1.1 Purpose of guidelines

The guidelines are directed at consultant gastroenterologists, gastrointestinal surgeons, specialist registrars in training and general practitioners, and refer specifically to adult not paediatric gastroenterology. Their purpose is to provide guidance on the best available methods of investigating symptoms of chronic diarrhoea. Given this broad symptom-based focus, the guidelines cover a wide range of gastroenterological conditions and are not intended as a comprehensive review of all aspects of the clinical conditions mentioned herein, but rather an attempt to rationalise the approach to investigation in the context of this common clinical scenario.

1.2 Development of guidelines and rigour

The guidelines were prepared following a comprehensive literature search by the guideline development group (GDG). The GDG membership comprises elected members of the BSG, Association of Coloproctology of Great Britain and Ireland, Association of Biochemistry UK, British Institute of Radiology, Primary Care Society for Gastroenterology, and nurse and patient representatives. Each main section was authored by a designated member of the GDG following a comprehensive review of the literature including NICE, American and European guidelines. This involved a review of electronic databases (Medline and PubMed) using keywords (in both British and American spelling) such as ((((‘diarrhoea-predominant irritable bowel syndrome’ OR ‘chronic diarrhoea’ OR ‘functional diarrhoea’ OR ‘loose stools’ OR ‘faecal urgency’ OR ‘faecal incontinence’ OR ‘stool frequency’) AND ((diarrhoea[Title/Abstract]) AND (investigation OR investigate OR diagnostic OR diagnosis) AND "2000’(Publication Date): ‘3000’(Publication Date)) AND English(Language)) NOT case reports (Publication Type))). Additional terms related to the specific conditions mentioned in the text (eg, coeliac disease, bile acid diarrhoea or malabsorption and small bowel bacterial overgrowth). The time frame for literature review was from 2002 to April 2017. A total of 1292 key papers and relevant abstracts in English in peer-reviewed journals were identified and read, and relevant work has been cited and referenced. An initial draft document was produced and subsequently reviewed and modified in accordance with the AGREE tool.1 Two face-to-face meetings as well as a further two telephone meetings were held in preparing this guideline. We used a modified Delphi system to a maximum of three rounds for any contentious issues. A final decision was made once agreement was reached by 70% of the group. The lead author acted as facilitator. The review was undertaken through submission to members of the BSG Clinical Standards Service Committee as well as to BSG Council and finally international peer review.

1.3 Grading of recommendations

In accordance with the BSG advice on production of guidelines, the GDG applied the GRADE system.2 Strength of recommendation was strong, moderate or weak. Where the recommendation was unanimous a ‘strong’ recommendation was used, and where the decision was by majority and the recommendation was moderate or weak, ‘we suggest’ was used. We graded the evidence based on levels 1–5 as per the Oxford Centre for Evidence Based Medicine.3 In brief, Level 1a–c ranges from systematic reviews with homogeneity, individual randomised controlled trials (RCTs); Level 2a–c ranges from systematic reviews of cohort studies, low quality RCTs and outcomes research; Level 3a–b ranges from systematic reviews with heterogeneity and individual case control studies; Level 4 are poor quality cohort or case series; and Level 5 is expert opinion without critical appraisal.

Specific RCTs addressing the investigation of ‘chronic diarrhoea’ are absent. Thus our grading of evidence was based on the level of evidence (1–5) and the strength of our recommendation (strong, moderate or weak).

1.4 Scheduled review of guidelines

These guidelines will be subject to future revisions within 5 years to take into account new developments and alternative investigative methods.

1.5 Possible audit goals

The aim of these guidelines was to establish an optimal investigative scheme for patients presenting with chronic diarrhoea that would maximise a positive diagnosis while minimising the number and invasiveness of investigations. These two potentially opposing directives are influenced by the potential seriousness of the diagnostic outcome. Thus a low threshold for the use of colonoscopy is acceptable in the context of the frequency and clinical significance of colonic neoplasia in older subjects. However, there is less need for extensive investigation where the probability of benign disease is high (eg, in young patients with functional symptoms).4 Suggested goals for future audit include:

1. All patients undergoing colonoscopy for chronic diarrhoea should undergo biopsies of the right and left colon for histological examination.

2. Reduction of missed diagnoses of colorectal cancer to <1% through utility of faecal immunochemical testing (FIT) and endoscopic examination.

3. Minimising inappropriate first-line investigations (eg, colonoscopy) in patients less than 40 years of age without rectal bleeding and normal faecal calprotectin.

4. Initial non-invasive investigations, including coeliac serology, faecal calprotectin and possibly FIT, should be completed in primary care prior to specialist referral.

5. All patients with persistent undiagnosed chronic diarrhoea should be investigated for bile acid diarrhoea with SeHCAT or serum 7-alpha-hydroxy-4-cholesten-3-one or faecal bile acid measurement where available.

2.1 Definition

Diarrhoea may be defined in terms of stool frequency, consistency, volume or weight. Patients’ concept of diarrhoea often focuses around stool consistency.5 Indeed, faecal consistency is determined by the water-holding capacity of the stool (ie, the amount of non-bound ‘free’ water), and this perhaps best defines the concept of diarrhoea. However, quantification of this in clinical practice may prove difficult, hence utility of the Bristol stool chart is recommended—type 5 and above (see online supplementary material).6

In the past, stool weights were used (≥200 g/day), but this can be misleading as stool weights vary greatly and ‘normal’ stool volumes can exceed this value, particularly when non-Western diets are encountered. Hence stool weights are not recommended as a measure of diarrhoea.

