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Refractory Diarrhoea in stable IBD

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Authors

Dr Aditi Kumar
Professor Matthew Brookes

Introduction

Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory disorder of the gastrointestinal tract.1 Diarrhoea is the presenting complaint in the majority of patients, with 85% reporting it as their initial symptom.2 It can become confusing whether persistent diarrhoea is due to active IBD or other co-existing diseases, often leading physicians to believe that a patient has refractory IBD when they do not respond to standard IBD treatment.3 In this instance, measuring faecal calprotectin levels and comparing them with previous measurements during active disease can be useful to confirm active inflammation.4,5 A full list of potential causes of diarrhoea is given in Table 1. This article focuses on three common causes seen with stable IBD: bile acid malabsorption (BAM), small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS).

Table 1: Differential Diagnosis of Diarrhoea3

  Type Specific
Infective

 

 

 

Bacterial Salmonella
Shigella
Enterohaemorrhagic Escherichia  coli
Yersinia
Campylobacter
Aeromonas
Clostridoides difficile
Infective  Viral Norovirus
Rotavirus
Enteric adenovirus
Astrovirus
Sapovirus
Cytomegalovirus
Infective Fungal Histoplasmosis
Coccidoides
Infective Protozoal Giardia
Cryptosporidium
Entamoeba
Enterohaemorrhagic E coli
Vascular Ischaemic colitis
Behçets disease
Vasculitis
Drug Induced NSAIDs
Chemotherapy
Antibiotics
Hypoglycaemics
Magnesium agents
Other Radiation enteritis
Diverticulitis
Small intestinal bacterial overgrowth
Bile acid malabsorption
Irritable bowel syndrome
Tuberculosis
Coeliac disease
Autoimmune enteropathy
Pancreatic insufficiency

(NSAIDs: non-steroidal anti-inflammatory drugs)

Bile acid malabsorption

There is a well-known association between BAM and diarrhoea accompanying other intestinal diseases. However, while BAM is a frequent condition, with an estimated prevalence of 4–5%,6 it is often neglected.2

Bile acids are produced from cholesterol in the liver and excreted into the small intestine to aid with fat digestion, after which 95% are absorbed in the terminal ileum.7 Thus, patients with a history of ileal disease or resection are at particular risk of developing diarrhoea.8 One study found that the incidence of BAM in patients with Crohn’s disease (CD) who had had an ileal resection was 97%, compared with and 54% those with CD and no resection.9 Another study estimated the prevalence of BAM in patients with resected CD to be >90% versus 11–52% in patients without ileal resection.6 Resection of <100 cm of the terminal ileum leads to mild BAM and can present with secretory diarrhoea. Severe BAM occurs when >100 cm of the terminal ileum is resected and can lead to fat maldigestion and steatorrhoea.3

SeHCAT testing is the gold standard diagnostic test for BAM, having high sensitivity of 80–90% and specificity of 70–100%.8 However, it is not widely available; it used in only 12 European countries and Canada, but is not used in the USA. This test is expensive test and is mostly available in tertiary centers.10 Consequently, many clinicians opt for an empirical trial of bile acid sequestrants, which is less time consuming and cheaper, although compliance can be variable.11 The full list of bile acid sequestrant treatment options is provided in Table 2. Smith et al.9 found that the response to bile acid sequestrants in patients with CD who had undergone ileal resection was 60% and in those without ileal resection was 40%. There was an estimated 70% response rate in people with a diagnosis of IBS with diarrhoea and a 64% response rate if patients had had previous gastric surgery (i.e. gallbladder removal).9

Table 2: Bile acid sequestrant prescribing options and appropriate dosing12

Bile acid sequestrant Dose Availability Side-effects
Colestyramine 4 g once daily, increased by 4 g weekly to a maximum dose of 36 g per day (1–4 divided doses) Sachets Unpleasant taste, constipation, nausea, borborygmus, flatulence, bloating, abdominal pain
Colestipol 5 g 1–2 times per day, increased by 5 g monthly to a maximum dose of 30 g per day Sachets or tablets
Colesevelam* 625 mg 1–2 times per day, increased to three times per day maximum Tablets Constipation, gastrointestinal discomfort, headache, nausea, vomiting

