ORGANIC VERSUS FUNCTIONAL DIARRHOEA Chronic diarrhoea, defined arbitrarily as loose stools more than three times daily for more than three weeks, may have a multitude of different organic or non-organic causes. When seeing the patient with chronic diarrhea, certain clues may suggest an organic etiology (Table 4). Due to an often long patient’s delay in functional disease, a history of less than 1 –2 years is suggestive of an organic cause, as is age above 60 at the onset of symptoms. Acute onset of diarrhoea is always due to an organic cause, but may have developed into IBS, as discussed above. The consistency of stools is almost always somewhat varying over time, even with diarrhoea-predominant or constipation-predominant IBS; whereas chronic diarrhoea from other causes is never interrupted with hard stools. Nocturnal symptoms are very uncommon in IBS, pain and diarrhoea may occur on going to bed or getting up early, but sleep is not interrupted by symptoms. Significant weight loss may suggest an organic or even malignant cause, but not invariably so, since aggravation of pain or diarrhoea with meals may limit food intake. Mucus on stools is described by some patients and this does not speak against IBS, nor does blood, provided that a trivial cause, such as bleeding from haemorrhoids or an anal fissure can subsequently be shown to be the only likely explanation.
ALARM SYMPTOMS OR ‘RED FLAGS’ More importance must be given to certain observations that experience has taught us to associate with malignant or premalignant disease of the colon (Table 5). This short list includes aspects of the history that should lead to a search for malignant disease or other potentially serious disease, such as colitis.
740 J. G. Hatlebakk and M. V. Hatlebakk
Table 5. Red flag symptoms and signs that should indicate the need for colonoscopy in patients suspected of IBS. Age .50 years Weight loss (Occult) blood in faeces Family history of colorectal cancer
MAJOR DIFFERENTIAL DIAGNOSES TO IBS The list of disease that can be mimicked by typical or atypical cases of IBS is long (Table 6). Some of the more important, due to high incidence or seriousness, will be discussed in more detail below. Since these will vary in different age ranges, differential diagnoses will also differ in young and elderly patients.
CELIAC DISEASE INCLUDING POTENTIAL AND LATENT DISEASE Celiac disease is very common in northern Europe, and is often associated with mild and atypical symptoms. Recent population-based studies from Scandinavia and the United Kingdom have shown a prevalence up to 500 –1000/100 000 adults, based on serologic criteria. When screening 300 patients referred to a university outpatient clinic for symptoms of IBS, according to the Rome II criteria, Sanders and coworkers7 found a seven-fold increased probability for celiac disease, as compared with age- and gender-matched control subjects. Patients were screened with serologic tests (Immunoglobulin A and G against gliadin and endomysial antibodies) and positive cases were referred for endoscopic biopsy from the duodenum. Sixty-six patients had positive antibodies, 14 of whom proved to have celiac disease.7 This suggested that celiac disease is a major differential diagnosis, particularly in young to middle-aged patients, and that immunological tests are useful to detect it.8 Later publications have
Table 6. Differential diagnoses for irritable bowel syndrome. Celiac disease Food intolerance Disaccharide intolerance Inflammatory bowel disease Infection Bacterial overgrowth Diverticular disease of the colon Colorectal carcinoma Bile acid induced diarrhoea
Diagnostic approach to suspected irritable bowel syndrome 741
however questioned this finding, particularly a study performed in primary care, which involved serological testing of primary care patients fulfilling Rome I criteria for IBS. None of 121 patients had abnormal endomysial antibodies, thought to be a highly sensitive test for celiac disease.9 It is clear that the clinical setting is important, the selection of patients for referral to tertiary care centres increases the probability of finding organic disease. Improved and less expensive serologic methods make it easier to screen for manifest celiac disease in patients with gastrointestinal symptoms. In particular, antibodies against tissue transglutaminase (tTGA), believed to be of pathophysiological importance, are thought to be relatively sensitive and specific for the disorder, at least in its fully developed forms. Given the similarity of symptoms and high prevalence of both disorders, it has been suggested that a subgroup of IBS patients might suffer from a mild form of celiac disease, not detectable by serology or routine duodenal biopsies. Potential celiac disease, defined as normal duodenal biopsy morphology, but with some immunological markers of celiac disease, has been found in a subgroup of 102 patients with IBS, who were compared to 41 patients with manifest disease.10 Antibodies against tTGA and gliadin were analysed in duodenal aspirate and biopsies were studied for intraepithelial lymphocytes. It was concluded that a subgroup of IBS patients had immunological markers for potential celiac disease, and a trial of gluten-free diet for six months tended to normalise these values.10 A symptomatic response to gluten-free diet does not strongly support the diagnosis of celiac disease, since such a relatively residue-free diet is also likely to benefit patients with IBS. Instead, patients need to go back to their normal diet for at least four weeks before adequate biopsies can be taken. It is malpractice to use a trial of gluten-free diet as a diagnostic modality, due to the high frequency of non-specific response in various functional bowel disorders.