Further potential for confusion arises from the discrepancy between the medical and ‘lay’ concepts of diarrhoea, and this needs to be clarified at the initial appraisal. Faecal incontinence in particular is commonly misinterpreted as diarrhoea,7 while symptoms relating to functional bowel disease can be difficult to distinguish from organic pathology on the basis of history alone.

There is no consensus on the duration of symptoms that define chronic as opposed to acute diarrhoea. However, most groups including this GDG accept that symptoms persisting for longer than 4 weeks suggest a non-infectious aetiology and merit further investigation.8

A recent report suggests that both increased frequency and altered consistency is indicative of organic aetiology.9 Thus a pragmatic definition incorporates these elements: chronic diarrhoea is the persistent alteration from the norm with stool consistency between types 5 and 7 on the Bristol stool chart and increased frequency greater than 4 weeks' duration.

2.2 Prevalence

Chronic diarrhoea is one of the most common reasons for referral to a gastroenterology clinic. Prevalence rates in Western populations are difficult to estimate, partly through population differences but also through difficulties in definition. In two population surveys, Talley et al reported a prevalence of ‘chronic diarrhoea’ of between 7% and 14% in an elderly population, a proportion of which is likely to include patients with motility disorders (ie, ‘functional bowel disease’). Using a definition based on excessive stool frequency without the presence of abdominal pain, estimates of the prevalence of chronic diarrhoea in a Western population are 4–5%.10

2.3 Difficulties in establishing guidelines for the investigation of chronic diarrhoea

Reported change in stool frequency or form is characteristic of irritable bowel syndrome (IBS) and indeed forms part of the definition of the condition, which relies on symptom-based criteria and negative physical examination.11 12Although stool weight does not usually increase in IBS, as symptom reporting forms the basis for the diagnosis and stool weight is rarely performed early in the course of investigation, considerable overlap between functional bowel disease and true ‘diarrhoea’ occurs. As IBS may affect 10–13% of the population,4 13 14 there is clearly the potential for inappropriate investigation of patients reporting diarrhoeal symptoms. Conversely, new onset of diarrhoea may reflect serious organic disease such as colonic neoplasia. It is this wide diagnostic potential given similar reported symptoms that makes the introduction of specific guidelines difficult.

The broad range of conditions which lead to diarrhoea also make it difficult to be too prescriptive with regard to the investigative pathways that should be adopted. Diarrhoea may result from: (a) colonic neoplasia; (b) inflammation; (c) small bowel inflammation; (d) small bowel malabsorption; (e) maldigestion due to pancreatic insufficiency; or (f) motility disorders, and it can be difficult to separate these on clinical grounds alone. The decision on whether to focus investigations on any one of these areas remains largely a matter of clinical judgement although, as will be discussed, the prevalence and potential seriousness of certain conditions (eg, colonic neoplasia) necessitates their exclusion early in the investigative scheme.

A further problem in the development of these guidelines has been the large number of investigative methods reported, particularly with regard to malabsorption. This reflects the failure of any single test to become established as the standard and, indeed, many of the available methods have not found a wide acceptance because of inadequate sensitivity, specificity or ease of use. Moreover, there is considerable variation in protocols and analytical methods between laboratories that leads to poor reproducibility of results.15 It is also unclear what place some of these tests (some of which were devised prior to the advent of endoscopy) hold in the current investigative scheme that incorporates access to small bowel and colonic histology. To circumvent this somewhat, we propose in figure 1 an outline algorithm for the investigation of chronic diarrhoea based on clinical differential diagnosis. This will be used to guide the text in this document.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Algorithm for the investigation of chronic diarrhoea based on clinical differential diagnosis.

3.1 Initial presentation in primary care

In most countries where there is a split primary/secondary care system, the first consultation is with the primary care physician. Around 10% of all consultations in primary care are for gastroenterological problems, of which half are for lower gastrointestinal (GI) problems.16 Most of these are for self-limiting symptoms or for functional GI disorders and only a very small proportion comprise chronic or persistent diarrhoea. Based on the accepted definition of chronic diarrhoea being abnormal passage of ≥3 loose stools per day for more than 4 weeks and a rate of 3–5% per year,17 a primary care physician with an average list size of 1700 patients may have 50–85 such patients each year. Only a proportion of these will consult, with many managing with self- or pharmacy-based treatments, while others will be managed within primary care, often with antidiarrhoeals.

No data are available on the proportion referred to secondary care, but these are likely to be a small minority of the total number of people with chronic diarrhoea in the community. First-line investigations are normally performed within primary care and patients may be referred if their condition causes interference with normal activities or a compromise of quality of life sufficient to warrant further action. As with other conditions, many patients merely adapt their lives to their symptoms. No formal primary care referral guidelines or recommendations exist for patients with chronic diarrhoea, but the presence of normal first-line investigations with symptoms severe enough to impair quality of life and not responding to treatment constitutes a rationale for referral.