*Not currently licensed for use in BAM.12

Small Intestinal Bacterial Overgrowth

SIBO is characterised by excessive and/or abnormal microbiota in the small bowel.13 The most common symptom associated with SIBO is diarrhoea, followed by abdominal pain and then bloating.14 There is an increased prevalence of SIBO in patients with IBD, and it is commonly seen in patients with CD (18–30%).15 Risk factors include previous small bowel resection (especially involving resection of the ileocaecal valve), ileal involvement and the presence of fistulising or fibrostenosing disease.16 Risk does not appear to increase with disease activity or duration or with the use of immunotherapy.15,16

The gold standard for diagnosis is jejunal aspirate and culture, but there are several limitations to this investigation.17 It is time-consuming and expensive and has a high false-negative rate.17 Hydrogen breath testing is now more commonly used, as it is simple, cheap and non-invasive.14 However, it has a low sensitivity rate of 62.5% and specificity of 81.7%.15 Prior to the test, patients are required to go on a low-fibre diet for 24 hours and asked to avoid smoking, antibiotics, laxatives and exercise, as these can affect test accuracy.17 Most physicians opt for a therapeutic trial, taking clinical response to antibiotics as an affirmation of SIBO, although there is currently no consensus on the choice of antibiotic, dose or duration of treatment.18 As a result, clinical response rates range from 35% to 100%.13 Treatment with ciprofloxacin or rifaximin have both shown a 70% response rate, and a regimen with amoxicillin-clavulanic acid and cefoxitin has eradicated more than 90% of strains isolated from SIBO patients.15,16 Rifaximin is a popular choice as it is not absorbed, has few side-effects and shows little evidence of resistance. Regardless of the antibiotic choice, most patients will need to be re-treated, leading to long-term antibiotic use.19 Other management approaches to consider include treating the underlying disease or structural defect and correction of any nutritional deficiencies.19

Further information on SIBO is available in a British Society of Gastroenterology web education article.20

Irritable Bowel Syndrome

As per the Rome IV Diagnostic Criteria for IBS, patients must have had recurrent abdominal pain on average at least 1 day per week in the past 3 months, associated with two or more of the following:

  1. Defecation either increasing or improving pain
  2. Change in stool frequency
  3. Change in stool form (appearance).21

The global prevalence of IBS is 11.2%, with higher rates seen in females and individuals younger than 50 year.22 Patients with IBD can also develop IBS in the absence of any objective evidence of inflammation.23 In fact, 40% of IBD patients in remission may suffer from IBS-like symptoms. Prevalence of these is 33% in patients with ulcerative colitis and 42–57% in those with CD.24  The crucial difference between IBD and IBS is the lack of alarm symptoms, such as weight loss or rectal bleeding.3 Both conditions are associated with an equal magnitude of impairing psychological effects and reduced quality of life.25

Treatment options are varied and include antibiotics (rifaximin), antidiarrhoeals, antidepressants, antispasmodics and laxatives.3 Studies have shown that antidepressants have a greater efficacy than placebo in the improvement of somatic bowel symptoms.26 Dietary changes, such as maintaining a low FODMAP (fermentable oligo-, di-, mono-saccharides and polyols) diet, may also help with symptoms, and have been shown to have most benefit in patients with CD, in particular those who have a history of bowel surgery.27

Although IBS-like symptoms are common among IBD patients in remission, they may still reflect ongoing (albeit subclinical) activity of IBD, and their presence should always be initially interpreted as such.24 Until an IBD flare is excluded through laboratory tests and/or endoscopic evaluation with tissue diagnosis, the diagnosis should not simply be considered to be IBS.24

Conclusion

Diarrhoea is a common presenting feature in many different conditions and its presence can significantly reduce a patient’s quality of life.28 Clinicians are often challenged to interpret this symptom in patients with IBD who appear to be in remission.29 Although it is important to understand and consider other potential causes of diarrhoea in stable IBD, the first priority should always be to exclude the possibility of an acute IBD flare.24

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Authors

Dr Aditi Kumar

Dr Aditi Kumar is a Gastroenterology Trainee in the West Midlands. She is currently undertaking her PhD with a sub-specialty interest in inflammatory bowel disease. She received her MBChB degree from the University of Birmingham, UK and BSc Hon in Biomedical Sciences at the University of Ottawa, Canada.

Professor Matt Brookes

Professor Matt Brookes is a Consultant Clinical Gastroenterologist at the Royal Wolverhampton NHS Trust. He is a Professor of Gastroenterology at Wolverhampton University and an honorary Senior Lecturer at the University of Birmingham.

He is the deputy chair of the national speciality group and also holds the position of deputy clinical director for the NiHR West Midlands CRN.