FOOD INTOLERANCE Up to 40% of adults are convinced they are ‘allergic’ to one or more foodstuffs, but an immunological mechanism for discomfort from food intake can be proved with doubleblind provocation in less than 2 percent. In a large proportion of the remainder, IBS is the likely explanation for gastrointestinal symptoms, and extra-intestinal symptoms may also be due to various functional disorders. Around 50% of patients with IBS report food intolerance, most often suspected to be against dairy products, wheat, eggs, yeast, chemical additives etc.11
DISACCHARIDE INTOLERANCE Lactose intolerance has been listed as a major cause for abdominal pain and diarrhea, and therefore an alternative explanation for IBS-like symptoms. Most subjects with lactose intolerance are well aware of their problem, and can manage symptoms quite well by limiting dairy products in their diet. Most patients with longstanding symptoms of IBS have also tried to omit certain foods from their diet, including milk, often with at least transient improvement in symptoms. Objective testing is not unproblematic. A breath test, as used by Parker and coworkers, turned
742 J. G. Hatlebakk and M. V. Hatlebakk
out abnormal in 27% of 122 IBS patients11, but more patients responded to a lowlactose diet for 3 weeks, suggesting intolerance to other components of milk. We have disappointing experience using the traditional oral lactose tolerance test. By whatever test is used, it seems clear that more subjects experience discomfort from dairy products than can be explained by lactase deficiency. It is important, therefore, not to discredit the subjective experience of these patients, but accept their need to avoid milk and other dairy products. Other osmotically active saccharides, such as fructose and sorbitol have also been reported to cause diarrhea and abdominal pain. When investigating 183 patients with unexplained abdominal symptoms with a fructose breath test, Choi and coworkers found abnormal tests in 134 (73%).12 Up to 75% of patients with positive tests had symptoms during the (uncontrolled) challenge. A large proportion of these patients had symptoms compatible with IBS (flatus 83%, pain 80%, bloating 78%, altered bowel habits 65%). In a previous, smaller study, it was found that nine out of 25 patients with IBS had fructose malabsorption.13 It is of value to interrogate about excessive use of sugar-free chewing gum and lozenges, and a simple trial of excluding these may suffice for a clinical diagnosis. Suspected fructose malabsorption should however be confirmed objectively since excluding fructose from the diet is a much more difficult task.
INFLAMMATORY BOWEL DISEASE In the younger population in particular, ulcerative colitis and Crohn’s disease are not uncommon, and symptoms may be confused with those of IBS. Simple blood tests, including inflammatory parameters, C-reactive protein (CRP), ESR and a leucocyte count, may all be normal. There has been a lack of a simple (in vitro) test for inflammation of the intestinal wall and only recently has a candidate appeared: faecal calprotectin (f-calprotectin). This is a highly stable glycoprotein present in neutrophilic leucocytes, and is found increased when these cells are recruited to sites of inflammation or neoplasia.14 Calprotectin can be analysed from one single faecal specimen, securing a patient compliance above 95% in one study.15 Tibble and coworkers obtained faecal calprotectin samples from 602 patients with bowel symptoms, classifying them into low, medium or high risk for organic disease (IBD or cancer), based on absence or presence of alarm symptoms. In all groups, f-calprotestin showed a sensitivity in the order of 90% and specificity in the order of 80%. This is a significant improvement compared with routine tests for inflammation, such as CRP, ESR and leucocyte count. A recent study showed that f-calprotectin could not discern reliably between colorectal cancer, benign polyps or inflammation.16 Still, it is likely that f-calprotectin may prove useful for excluding inflammatory disease in patient suspected of IBS, without or with alarm symptoms or other clinical features of serious disease.
INFECTIONS INCLUDING BACTERIAL OVERGROWTH Infections with Giardia lamblia and certain other parasites may cause chronic abdominal pain and diarrhea, which has been confused with IBS. The question of bacterial overgrowth with colonization of the proximal small bowels in patients with IBS-like
Diagnostic approach to suspected irritable bowel syndrome 743
symptoms is controversial. One reason is the difficulty of obtaining adequate material for diagnosis. Pimentel and coworkers17 used a lactulose breath test to investigate for bacterial overgrowth in 111 patients with IBS according to the Rome I criteria, as compared with a group of healthy controls. An abnormal breath test was found in 84%, compared with 20% of controls (p , 0:01). Abnormal tests in patients were followed up with a trial of therapy with Neomycin 500 mg b.i.d. for 10 days, with placebo control, resulting in improved symptom scores in 43%, correlating with normalization of the breath test.17 It is clear that the lactulose breath test has insufficient sensitivity and specificity and that results may not be reliable in all patient groups. Simren and coworkers investigated bacterial overgrowth with what is considered the gold standard, bacterial culture from jejunal aspirate at the time of gastroduodenoscopy, finding bacterial colonization in only four out of 33 IBS patients.18 An open trial of antibiotic therapy improved symptoms significantly in only one patient. It was therefore concluded that it is unlikely that bacterial overgrowth is a common cause for symptoms in patients suspected to have IBS.
DIVERTICULAR DISEASE OF THE COLON Diverticula may result from abnormal bowel function, but may also give rise to symptoms compatible with IBS. Diverticular disease is uncommon in the younger age range, in which most IBS patients first experience symptoms and seek medical assistance. Diverticulosis was found in only 9% of subjects below the age of 50, but in 56% of elderly patients above 70.19 The majority of patients with diverticula are asymptomatic, with occasional symptoms most often due to such complications as diverticulitis or haemorrhage.
COLORECTAL CARCINOMA The most serious diagnosis to overlook in patients suspected of irritable bowel syndrome is colorectal carcinoma (CRC), one of the major malignant diseases in western societies. Furthermore, early detection of cancer of the colon even in symptomatic individuals can lead to excellent treatment results, emphasizing the need for liberal access to diagnostic activity. Symptoms due to colorectal cancer are typically pain and recent change in bowel habits, toward either looser or harder stools, which can also easily be ascribed to IBS. Cancer registries show very few cases below the age of 50, which has implications for referral practice. The family history of CRC is furthermore important when deciding on a diagnostic strategy in individual patients.