The impact of the symptoms of chronic diarrhoea and the differential diagnoses that need to be considered are clearly different in individual patients. A patient with recent change in bowel habit to include diarrhoea over 6 weeks is likely to need a different approach compared with another patient who has suffered from intermittent watery diarrhoea which has been present for over 5 years. Blood, stool (if an infectious aetiology or if an inflammatory component is suspected) and serological tests (for coeliac disease, hyperthyroidism and anaemia) should be performed in primary care as an initial assessment. Equally, if alarm features (such as unexplained change in bowel habit, persistent blood in the stool and unintentional weight loss) are detected, then referral for further investigations should be initiated.

3.2 History and examination: secondary care assessment

A detailed history is essential in the assessment of patients with chronic diarrhoea. This should attempt (a) to establish the likelihood that the symptoms are organic (as opposed to functional) based on presence of ‘alarm features’ as outlined above; (b) to distinguish malabsorptive from colonic/inflammatory forms of diarrhoea; and (c) to assess for specific causes of diarrhoea.

Symptoms suggestive of an organic disease include a history of diarrhoea of <3 months’ duration, predominantly nocturnal or continuous (as opposed to intermittent) diarrhoea and significant weight loss. The absence of these, in conjunction with positive symptoms such as those defined in the Rome IV criteria (improved clinical validation)18 and a normal physical examination, are suggestive of a functional bowel disturbance, but only with a specificity of approximately 52–74%.19 Unfortunately, these criteria do not reliably exclude inflammatory bowel disease (IBD), microscopic colitis or bile acid diarrhoea, all of which are relatively common and treatable with specific approaches.20

Malabsorption is often accompanied by steatorrhoea and the passage of bulky malodorous pale stools. However, milder forms of malabsorption may not result in any reported stool abnormality. Colonic, inflammatory or secretory forms of diarrhoea typically present with liquid loose stools with blood or mucous discharge.

Specific risk factors which increase the likelihood of organic diarrhoea or point to potential lines of investigation should be sought (see box 1). These include:

1. Family history: particularly of neoplastic, inflammatory bowel or coeliac disease.

2. Previous surgery: extensive resections of the ileum and right colon lead to diarrhoea due to lack of absorptive surface and hence fat and carbohydrate malabsorption, decreased transit time or changes in the bile acid pool including malabsorption.21 Bacterial overgrowth can often be a problem in this situation, particularly in bypass operations such as in gastric surgery and jejunoileal bypass procedures for morbid obesity. Shorter resections of the terminal ileum can lead to bile acid diarrhoea, which typically occurs after meals and usually responds to fasting and bile acid sequestrants (see sections 5 and 6). 

   Chronic diarrhoea may also occur in up to 10% patients after cholecystectomy through mechanisms that include increased gut transit, bile acid diarrhoea, and increased enterohepatic cycling of bile acids.22

3. Previous pancreatic disease.

4. Systemic disease: thyrotoxicosis and hypoparathyroid disease, diabetes mellitus,23 adrenal disease or systemic sclerosis may predispose to diarrhoea through various mechanisms including endocrine effects, autonomic dysfunction, small bowel bacterial overgrowth or the use of concomitant drug therapy.

5. Alcohol: diarrhoea is common in alcohol abuse. Mechanisms include direct toxic effect on intestinal epithelium, rapid gut transit, decreased activity of intestinal disaccharidases and decreased pancreatic function.24

6. Diet: excessive intake of caffeine (eg, coffee, energy drinks), milk in patients with lactase deficiency, food additives (eg, sorbitol), fructose and other FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols) should be sought (see section 5.3).

7. Drugs: up to 4% of cases of chronic diarrhoea may be due to medications (particularly magnesium supplements, antihypertensives (eg, ACE inhibitors) and non-steroidal anti-inflammatory drugs, newer gliptins (dipeptidyl peptidase-4 inhibitor), theophyllines, antibiotics, antiarrhythmics and antineoplastic agents).25

8. Recent overseas travel or other potential sources of infectious gastrointestinal pathogens.

9. Recent antibiotic therapy and Clostridium difficile infection: many different tests are now available for the detection of C. difficile, but most clinical laboratories use a commercial enzyme immunoassay for C. difficile toxin (details in section 3.3.3).

3.3 Initial investigations

4.1 Stool tests

The Bristol stool chart (see online supplementary material), which is validated, is a good tool to determine stool consistency and guide subsequent investigations.65 Stool weights are no longer used or recommended due their limited clinical value.

4.2 Endoscopic and histological assessment

In most patients with chronic diarrhoea, some form of endoscopic investigation will be necessary. In young patients (less than 40 years) reporting ‘diarrhoea’ but who have other typical symptoms of a functional bowel disorder and negative initial investigations, a diagnosis of IBS may be made in the primary care setting without recourse to further investigations.76 There is some evidence that using anti-vinculin and anti-cytolethal distending toxin B antibodies may help with making a positive diagnosis of IBS.77 However, patients under 40 years without typical symptoms of functional bowel disorder and/or severe symptoms and documented diarrhoea (as previously defined) should have further evaluation (see section 3.2.3).

4.3 Small bowel imaging and visualisation for inflammation

5.1 Bile acid diarrhoea

Given that a third of patients labelled with diarrhoea-predominant IBS actually suffer from bile acid diarrhoea, this condition is more common than initially perceived with a significant impact on patients.109 110 Bile acids are required for the digestion of fat and are synthesised from cholesterol in the liver and excreted in the bile mainly in the form of glycine or taurine conjugates. This process is regulated through a negative feedback manner by nuclear farnesoid receptor as well as by fibroblast growth factor 19 (FGF-19),111 112 a protein released from ileal enterocytes. Up to 95% of bile acids are reabsorbed through the enterohepatic circulation.