COLONOSCOPY IN SUSPECTED IBS Colonoscopy has only negative diagnostic value in IBS, by excluding other pathology. When judged to be necessary in patients suspected of suffering from IBS, it is invariably the most expensive diagnostic method used with any frequency. It is thought of as having a high incremental cost-effectiveness ratio. Therefore, unless alarm symptoms are present, its use should be limited to when “…a serious organic disease is reasonably
744 J. G. Hatlebakk and M. V. Hatlebakk
Table 7. Diagnostic workup in refractory irritable bowel syndrome20. Anorectal motility studies 24-hour fecal weight and fat content Cholestyramin trial Jejunal aspirate for bacterial culture Fructose breath test Plain abdominal X-ray Small bowel X-ray
likely and needs to be ruled out” (ACG). Colonoscopy is however sometimes needed in order to reassure the patient of the absence of serious disease, and may in some settings be considered indicated as a general screening procedure for CRC, particularly in a middle-aged to elderly patient with a family history of the condition. In patients with diarrhea, biopsies should always be taken to look for microscopic colitis. In patients with chronic IBS referred to specialist care, colonoscopy is usually performed, sooner or later.
REFRACTORY IBS Sometimes symptoms compatible with IBS do not improve as expected and an increased effort to look for alternative causes is necessary. Depending on which symptom predominates in the individual patient, and provided that colonoscopy with biopsies has already been performed with normal findings, one might consider motility studies to investigate causes for constipation, a trial of cholestyramine for up to a week to exclude bile acid induced diarrhea and / or radiographic examinations to look for causes for abdominal pain (Table 7).20
SUMMARY The diagnosis of IBS is clinical, and is robust over time, although other symptoms may add to the picture. Adequate time must be spent with the patient, to discuss the important points in the history that might allow for a positive diagnosis of IBS according to the Rome II criteria. In addition, any Red Flag symptoms and signs should be identified, which calls for a more invasive diagnostic approach, including a full colonoscopy. At least in specialist care, serologic markers should be analyzed to exclude celiac disease. Calprotectin in faeces might prove a useful method to exclude inflammatory bowel disease but is not reliable to exclude cancer of the colon or rectum. Colonoscopy is sometimes needed to make the patient relax and may be indicated in patients above the age of 50, when colorectal cancer becomes a relevant differential diagnosis.
Diagnostic approach to suspected irritable bowel syndrome 745
Practice points † irritable bowel syndrome is very common in all parts of the world and in all age groups † a brief and evidence-based diagnostic workup will save resources and create a better basis for future therapy † red flag symptoms and signs are important when deciding on the indication for colonoscopy † the Rome II criteria are useful not only for research, but improves the interpretation of symptoms and creates a better basis for a positive diagnosis
Research agenda † investigate differences in symptom patterns, which are not well understood † investigate whether mild forms of celiac disease and small intestinal bacterial overgrowth can explain IBS-like symptoms in significant subgroups. † larger studies are needed to investigate the health economic and quality of life aspects of the diagnosis and follow-up of patients with suspective IBS
REFERENCES 1. Vanner SJ, Depew WT, Paterson WG, et al. Predictive value of the Rome criteria for diagnosis the irritable bowel syndrome. The American Journal of Gastroenterology 1999; 94: 2912–2917. 2. Harvey RF, Mauad EC & Brown AM. Prognosis in the irritable bowel syndrome: A five year prospective. Lancet 1987; 1: 963–965. 3. Manning AP, Thompson WG, Heaton KW & Morris AF. Towards a positive diagnosis of the irritable bowel. British Medical Journal 1978; 2(6138): 653 –654. 4. Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999; 45(supplement II): II43– II47. 5. Boyce PM, Koloski NA & Talley NJ. Irritable bowel syndrome according to varying diagnostic criteria: are the new Rome II criteria unnecessarily restrictive for research and practice? The American Journal of Gastroenterology 2000; 95: 3176–3183. 6. Wilhelmsen I, Haug TT, Ursin H & Berstad A. What are the real problems for patients with functional dyspepsia? Scandinavian Journal of Gastroenterology 1995; 30: 97 –100. 7. Sanders DS, Carter MJ, Hurlstone DP, et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. The Lancet 2001; 358: 1504–1508. 8. Cash BD, Schoenfeld P & Chey WD. The utility of diagnostic tests in irritabe bowel syndrome patients: a systematic review. The American Journal of Gastroenterology 2002; 97: 2812–2819. 9. Holt R, Darnley SE, Kennedy T, et al. Screening for coeliac disease in patients with clinical diagnosis of irritable bowel syndrome. Gastroenterology 2002; 122: A757. 10. Wahnschaffe U, Ullrich R, Riecken ED & Schulzke JD. Celiac disease like abnormalities in a subgroup of patients with irritable bowel syndrome, Gastroenterology 2001; 121: 1329– 1338. 11. Parker TJ, Woolner JT, Prevost AT, et al. Irritable bowel syndrome: is the search for lactose intolerance justified? European Journal of Gastroenterology and Hepatology 2001; 13: 219– 225. 12. Choi YK, Johlin FC, Summers RW, et al. Fructose intolerance: an under-recognized problem. The American Journal of Gastroenterology 2003; 98: 1348– 1353. 13. Rumessen JJ & Gudmand-Hoyer E. Functional bowel disease: malabsorption and abdominal distress after ingestion of fructose, sorbitol, and fructose–sorbitol mixtures. Gastroenterology 1988; 95: 694–700. 14. Roseth AG, Fagerhol MK, Aadland E, et al. Assessment of the neutrophile cominating protein calprotectin in feces. Scandinavian Journal of Gastroenterology 1992; 27: 793– 798.