⁷⁵SeHCAT testing (the standard radiolabelled test used to identify bile acid diarrhoea: tauroselcholic (Se) acid) was first described in 1982.113 114 A retention of 10–15% at 7 days is usually defined as mild bile acid loss, 5–10% as moderate and 0–5% as severely abnormal. These values also predict response to therapy with bile acid sequestrants.115

The serum bile acid precursor 7α-hydroxy-4-cholesten-3-one116 is an intermediary product in the synthesis of bile acids from cholesterol by the liver enzyme CYP7A1 and so provides a measure of bile acid synthesis. It has a negative predictive value of 95% (positive predictive value of 74%) compared with SeHCAT, hence making it attractive as a screening test for excessive bile acid turnover.117 Levels above 47.1 ng/mL are indicative of bile acid diarrhoea.118 C4 requires a fasting sample, like FGF-19; both undergo diurnal and postprandial variation, with false positives also occurring in those with liver disease.119

Faecal bile acid measurement is another option with values >2300 µmol/48 hours indicative of bile acid diarrhoea.119 However, as dietary fat intake and consequently bile acid levels are variable, it requires a 48-hour sample. Moreover, it is cumbersome and not yet commercially available in the UK. Additionally, other less invasive and economical tests such as urine testing for 2-propanol and acetone are currently being evaluated.120 A summary table of tests in bile acid diarrhoea are presented in these studies.121 122

Up to 30% of patients with diarrhoea-predominant IBS have evidence of bile acid diarrhoea as determined by SeHCAT testing.87 109 123 Compared with controls, IBS patients had lower SeHCAT values and higher C4 levels but similar FGF-19 levels. More than 50% responded to bile acid sequestrants (colestipol).124 In addition to patients with ileal disease (eg, Crohn’s disease),125 bile acid diarrhoea has also been reported in patients following cholecystectomy and post-infectious diarrhoea.126 For those not responding to treatment, other additional causes should be sought (eg, bacterial overgrowth, pancreatic insufficiency or microscopic colitis),127 even if SeHCAT testing has been abnormal. Another under-recognised group are those with cancer who have received pelvic chemoradiotherapy as >50% have bile acid diarrhoea.128

The NICE DG7 diagnostic guidance report on SeHCAT in 2013 and subsequent update in 2016 recognised the potential for patient and system benefits associated with SeHCAT investigations.129 One study suggests that the economic evaluation needs to be reconsidered as the impact of not making a positive diagnosis leads to repeat (unnecessary) testing with additional cost to the NHS.130 More recently it has been shown that making a positive diagnosis of bile acid diarrhoea (in this study using SeHCAT) was economically beneficial as those who had negative SeHCAT tests underwent significantly more investigations (1.8x more), especially cross-sectional imaging (13x more likely), although those with a positive SeHCAT had more clinical appointments.131

A systematic review and meta-analysis comprising 36 studies and 5028 patients on bile acid diarrhoea biomarkers concluded that SeHCAT had the highest diagnostic yield to date (limited by study heterogeneity), with 25% previously diagnosed as having functional diarrhoea actually having primary bile acid diarrhoea.122

In a series of 264 patients where 53% had bile acid diarrhoea, 44% failed to respond to cholestyramine alone. Half of these non-responders derived benefit from colesevelam (unlicensed but used with extended indication). Thus, lack of response to cholestyramine does not constitute exclusion of bile acid diarrhoea,132 hence therapeutic trials of bile acid sequestrants (cholestyramine or colesevelam) are not recommended. Pooled data from 15 studies show a dose-response relationship between the severity of malabsorption and the effect of treatment with a bile acid sequestrant: clinical response to cholestyramine occurred in 96% of patients with <5% retention of SeHCAT, 80% at <10% retention and 70% at <15% retention.115

There are also logistic considerations for high throughput nuclear medicine departments as other concurrent studies may result in background radiation which could affect the 7-day SeHCAT retention value; individual departmental protocols should be in place to circumvent this issue.87

Bile acid diarrhoea should no longer be missed given the available option to test with either SeHCAT or serum C4. Other emerging serum and urine tests may soon be available. Once diagnosed, treatment is simple and effective.

5.2 Microscopic colitis

Collagenous colitis and lymphocytic colitis are two forms of microscopic colitis, both commonly presenting with chronic, non-bloody watery diarrhoea and with few or no endoscopic abnormalities.133 They were first described around 1980.134 135Histological features are distinct from ulcerative colitis or Crohn’s disease and are not reliably detected on macroscopic examination at colonoscopy. Microscopic examination shows an increased number of intraepithelial and lamina propria lymphocytes (>20/100 cells) in both forms of microscopic colitis, together with a thickened subepithelial collagen band (>10 µm) in collagenous colitis.136

These conditions have been the subject of several recent systematic reviews and meta-analyses and data from these have been used to inform the current guidance. The clinical presentation, risk factors, pathology, disease course and response to treatment have been reviewed and compared for lymphocytic and collagenous colitis.137 138 The epidemiology and trends139 and the diagnostic overlaps with IBS and functional GI disease have been reviewed.140 141 The American Gastroenterology Association has developed guidelines on the medical management of microscopic colitis.142 143

The overall prevalence of microscopic colitis ranges from about 50 to 200/100 000.143 Both forms are commoner in women (collagenous colitis 77%, lymphocytic colitis 68%) and the mean age at presentation is around 60.138 However, microscopic colitis can present in much younger patients with 25% of cases being under 45.137 The incidence of collagenous and lymphocytic colitis has been increasing in parallel, possibly related to greater awareness of the need to look for this diagnosis. There are overlapping histological features and the two forms cannot be distinguished on the basis of symptoms, although they may be less severe in lymphocytic compared with collagenous colitis.133 Nocturnal diarrhoea and incontinence are frequently present.

In a meta-analysis of studies of patients meeting the criteria for diarrhoea-dominant IBS, the prevalence of microscopic colitis was 9.8% (95% CI 4.4% to 17.1%).140 Other reviews have also quoted a prevalence in patients being investigated for chronic diarrhoea of around 7.5–10%.133 142 Other functional bowel disorders, including constipation-predominant or mixed IBS, may also coexist with microscopic colitis. In patients with a diagnosis of microscopic colitis, about one-third have symptoms compatible with IBS, but this is a similar proportion to patients with other causes of chronic diarrhoea.141

Conditions associated with microscopic colitis include autoimmune diseases such as rheumatic disease, thyroid disease and coeliac disease (in around 5–7%).133 137 142 Bile acid diarrhoea (diagnosed by SeHCAT testing) has been reported to be prevalent in both collagenous colitis (41%; 37–45%) and lymphocytic colitis (29%; 24–34%).138 Use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and sertraline is also high and withdrawal of these can be associated with improvement in symptoms.138

Diagnosis of microscopic colitis is made by histological examination of colonic mucosal biopsies. Multiple biopsies should be taken and examined to detect the histological changes of lymphocyte infiltration and a possible collagenous subepithelial band.136 It needs to be stressed that the colonoscopic macroscopic appearances may be essentially normal, but biopsies are still needed. Right-sided biopsies, taken at colonoscopy, have a greater yield than rectal biopsies, but most patients will have changes detectable in the distal colon and so can be diagnosed by biopsies taken at flexible sigmoidoscopy.82 83 There is no reliable biomarker for microscopic colitis, although a raised faecal calprotectin may be found,144 which will suggest the need for further colonoscopic assessment. A scoring system has been developed which has a good negative predictive value (97%) to exclude microscopic colitis.145 This may have a role in avoiding unnecessary colonoscopic biopsies in some patients.

Making the diagnosis of microscopic colitis in a patient with chronic diarrhoea is important as specific and effective treatment for the condition is now available. Budesonide, in controlled release preparations, has been shown to induce remission in active disease for both forms of microscopic colitis, and these trials have recently been reviewed.143 There is also good evidence for budesonide in the maintenance of remission in collagenous colitis.146 Up to 70% can relapse and require further treatment,147 but others can remain symptom-free. Other drugs have been used, including prednisolone, bile acid sequestrants in appropriate patients with demonstrated bile acid diarrhoea and, in steroid-refractory patients, immunosuppressives.142

5.3 Maldigestion of fructose-based carbohydrates and lactose and polyhydric alcohols

Maldigestion of fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) is a cause of diarrhoea in patients with IBS and other patient groups148 (eg, IBD in remission, enteral nutrition). The mechanism by which these nutrients have effects on the GI tract has been described through detailed physiological and imaging studies.149–152

Fructose is a hexose monosaccharide that is found in food on its own, as a disaccharide with glucose-forming sucrose and as longer chain polymers called fructans. Fructose is usually absorbed at the epithelium via the facilitative transporter GLUT5 and the GLUT2 glucose-fructose co-transporter.153 The modern diet may contain high levels of isolated fructose or fructose in excess of glucose that exceed the absorption capacity of the small bowel (eg, soft drinks sweetened with corn syrup). Undigested fructose then passes into the colon and is fermented in the same manner as lactose in patients who are deficient in small intestinal lactase due to non-persistence of this enzyme expression into adult life.

Fructans are present in large concentrations in wheat, a staple of the diet for many populations (eg, bread, noodles). Fermentation of fructans by colonic bacteria is the cause of ‘wheat intolerance’ in many patients without coeliac disease.154 155 Similarly, sorbitol and other non-absorbed sugar alcohols (‘polyols’) used as artificial sweeteners pass unchanged into the colon and can induce diarrhoea if taken in large quantities (eg, diet drinks, chewing gum).