746 J. G. Hatlebakk and M. V. Hatlebakk 15. Tibble JA, Sigthorsson G, Foster R, et al. Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology 2002; 123: 450 –460. 16. Limburg PJ, Devens ME, Harrington JJ, et al. Prospective evaluation of fecal calprotectin as a screening biomarker for colorectal neoplasia. The American Journal of Gastroenterology 2003; 98: 2299–2305. 17. Pimentel M, Chow EJ & Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. The American Journal of Gastroenterology 2003; 98: 412– 419. 18. Simren M, Ringstrom G, Agerforz P, et al. Small intestinal bacterial overgrowth is not of major importance in the irritable bowel syndrome. Gastroenterology 2003; 125: A163. 19. Hughes LE. Post mortem survey of diverticular disease of the colon. I. Diverticulosis and diverticulitis. Gut 1969; 10: 336–344. 20. Drossman DA, Camilleri M, Mayer EA & Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology 2002; 123: 2108–2131.
9 Diagnostic approach to suspected irritable bowel syndrome J. G. Hatlebakk*
MD, PhD
Associate Professor
M. V. Hatlebakk
MD, MHA
Researcher Institute of Medicine, Haukeland University Hospital, University of Bergen, Bergen, Norway
Diagnostic activity in patients with suspected irritable bowel syndrome (IBS) should be brief and focussed, limited to investigations that are likely to exclude serious alternative diagnoses and when negative support a positive diagnosis of IBS. The diagnosis of IBS is clinical, and is robust over time, although other symptoms may add to the clinical picture and other symptoms of functional disorders are common. The most important differential diagnoses are celiac disease, colorectal carcinoma and colitis. ‘Red Flag’ symptoms and signs should be considered indications for full colonoscopy, which should be performed with a low threshold in patients above 50 years of age. Serologic markers are useful to exclude celiac disease, but positive tests must be confirmed with duodenal biopsies. Key words: irritable bowel syndrome; celiac disease.
The prevalence of irritable bowel syndrome (IBS) is high in all populations/regions of the world in which epidemiological studies have been performed, which includes several European, North American, but also Asian and African countries. Prevalence rates in the order of 9 to 25% are most often cited, always highest in women. Differences in cultural factors, including reporting of symptoms and health care seeking behaviour, extent of urbanisation and diet, are likely to explain the modest differences that are found between studies and between countries. For the medical profession and health care systems, the group of patients with IBS is resource-demanding and requires a structured approach to diagnostic management, for several reasons. First and foremost should potentially serious disease not be overlooked in the setting of common and often non-specific symptoms. Secondly, care should be taken to avoid overuse of often limited diagnostic resources. A prolonged and unfocussed diagnostic workup is likely to create anxiety and confusion with the patient, whereas a more brief and evidence-based approach will create more confidence and be a better basis for * Corresponding author. Tel.: þ47-55-97-70; Fax: þ 47-55-97-29-50. E-mail address: [email protected] (J.G. Hatlebakk). 1521-6918/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.
736 J. G. Hatlebakk and M. V. Hatlebakk
a future therapeutic relationship. At least in primary care, subjects with symptoms of IBS often demand primarily reassurance and simple lifestyle advice.
THE DIAGNOSIS OF IBS The diagnosis of IBS is and must be clinical, since any objective confirmative diagnostic test for the disorder is lacking. For practical purposes, the history most often gives all necessary information for a positive working diagnosis: a symptom complex compatible with IBS and absence of alarm or ‘Red Flag’ symptoms. This may be supplemented with a limited number of diagnostic tests, designed to exclude alternative and more serious disease, depending on symptoms as well as age and clinical findings. The clinical setting of the consultation is all-important, since we know that only a minority of subjects with IBS-like symptoms consult at the primary care level and less than 3% are referred to the secondary level of medical care. Those who are seen at the secondary care level are much more likely to have organic disease and may need a somewhat more sophisticated diagnostic workup and follow-up. Whenever diagnostic tests are used to exclude organic disease, it is important to let this information lead to a conclusion and explanation for symptoms within a limited period of time, to avoid confusion and create insight and a platform for future therapy of IBS. How reliable is a clinically based diagnosis of IBS over time? This has been studied in at least two studies. Vanner and coworkers1 retrospectively identified 98 patients and prospectively 95 patients with IBS according to Rome criteria, with no red flags fulfilled. The positive predictive value was 100% with no patient requiring a revision of the diagnosis within an observational period of 2 years.1 Harvey and coworkers studied 101 patients who fulfilled the Manning criteria for IBS, again with no patient proving to be incorrectly diagnosed after an observational period of 5 years.2
DIAGNOSTIC CRITERIA IN A CLINICAL SETTING Classically, IBS was defined as altered bowel habits with abdominal pain, with no structural or biochemical abnormalities present. This left much to subjective theories of what were the essential components of the clinical picture and required for the diagnosis. More practically, in 1978 Manning and coworkers3 published a list of symptoms and observations that were found to distinguish between patients with organic disease of the abdomen and patients ultimately diagnosed with IBS. The Manning criteria are given in Table 1. They have been confirmed as useful in Table 1. The Manning criteria for irritable bowel syndrome3. Visible abdominal distension Relief of pain with bowel movement More frequent bowel movement with the onset of pain Loose stools at the onset of pain Passage of mucus per rectum Feeling of incomplete evacuation
Diagnostic approach to suspected irritable bowel syndrome 737
Table 2. The Rome II criteria for irritable bowel syndrome.4 At least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two of three features: 1. Relieved with defecation; and/or 2. Onset associated with a change in frequency of stool; and/or 3. Onset associated with a change in form (appearance) of stool Supportive (non-essential) symptoms of the irritable bowel syndrome: 1. Fewer than three bowel movements a week 2. More than three bowel movements a day 3. Hard or lumpy stools 4. Loose or watery stools 5. Straining during a bowel movement 6. Urgency 7. Feeling of incomplete emptying 8. Passing mucus during a bowel movement 9. Abdominal fullness, bloating or swelling
several later publications and have been used for patient selection in epidemiological and clinical studies. The later Rome criteria were created for clinical research and may be perceived as too restrictive for everyday clinical use.4 This is particularly the case for the Rome II criteria5, which require symptoms (pain or pain-related discomfort) to have been present for at least 12 weeks out of the preceding 12 months, whereas the earlier Rome I criteria had no such time window defined. The great emphasis on pain may also be unsatisfactory, since most patients have a complex pattern of symptoms. There will always be patients in whom Rome I and II criteria are not fulfilled, but who clearly suffer from IBS as judged by clinical perception and experience. The Rome II consensus report defines several other groups of functional gastrointestinal disorders giving symptoms localized to the lower abdomen, and these can be important differential diagnoses. It is also very common for patients to suffer from more than one functional gastrointestinal disorder, as evidenced by reports that suggest that up to 30% of IBS patients suffer from functional dyspepsia. Still it is the opinion of the authors that the clinician should be familiar with the main and non-essential criteria for IBS in the Rome II classification, since this will facilitate a systematic and rational history taking and interpretation of symptoms. The Rome II criteria are shown in Table 2.