Interpretation of carbohydrate breath tests is particularly contingent on the challenge dose used. Double-blind randomised controlled dietary challenge studies show a dose-response relationship between the intake of lactose, fructose and fructans with the likelihood of malabsorption (as assessed by an increase in breath hydrogen) and the development of abdominal symptoms, including diarrhoea.150 The prevalence of primary lactase deficiency based on the presence of the 13 910 C/C genotype in the promoter region of the lactase enzyme gene is 2–15%, predominantly in Caucasian populations in Northern Europe.156 A recent meta-analysis of epidemiological data reported that 68% (95% CI 64% to 72%) of the world’s population are lactase-deficient,157 and this approaches 100% in the Han Chinese population.158 There is a high level of concordance between the presence of this genotype and lactose malabsorption.156 In contrast, there is no unique genotype linked with fructose or fructan malabsorption and a review of nine studies found that 25 g fructose may induce an increase in breath hydrogen in 40% of healthy subjects, but rarely induces symptoms.153 Prospective studies have shown that self-reported dietary intolerance is a poor predictor of objective test results158 159 or even response to dietary restriction. Thus, breath testing after carbohydrate challenge could be useful if it identifies the cause of symptoms and predicts response to therapy. A positive lactose breath test fulfils these criteria,160 161 although avoidance of dairy products alone is rarely sufficient treatment in patients with IBS.161 162 No trials have directly addressed patients with isolated diarrhoea but, in diarrhoea-predominant IBS, two randomised controlled trials163 164 and one prospective study165 have found no relationship between the result of breath testing and response to dietary fructose reduction. At present, fructose breath testing cannot be said to inform diagnosis and treatment of fructose intolerance.

5.4 Post radiation diarrhoea

This is increasingly more common given that there is a threefold rise in cancer survivors in the last three decades. Many of the causes of chronic diarrhoea discussed in other sections of these guidelines are common in people who have been treated for GI and other cancers (eg, bile acid diarrhoea, pancreatic insufficiency). Specific guidance is now available as to how to investigate such patients, especially for the late effects of radiation therapy.166

5.5 Rapid intestinal transit

Many conditions associated with diarrhoea have been ascribed to abnormalities of gut motility and increased intestinal transit time. These include post-surgical states (eg, vagotomy), endocrine conditions (eg, hyperthyroidism), bile acid diarrhoea, autonomic neuropathy (eg, diabetes) and, most often, primary functional diarrhoea. Assessment of the contribution of disordered motility and transit to diarrhoeal disease is hampered by the fact that (a) many of these conditions have multifactorial aetiologies; (b) available tests have limited ability to identify the cause of symptoms; and (c) wide individual variation in normal values precludes a definitive diagnosis in all except the most severe cases.

Detailed measurements of motility can be acquired by small intestinal or colonic manometry, ideally with high-resolution technology that clearly visualises propulsive and retrograde contractions that promote and inhibit transit.167 Pressure measurements are abnormal in the presence of obstruction and gross neuromuscular dysfunction, but findings in patients with severe symptoms do not correlate well with pathology on small bowel biopsy.168 In patients with chronic diarrhoea and IBS, the results are almost always normal and such invasive techniques are not well tolerated.169 170

Only patients who remain undiagnosed after extensive traditional investigation and failed medical therapy should be considered for manometry studies.171 In the future non-invasive MRI  may find a role in the diagnosis of diarrhoeal conditions. Recent studies have shown that this technique can provide comprehensive measurements of both motility and transit and can identify specific abnormalities in patients with diarrhoea-predominant IBS.172

6.1 Fat malabsorption

Pancreatic exocrine insufficiency can lead to malabsorption (or more correctly maldigestion) and diarrhoea due to impairment of pancreatic enzyme and bicarbonate secretion. In adults, this is usually the result of chronic pancreatitis, pancreatic carcinoma or pancreatic surgery. Maldigestion of fat can result in steatorrhoea and weight loss but may not be clinically apparent. Steatorrhoea can be caused by small bowel malabsorption and clinical assessment of steatorrhoea (eg, by stool inspection) is unreliable.175 Symptoms of pancreatic exocrine insufficiency usually develop 10–15 years after first symptoms of chronic pancreatitis and when secretion of lipase and other pancreatic enzymes is reduced to <10% of normal values. The diagnosis of advanced chronic pancreatitis in patients presenting with diarrhoea is often suggested by the clinical history and confirmed with imaging. A number of recent guidelines outline the current strategies for diagnosing chronic pancreatitis.176–179 There are international variations in practice depending on the availability of various modalities such as endoscopic ultrasound (EUS) and direct pancreatic function tests. However, there is a broad agreement that invasive direct pancreatic function testing has become largely redundant in routine clinical practice, replaced by indirect pancreatic function testing and imaging. It is also recognised that there is currently no ideal test to diagnose chronic pancreatitis in early/mild disease.

6.2 Pancreatic imaging

The progressive inflammatory change that occurs in chronic pancreatitis leads to significant changes in pancreatic structure. Focal segmental or diffuse destruction of the parenchyma occurs in the early stages while structuring, dilation of the duct and calcification tend to occur late in the disease. There has been debate around the significance of the sometimes subtle changes found at EUS or endoscopic retrograde pancreatography (ERP) in the diagnosis of early chronic pancreatitis, particularly in patients presenting with abdominal pain. For more advanced pancreatic disease with significant morphological change, CT scanning has become the initial imaging of choice given the poor sensitivity of USS in this situation (approximately 60%)184 185 and in assessing for pancreatic malignancy. Its sensitivity in detecting early pancreatic changes is unknown, but it is significantly less than EUS or magnetic resonance cholangiopancreatography (MRCP)/ERP. Newer non-invasive methods for diagnosing pancreatic cancer are beginning to emerge.186

MRCP with secretin (MRCP-S) appears to significantly increase the diagnostic yield in patients with asymptomatic hyperamylasaemia187and showed equivalent sensitivity to endoscopic retrograde cholangio-pancreatography (ERCP) in determining ductal changes in patients with idiopathic recurrent pancreatitis.188 The technique has been proposed as an alternative to direct pancreatic function tests, but issues of standardisation and interpretation remain to be resolved.189 190 Quantitative MRCP after secretin has also been correlated with faecal elastase and pancreolauryl testing191 192 and has been shown to correlate with histology.193 However, it is a specialised procedure and not recommended for initial diagnostic investigation for chronic pancreatitis.