PSYCHOPATHOLOGIC FACTORS In a subgroup of IBS patients, particularly so in secondary care, psychopathology plays a more extensive role and questions need to be addressed in a sympathetic manner, allowing adequate time for identification of worries and discussion. There is often a paradoxical discrepancy between subjective symptom burden, and objective clinical findings. In all patients it is useful to identify any ‘hidden agenda’,
738 J. G. Hatlebakk and M. V. Hatlebakk
including why he or she decided to consult just now. There are often health worries (cancer) within the family, anxiety for marital life, unemployment, economic problems etc. It is also important to ask for symptoms of other functional disorders, including sleep disorders, pelvic pain and fibromyalgia, conditions that coexist with IBS more often than by sheer chance. Indeed, it is known that patients with functional gastrointestinal disorders rank their bowel symptoms on average fourth, after back pain, headache and anxiety/depression.6
THE HISTORY IN IBS Some important elements of the history are shown in Table 3: time and type of onset of disease, course and pattern of symptoms, predominant and less prominent symptoms, aggravating and relieving factors. As an important element in the definition of IBS, according to the Rome criteria, it is important to ask about the relationship of symptoms to bowel movements. The severity of symptoms may vary in each patient over time and between patients. It is useful to chart major consequences of symptoms, including absence from work or school. If symptoms started acutely with a (febrile) gastroenteritis, which instead of subsiding spontaneously continued with pain and diarrhoea over months, this may indicate infection-induced IBS (or colitis). Negative lifetime events preceding the onset of a period with pain may also be worth noting.
CLINICAL EXAMINATION AND SIMPLE LABORATORY TESTS Clinical examination is important to not overlook easily identifiable pathology, but usually contributes little toward a diagnosis in this patient group. A mild tenderness in the lower left abdomen, or even some resistance corresponding to a spastic sigmoid colon is not uncommon, but certainly not diagnostic, as other causes for this must be ruled out. Simple blood tests, such as erythrocyte sedimentation rate (ESR), haemoglobin, leucocyte count and albumin are useful to screen for inflammation and other pathology. Thyroid-stimulating hormone (TSH) and free thyroxin in plasma (FT4) are often analyzed and should be recommended, but in our experience clinically important abnormalities are infrequent. Faecal occult
Table 3. Important elements of the history in patients suspected of suffering from IBS. Acute, subacute or gradual onset of symptoms Predominant symptom (Pain? Discomfort?) Improvement in symptoms after bowel movements? Chronic course of disease? Variation over time? Presence of blood or mucus on stools? Associated symptoms?
Diagnostic approach to suspected irritable bowel syndrome 739
Table 4. Observations that may indicate an organic cause for abdominal symptoms. Complaints over less than 24 months Elderly patient Diarrhoea is persistent Nighttime diarrhoea Sudden onset Weight loss of 5 kg or more Abnormal ESR, Hb and / or albumin Mean faecal mass .225 g/24 h
blood test, from three to six separate stool samples, and taken with adequate exclusion of meats from the diet, is clearly important to detect bleeding lesions in the gastrointestinal tract, and decide on the indication for colonoscopy.
ORGANIC VERSUS FUNCTIONAL DIARRHOEA Chronic diarrhoea, defined arbitrarily as loose stools more than three times daily for more than three weeks, may have a multitude of different organic or non-organic causes. When seeing the patient with chronic diarrhea, certain clues may suggest an organic etiology (Table 4). Due to an often long patient’s delay in functional disease, a history of less than 1 –2 years is suggestive of an organic cause, as is age above 60 at the onset of symptoms. Acute onset of diarrhoea is always due to an organic cause, but may have developed into IBS, as discussed above. The consistency of stools is almost always somewhat varying over time, even with diarrhoea-predominant or constipation-predominant IBS; whereas chronic diarrhoea from other causes is never interrupted with hard stools. Nocturnal symptoms are very uncommon in IBS, pain and diarrhoea may occur on going to bed or getting up early, but sleep is not interrupted by symptoms. Significant weight loss may suggest an organic or even malignant cause, but not invariably so, since aggravation of pain or diarrhoea with meals may limit food intake. Mucus on stools is described by some patients and this does not speak against IBS, nor does blood, provided that a trivial cause, such as bleeding from haemorrhoids or an anal fissure can subsequently be shown to be the only likely explanation.
ALARM SYMPTOMS OR ‘RED FLAGS’ More importance must be given to certain observations that experience has taught us to associate with malignant or premalignant disease of the colon (Table 5). This short list includes aspects of the history that should lead to a search for malignant disease or other potentially serious disease, such as colitis.
740 J. G. Hatlebakk and M. V. Hatlebakk
Table 5. Red flag symptoms and signs that should indicate the need for colonoscopy in patients suspected of IBS. Age .50 years Weight loss (Occult) blood in faeces Family history of colorectal cancer
MAJOR DIFFERENTIAL DIAGNOSES TO IBS The list of disease that can be mimicked by typical or atypical cases of IBS is long (Table 6). Some of the more important, due to high incidence or seriousness, will be discussed in more detail below. Since these will vary in different age ranges, differential diagnoses will also differ in young and elderly patients.
CELIAC DISEASE INCLUDING POTENTIAL AND LATENT DISEASE Celiac disease is very common in northern Europe, and is often associated with mild and atypical symptoms. Recent population-based studies from Scandinavia and the United Kingdom have shown a prevalence up to 500 –1000/100 000 adults, based on serologic criteria. When screening 300 patients referred to a university outpatient clinic for symptoms of IBS, according to the Rome II criteria, Sanders and coworkers7 found a seven-fold increased probability for celiac disease, as compared with age- and gender-matched control subjects. Patients were screened with serologic tests (Immunoglobulin A and G against gliadin and endomysial antibodies) and positive cases were referred for endoscopic biopsy from the duodenum. Sixty-six patients had positive antibodies, 14 of whom proved to have celiac disease.7 This suggested that celiac disease is a major differential diagnosis, particularly in young to middle-aged patients, and that immunological tests are useful to detect it.8 Later publications have
Table 6. Differential diagnoses for irritable bowel syndrome. Celiac disease Food intolerance Disaccharide intolerance Inflammatory bowel disease Infection Bacterial overgrowth Diverticular disease of the colon Colorectal carcinoma Bile acid induced diarrhoea
Diagnostic approach to suspected irritable bowel syndrome 741
however questioned this finding, particularly a study performed in primary care, which involved serological testing of primary care patients fulfilling Rome I criteria for IBS. None of 121 patients had abnormal endomysial antibodies, thought to be a highly sensitive test for celiac disease.9 It is clear that the clinical setting is important, the selection of patients for referral to tertiary care centres increases the probability of finding organic disease. Improved and less expensive serologic methods make it easier to screen for manifest celiac disease in patients with gastrointestinal symptoms. In particular, antibodies against tissue transglutaminase (tTGA), believed to be of pathophysiological importance, are thought to be relatively sensitive and specific for the disorder, at least in its fully developed forms. Given the similarity of symptoms and high prevalence of both disorders, it has been suggested that a subgroup of IBS patients might suffer from a mild form of celiac disease, not detectable by serology or routine duodenal biopsies. Potential celiac disease, defined as normal duodenal biopsy morphology, but with some immunological markers of celiac disease, has been found in a subgroup of 102 patients with IBS, who were compared to 41 patients with manifest disease.10 Antibodies against tTGA and gliadin were analysed in duodenal aspirate and biopsies were studied for intraepithelial lymphocytes. It was concluded that a subgroup of IBS patients had immunological markers for potential celiac disease, and a trial of gluten-free diet for six months tended to normalise these values.10 A symptomatic response to gluten-free diet does not strongly support the diagnosis of celiac disease, since such a relatively residue-free diet is also likely to benefit patients with IBS. Instead, patients need to go back to their normal diet for at least four weeks before adequate biopsies can be taken. It is malpractice to use a trial of gluten-free diet as a diagnostic modality, due to the high frequency of non-specific response in various functional bowel disorders.
FOOD INTOLERANCE Up to 40% of adults are convinced they are ‘allergic’ to one or more foodstuffs, but an immunological mechanism for discomfort from food intake can be proved with doubleblind provocation in less than 2 percent. In a large proportion of the remainder, IBS is the likely explanation for gastrointestinal symptoms, and extra-intestinal symptoms may also be due to various functional disorders. Around 50% of patients with IBS report food intolerance, most often suspected to be against dairy products, wheat, eggs, yeast, chemical additives etc.11
DISACCHARIDE INTOLERANCE Lactose intolerance has been listed as a major cause for abdominal pain and diarrhea, and therefore an alternative explanation for IBS-like symptoms. Most subjects with lactose intolerance are well aware of their problem, and can manage symptoms quite well by limiting dairy products in their diet. Most patients with longstanding symptoms of IBS have also tried to omit certain foods from their diet, including milk, often with at least transient improvement in symptoms. Objective testing is not unproblematic. A breath test, as used by Parker and coworkers, turned
742 J. G. Hatlebakk and M. V. Hatlebakk
out abnormal in 27% of 122 IBS patients11, but more patients responded to a lowlactose diet for 3 weeks, suggesting intolerance to other components of milk. We have disappointing experience using the traditional oral lactose tolerance test. By whatever test is used, it seems clear that more subjects experience discomfort from dairy products than can be explained by lactase deficiency. It is important, therefore, not to discredit the subjective experience of these patients, but accept their need to avoid milk and other dairy products. Other osmotically active saccharides, such as fructose and sorbitol have also been reported to cause diarrhea and abdominal pain. When investigating 183 patients with unexplained abdominal symptoms with a fructose breath test, Choi and coworkers found abnormal tests in 134 (73%).12 Up to 75% of patients with positive tests had symptoms during the (uncontrolled) challenge. A large proportion of these patients had symptoms compatible with IBS (flatus 83%, pain 80%, bloating 78%, altered bowel habits 65%). In a previous, smaller study, it was found that nine out of 25 patients with IBS had fructose malabsorption.13 It is of value to interrogate about excessive use of sugar-free chewing gum and lozenges, and a simple trial of excluding these may suffice for a clinical diagnosis. Suspected fructose malabsorption should however be confirmed objectively since excluding fructose from the diet is a much more difficult task.