EUS is able to detect mild parenchymal and ductal abnormalities not seen on CT. Comparison with ERCP in seven studies revealed sensitivity of 68–100% with specificity of 78–97%194 based on standard scoring of nine criteria. A study of 83 patients showed EUS to have an equivalent diagnostic accuracy for early and late stage chronic pancreatitis when compared with secretin direct pancreatic function tests.195 196 Two studies comparing MRCP-S and EUS with ERCP have suggested a slightly higher sensitivity of EUS for changes suggestive of chronic pancreatitis,197 198 but it remains questionable whether some of the subtle findings at EUS have clinical relevance. Based on these and other studies, both EUS and MRCP-S would seem effective diagnostic tests for chronic pancreatitis, which are best used in a complementary fashion.

Local availability will inevitably dictate the choice of test, and both modalities would seem to be useful in assessing patients with early/mild forms of chronic pancreatitis, particularly if other approaches such as CT or pancreatic function tests are negative or equivocal. MRI with MRCP protocol is more sensitive and accurate in the detection of chronic pancreatitis, as also recommended by the American Pancreatic Association.176

6.3 Invasive pancreatic function testing

Invasive tests of pancreatic function involving direct measurement of pancreatic secretions (catheter aspiration of secretions after secretin, cholecystokinin stimulation or a standard test meal—the ‘Lundh test’) have historically been regarded as the gold standard for determining exocrine pancreatic function.199 200 These tests are reported to correlate findings at ERCP,201 202 but some of these data are now more than three decades old with no recent re-evaluations of these earlier studies. Moreover, these tests are difficult to perform and compare as there is little standardisation. Although American guidelines continue to recommend direct pancreatic function tests as part of the diagnostic investigation for chronic pancreatitis,176 there is no place in UK and European practice for these invasive tests.

6.4 Non-invasive pancreatic function testing

These tests assess pancreatic enzymes or the consequences of maldigestion by measurement of stool, serum, urine or breath. The tests include fat, elastase and chymotrypsin measurement in stool, urine tests requiring detection of markers in urine or breath released from the gut and absorbed following digestion of synthetic substrate by pancreatic enzymes. All of these tests require significant loss of pancreatic function before becoming positive, with poor sensitivity and specificity in mild/early pancreatic disease.

6.5 Small bowel bacterial overgrowth (SBBO)

7.1 Faecal incontinence

Some groups of patients are directed towards surgeons because diarrhoea is not the primary patient-perceived symptom. A typical example is faecal incontinence. Such patients may well have a compromised sphincter complex but fail to maintain continence because of the underlying diarrhoea. Although an important risk factor for incontinence along with age, obstetric trauma, pelvic surgery, obesity and other medical conditions such as diabetes and stroke, it may not be recognised and investigated appropriately. Again, NICE gives guidance as to appropriate management with baseline assessment aimed at addressing underlying conditions such as potentially treatable causes of diarrhoea (https://www.nice.org.uk/guidance/cg49). An associated group who may complain of both faecal incontinence and diarrhoea are those with severe faecal loading where the diarrhoea is essentially overflow. Typical patients tend to be those with cognitive or behavioural issues, have learning difficulties, or those with neurological or spinal disease. A focused baseline assessment should therefore include an anorectal examination which will identify impaction and, for instance, rectal prolapse. Plain radiography or radio-opaque marker studies have been used but there is poor correlation between the two.224 Specialist investigations include anorectal manometry and endoanal ultrasound, but there are no accepted standards for performing these specialist tests. The evidence behind their use is limited to the fact that they are better than simple clinical assessment in deciding surgical management. Therefore, they should only be instigated once conservative measures for faecal incontinence have been exhausted and surgical intervention is contemplated.

7.2 Post-surgical diarrhoea

There is a third group of ‘surgical’ patients with diarrhoea. These are the patients who have developed diarrhoea as a result of surgical intervention. The underlying aetiology of the diarrhoea may be attributed to pyloric dysfunction, bile salt malabsorption, bacterial overgrowth or gut bypass reducing absorptive capacity.

Upper GI surgery may result in damage or division of the vagus nerve accompanied in part by reduction in capacity of the stomach in the case of gastric resection. Rapid gastric emptying may result in osmotic diarrhoea and associated symptoms of ‘dumping’ syndrome. Surgery can also provide an ideal environment for bacterial colonisation and overgrowth leading to chronic diarrhoea. GI tract surgeries that create a blind loop (eg, a Billroth II procedure or a Roux-en-Y anastomosis) may predispose to stasis and overgrowth due to abnormal motility and ineffective clearance of retained food and secretions.225 In addition, those who have undergone jejunoileal bypass, an end-to-side enteroenteric anastomosis or the creation of a Koch distal ileal pouch are at risk. In the same way, small bowel strictures may lead to bacterial stasis and overgrowth. These may occur after surgery but can also be seen after radiotherapy, in Crohn’s disease and secondary to some medications.226