INFLAMMATORY BOWEL DISEASE In the younger population in particular, ulcerative colitis and Crohn’s disease are not uncommon, and symptoms may be confused with those of IBS. Simple blood tests, including inflammatory parameters, C-reactive protein (CRP), ESR and a leucocyte count, may all be normal. There has been a lack of a simple (in vitro) test for inflammation of the intestinal wall and only recently has a candidate appeared: faecal calprotectin (f-calprotectin). This is a highly stable glycoprotein present in neutrophilic leucocytes, and is found increased when these cells are recruited to sites of inflammation or neoplasia.14 Calprotectin can be analysed from one single faecal specimen, securing a patient compliance above 95% in one study.15 Tibble and coworkers obtained faecal calprotectin samples from 602 patients with bowel symptoms, classifying them into low, medium or high risk for organic disease (IBD or cancer), based on absence or presence of alarm symptoms. In all groups, f-calprotestin showed a sensitivity in the order of 90% and specificity in the order of 80%. This is a significant improvement compared with routine tests for inflammation, such as CRP, ESR and leucocyte count. A recent study showed that f-calprotectin could not discern reliably between colorectal cancer, benign polyps or inflammation.16 Still, it is likely that f-calprotectin may prove useful for excluding inflammatory disease in patient suspected of IBS, without or with alarm symptoms or other clinical features of serious disease.
INFECTIONS INCLUDING BACTERIAL OVERGROWTH Infections with Giardia lamblia and certain other parasites may cause chronic abdominal pain and diarrhea, which has been confused with IBS. The question of bacterial overgrowth with colonization of the proximal small bowels in patients with IBS-like
Diagnostic approach to suspected irritable bowel syndrome 743
symptoms is controversial. One reason is the difficulty of obtaining adequate material for diagnosis. Pimentel and coworkers17 used a lactulose breath test to investigate for bacterial overgrowth in 111 patients with IBS according to the Rome I criteria, as compared with a group of healthy controls. An abnormal breath test was found in 84%, compared with 20% of controls (p , 0:01). Abnormal tests in patients were followed up with a trial of therapy with Neomycin 500 mg b.i.d. for 10 days, with placebo control, resulting in improved symptom scores in 43%, correlating with normalization of the breath test.17 It is clear that the lactulose breath test has insufficient sensitivity and specificity and that results may not be reliable in all patient groups. Simren and coworkers investigated bacterial overgrowth with what is considered the gold standard, bacterial culture from jejunal aspirate at the time of gastroduodenoscopy, finding bacterial colonization in only four out of 33 IBS patients.18 An open trial of antibiotic therapy improved symptoms significantly in only one patient. It was therefore concluded that it is unlikely that bacterial overgrowth is a common cause for symptoms in patients suspected to have IBS.
DIVERTICULAR DISEASE OF THE COLON Diverticula may result from abnormal bowel function, but may also give rise to symptoms compatible with IBS. Diverticular disease is uncommon in the younger age range, in which most IBS patients first experience symptoms and seek medical assistance. Diverticulosis was found in only 9% of subjects below the age of 50, but in 56% of elderly patients above 70.19 The majority of patients with diverticula are asymptomatic, with occasional symptoms most often due to such complications as diverticulitis or haemorrhage.
COLORECTAL CARCINOMA The most serious diagnosis to overlook in patients suspected of irritable bowel syndrome is colorectal carcinoma (CRC), one of the major malignant diseases in western societies. Furthermore, early detection of cancer of the colon even in symptomatic individuals can lead to excellent treatment results, emphasizing the need for liberal access to diagnostic activity. Symptoms due to colorectal cancer are typically pain and recent change in bowel habits, toward either looser or harder stools, which can also easily be ascribed to IBS. Cancer registries show very few cases below the age of 50, which has implications for referral practice. The family history of CRC is furthermore important when deciding on a diagnostic strategy in individual patients.
COLONOSCOPY IN SUSPECTED IBS Colonoscopy has only negative diagnostic value in IBS, by excluding other pathology. When judged to be necessary in patients suspected of suffering from IBS, it is invariably the most expensive diagnostic method used with any frequency. It is thought of as having a high incremental cost-effectiveness ratio. Therefore, unless alarm symptoms are present, its use should be limited to when “…a serious organic disease is reasonably
744 J. G. Hatlebakk and M. V. Hatlebakk
Table 7. Diagnostic workup in refractory irritable bowel syndrome20. Anorectal motility studies 24-hour fecal weight and fat content Cholestyramin trial Jejunal aspirate for bacterial culture Fructose breath test Plain abdominal X-ray Small bowel X-ray
likely and needs to be ruled out” (ACG). Colonoscopy is however sometimes needed in order to reassure the patient of the absence of serious disease, and may in some settings be considered indicated as a general screening procedure for CRC, particularly in a middle-aged to elderly patient with a family history of the condition. In patients with diarrhea, biopsies should always be taken to look for microscopic colitis. In patients with chronic IBS referred to specialist care, colonoscopy is usually performed, sooner or later.