Small and large bowel resection clearly reduces absorptive capacity. At the extreme, this results in short bowel syndrome characterised clinically by chronic diarrhoea, dehydration, electrolyte abnormalities and malnutrition. The severity and management depend on the site and extent of the intestinal resection, whether there is disease in the residual bowel and the degree of adaptation of the remaining bowel. However, even a simple limited right hemicolectomy may result in diarrhoea as a result of loss of the ileocaecal valve and resorptive capacity of the right colon. This increases the risk of developing bacterial overgrowth because of retrograde movement of bacteria from the colon into the small intestine. This has been clearly demonstrated in one trial of patients with Crohn’s disease which showed that resection of the ileocaecal valve almost doubled the prevalence of bacterial overgrowth.227

7.3 Fistulae

The common theme in many of these surgical conditions is structural change. However, structural change may not necessarily be surgically induced. Disease processes can also predispose to gut bypass, bile acid diarrhoea and bacterial overgrowth. Fistula formation, such as commonly seen in Crohn’s disease, is one example of gut bypass. Cholecystoenteric fistulae are a potential cause of bile acid diarrhoea, particularly if the fistula is to the colon.228 Small bowel diverticula which occur in approximately 1–6% of the population may harbour bacteria and result in bacterial overgrowth.229

7.4 Investigations

In terms of investigation, clearly surgically-induced structural change may be obvious from the history. A digital rectal examination is essential. It allows clinical assessment of the sphincter complex and will exclude faecal impaction as well as low anorectal lesions. Further investigations, if required, to examine for structural change are mainly radiological; CT scanning and contrast studies will identify the structural changes.

8.1 Neuroendocrine tumours

Hormone secreting tumours arising from gastroenteropancreatic tissue are rare causes of diarrhoea. The prevalence of functional pancreatic endocrine tumours is approximately 10 per million population, the incidence ranging from 1/106 cases per year in the case of gastrinomas to fewer than 1/107 cases per year for vasoactive intestinal peptide (VIP)omas and glucagonomas.230 Even this incidence value is likely to be an overestimate. Diarrhoea occurs as part of a symptom complex varying according to the tumour type (eg, 100% cases in VIPoma, approximately 65% in gastrinoma). Although diarrhoea has been reported at a prevalence of 15% in glucagonoma, this again is probably an overestimate. A wide variety of other symptoms may accompany hypersecretion of these hormones and detailed discussion is available elsewhere.231

Confirmation of the diagnosis in each case requires demonstration of an elevated serum hormone concentration. A VIP secreting tumour may be suspected in the context of large volumes of secretory diarrhoea (>1 litre/day), dehydration and hypokalaemia. Normal values for circulating VIP are less than 170 pg/mL, while mean VIP serum concentrations in patients with functioning tumours range from 675 to 965 pg/mL.232As serum levels fluctuate, the assay should be performed during an episode of diarrhoea. Similarly, serum gastrin levels in patients with gastrinomas are considerably higher than the normal range of 150 pg/mL, with average values of approximately 1000 pg/mL. However, comparable values can be found in patients with pernicious anaemia, other types of atrophic gastritis or potent acid suppressant therapy.233 Raised levels, although not to the same degree, also occur in other conditions such as diabetes mellitus, renal insufficiency and rheumatoid arthritis.

Diarrhoea is often a prominent feature (occuring in up to 50% of cases234) in carcinoid syndrome, which accounts for 20% of midgut neuroendocrine tumours.235 This almost always occurs in the context of hepatic metastases, even if the primary site remains undefined. The clinical diagnosis of ‘malignant disease’ is usually evident. A raised 24-hour urinary 5-hydroxyindoleacetic acid (above the local reference laboratory value) has a high sensitivity and specificity (88%)236 for the condition and correlates with tumour bulk, bioactive product secretion and, frequently, with the severity of symptoms.237 However, this is subject to patients adhering to dietary restrictions and often a 3-day dietary intake should accompany the sample so the laboratory can assess for any dietary interference (eg, serotonin-rich food such as bananas).235

8.2 Factitious diarrhoea

Factitious diarrhoea caused by laxative abuse or the spurious adding of water or urine to stool specimens has been recognised as a relatively common cause of reported chronic diarrhoeal symptoms in Western populations. The likelihood of this diagnosis increases as more numerous and repeated investigations reveal negative results. Thus, although only 4% of patients visiting district gastroenterology clinics had factitious diarrhoea, this value increased to 20% of those evaluated at tertiary referral centres, which made it the most common cause of diarrhoea of previously undetermined origin.15 Similarly, a survey of patients who had undergone extensive evaluation revealed 33% who were found to be taking laxatives or diuretics; 22% had undiagnosed colitis (ulcerative or microscopic colitis), 7% had faecal incontinence and 7% had other organic disorders.26

Repeated analysis of stool and urine is wise, as patients may ingest laxatives intermittently. Alkalinisation assays, although simple to use (phenolphthalein, some anthraquinones and rhubarb turn the stool red, bisacodyl turns it purple-blue), are not of sufficient sensitivity and should be abandoned. A screen for ‘laxative abuse’ should include the detection of anthraquinones, bisacodyl and phenolphthalein in urine and magnesium and phosphate in stool, and should be carried out in a specialist laboratory. Laboratories in the UK performing these tests should participate in the UK External Quality Assessment scheme for the detection of laxatives.