REFRACTORY IBS Sometimes symptoms compatible with IBS do not improve as expected and an increased effort to look for alternative causes is necessary. Depending on which symptom predominates in the individual patient, and provided that colonoscopy with biopsies has already been performed with normal findings, one might consider motility studies to investigate causes for constipation, a trial of cholestyramine for up to a week to exclude bile acid induced diarrhea and / or radiographic examinations to look for causes for abdominal pain (Table 7).20
SUMMARY The diagnosis of IBS is clinical, and is robust over time, although other symptoms may add to the picture. Adequate time must be spent with the patient, to discuss the important points in the history that might allow for a positive diagnosis of IBS according to the Rome II criteria. In addition, any Red Flag symptoms and signs should be identified, which calls for a more invasive diagnostic approach, including a full colonoscopy. At least in specialist care, serologic markers should be analyzed to exclude celiac disease. Calprotectin in faeces might prove a useful method to exclude inflammatory bowel disease but is not reliable to exclude cancer of the colon or rectum. Colonoscopy is sometimes needed to make the patient relax and may be indicated in patients above the age of 50, when colorectal cancer becomes a relevant differential diagnosis.
Diagnostic approach to suspected irritable bowel syndrome 745
Practice points † irritable bowel syndrome is very common in all parts of the world and in all age groups † a brief and evidence-based diagnostic workup will save resources and create a better basis for future therapy † red flag symptoms and signs are important when deciding on the indication for colonoscopy † the Rome II criteria are useful not only for research, but improves the interpretation of symptoms and creates a better basis for a positive diagnosis
Research agenda † investigate differences in symptom patterns, which are not well understood † investigate whether mild forms of celiac disease and small intestinal bacterial overgrowth can explain IBS-like symptoms in significant subgroups. † larger studies are needed to investigate the health economic and quality of life aspects of the diagnosis and follow-up of patients with suspective IBS
REFERENCES 1. Vanner SJ, Depew WT, Paterson WG, et al. Predictive value of the Rome criteria for diagnosis the irritable bowel syndrome. The American Journal of Gastroenterology 1999; 94: 2912–2917. 2. Harvey RF, Mauad EC & Brown AM. Prognosis in the irritable bowel syndrome: A five year prospective. Lancet 1987; 1: 963–965. 3. Manning AP, Thompson WG, Heaton KW & Morris AF. Towards a positive diagnosis of the irritable bowel. British Medical Journal 1978; 2(6138): 653 –654. 4. Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999; 45(supplement II): II43– II47. 5. Boyce PM, Koloski NA & Talley NJ. Irritable bowel syndrome according to varying diagnostic criteria: are the new Rome II criteria unnecessarily restrictive for research and practice? The American Journal of Gastroenterology 2000; 95: 3176–3183. 6. Wilhelmsen I, Haug TT, Ursin H & Berstad A. What are the real problems for patients with functional dyspepsia? Scandinavian Journal of Gastroenterology 1995; 30: 97 –100. 7. Sanders DS, Carter MJ, Hurlstone DP, et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. The Lancet 2001; 358: 1504–1508. 8. Cash BD, Schoenfeld P & Chey WD. The utility of diagnostic tests in irritabe bowel syndrome patients: a systematic review. The American Journal of Gastroenterology 2002; 97: 2812–2819. 9. Holt R, Darnley SE, Kennedy T, et al. Screening for coeliac disease in patients with clinical diagnosis of irritable bowel syndrome. Gastroenterology 2002; 122: A757. 10. Wahnschaffe U, Ullrich R, Riecken ED & Schulzke JD. Celiac disease like abnormalities in a subgroup of patients with irritable bowel syndrome, Gastroenterology 2001; 121: 1329– 1338. 11. Parker TJ, Woolner JT, Prevost AT, et al. Irritable bowel syndrome: is the search for lactose intolerance justified? European Journal of Gastroenterology and Hepatology 2001; 13: 219– 225. 12. Choi YK, Johlin FC, Summers RW, et al. Fructose intolerance: an under-recognized problem. The American Journal of Gastroenterology 2003; 98: 1348– 1353. 13. Rumessen JJ & Gudmand-Hoyer E. Functional bowel disease: malabsorption and abdominal distress after ingestion of fructose, sorbitol, and fructose–sorbitol mixtures. Gastroenterology 1988; 95: 694–700. 14. Roseth AG, Fagerhol MK, Aadland E, et al. Assessment of the neutrophile cominating protein calprotectin in feces. Scandinavian Journal of Gastroenterology 1992; 27: 793– 798.
746 J. G. Hatlebakk and M. V. Hatlebakk 15. Tibble JA, Sigthorsson G, Foster R, et al. Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology 2002; 123: 450 –460. 16. Limburg PJ, Devens ME, Harrington JJ, et al. Prospective evaluation of fecal calprotectin as a screening biomarker for colorectal neoplasia. The American Journal of Gastroenterology 2003; 98: 2299–2305. 17. Pimentel M, Chow EJ & Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. The American Journal of Gastroenterology 2003; 98: 412– 419. 18. Simren M, Ringstrom G, Agerforz P, et al. Small intestinal bacterial overgrowth is not of major importance in the irritable bowel syndrome. Gastroenterology 2003; 125: A163. 19. Hughes LE. Post mortem survey of diverticular disease of the colon. I. Diverticulosis and diverticulitis. Gut 1969; 10: 336–344. 20. Drossman DA, Camilleri M, Mayer EA & Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology 2002; 123: 2108–2131.