When should I test for BAD?

Graham Johnson, Managing Director at BIOHIT Ltd

Bile acid diarrhoea (BAD) is a lifelong and extremely upsetting condition, and often leaves patients housebound due to a fear of faecal incontinence or being unable to find a toilet when they need one. This distressing condition affects approximately 1-2 % of the UK population – a similar incidence to coeliac disease – as well as up to one third of patients diagnosed with diarrhoea-predominant irritable bowel syndrome (D-IBS).¹ Despite being more prevalent than some better-known conditions of the gut – such as Crohn’s and ulcerative colitis – diagnosis is often delayed or missed. It is therefore important that clinicians consider BAD in patients presenting with chronic functional diarrhoea or irritable bowel syndrome with diarrhoea. Here we summarise the key aspects of testing for and diagnosis of BAD, as discussed in a recent British Society of Gastroenterology webinar, Bile Salt Malabsorption,² presented by Michael Camilleri, Professor of Medicine, Pharmacology and Physiology at Mayo Clinic College of Medicine and Science. The webinar was followed by a panel discussion featuring UK-based consultant gastroenterologists Jervoise Andreyev, Professor of Medicine at the University of Nottingham, and Ramesh Arasaradnam, Professor of Medicine at the University of Warwick and University of Leicester, and chaired by Dr David Nylander, Newcastle upon Tyne Hospitals NHS Trust, UK.

Why is it important to consider a diagnosis of BAD?

Firstly, because it is so prevalent. A systematic review and meta-analysis of patients with functional diarrhoea has shown that 25-50 % of these individuals display evidence of BAD, as demonstrated by blood tests, bile acid retention or faecal measurements. With functional diarrhoea, or D-IBS, affecting 4 % of the population, this equates to a population prevalence of 1-2 %, which is similar to coeliac disease.^2,3 Secondly, it is associated with a poor quality of life for sufferers, which has been shown to impact both productivity and mental health.⁴ And, thirdly, it is a treatable disorder where patients respond well to therapy once diagnosed. A positive diagnosis of bile acid malabsorption and diarrhoea earlier in the patient flow can reduce healthcare costs associated with delayed diagnosis.

Early diagnosis matters

BAD often goes hand in hand with other digestive diseases, and the third edition of the British Society of Gastroenterology guidelines for investigation of chronic diarrhoea in adults stresses the need to consider the possibility of more than one pathology.⁵ Many diseases seen by gastroenterologists – including Crohn’s and coeliac disease – have a BAD component, and bile acid malabsorption should be considered when such patients do not respond fully to treatment for the prevailing disorder. Similarly, approximately 50 % of all women receiving pelvic radiotherapy for gynaecological cancer will develop BAD, as will about 5 % of men treated for prostate cancer. These patients can suffer from post-radiation enteropathy or bowel bacterial overgrowth, both of which can increase the likelihood of bile acid malabsorption by interrupting the enterohepatic recycling loop. BAD is also a common complication of GI surgery, such as cholecystectomy, ileal resection/right sided hemicolectomy and gastrectomy, affecting between one in 10 and one in three patients. In all of these interventional cases, it’s important to consider that the cause may be related to the treatment – rather than functional diarrhoea – if the symptoms have occurred post therapy. A similar situation has been described with immunotherapy, where 5 % of patients treated with lenalidomide – a drug used in the treatment of myelomas and lymphomas – develop intractable diarrhoea that is entirely due to bile acid malabsorption.

An early diagnosis of BAD is beneficial for both healthcare providers and patients, reducing the number of investigations required. In the UK, simple, non-invasive and cost-effective tests are available that can simultaneously test for – and exclude – cancer, inflammation and other major treatable conditions as the cause of the diarrhoea and direct appropriate treatment. For example, blood and stool tests can be used to rule out coeliac disease (e.g. serum anti-tissue transglutaminase, anti-endomysium, deamidated gliadin antibodies), intestinal inflammation (e.g. faecal calprotectin) and bowel cancer risk (e.g. faecal haemoglobin/FIT), but this is not the case worldwide. Moreover, while this battery of tests can rule out a wide range of well-known diarrhoea-predominant digestive diseases, it doesn’t exclude BAD, which remains undetected. In the absence of a readily available, relatively inexpensive diagnostic test for BAD, an empirical therapeutic trial is often used to see if symptoms improve. While not very scientific, this approach has gained popularity in the absence of a suitable and accessible test.

How is BAD diagnosed?

Some countries use the 7-day scintigraphy ⁷⁵selenium homotaurocholic acid (⁷⁵SeHCAT) retention test – which is a measure of bile acid retention – to identify BAD, but this is not widely available and is therefore not an option in a majority of cases. This is the situation in the USA, where the Mayo Clinic tends to use fasting serum 7α-hydroxy-4-cholesten-3-one (C4) levels – which reflect bile acid synthesis in the liver – as a first line test. However, despite good specificity, its relatively low sensitivity means that BAD cannot be definitively excluded where results are borderline or low, and the clinic is increasingly turning towards the 48-hour stool bile acid excretion test as the mainstay of diagnosis. Diagnosis using this approach is based on three parameters: the total faecal bile acid excretion over 48 hours, the presence of more than 10 % primary BAs in the stool, and the combination of total faecal BAs in excess of 1,000 µmol/48 h plus more than 4 % primary BAs. While sensitivity is good, as is the relative specificity, the test as it is time consuming and cumbersome in its current form.⁶

A more recently validated approach uses the combination of a single fasting serum C4 sample taken before 9am – because of diurnal variation – and primary bile acid measurement in a single stool sample.⁶ This demonstrated better sensitivity – around 60 % at 80 % specificity – compared to serum C4 alone. In the UK, researchers comparing total bile acids test concentration from a single stool sample with the SeHCAT retention test generated data that suggests this could be a good screening method for the diagnosis of BAD, with a sensitivity of around 75 % at 80 % specificity.⁷

A straightforward route to faecal bile acid quantification

Determining the faecal bile acid concentration is a key part of diagnosing BAD. The IDK^® faecal bile acids assay is a quick, inexpensive and non-invasive method for the routine differential diagnosis of chronic diarrhoea. This photometric assay can be incorporated with early investigations where, if the faecal calprotectin test is negative, the same stool sample can be used to test for faecal bile acids as a ‘reflex’ test, allowing physicians to gain more information from a single sample without additional consultation.

The availability of the IDK bile acids test in primary care offers a rapid option to help eliminate BAD as the possible cause of chronic diarrhoea, potentially preventing further unnecessary and intrusive procedures, such as the SeHCAT scan and colonoscopy. At around £15 per test – compared to nearly £400 for a SeHCAT scan, and more than £500 for a colonoscopy – examining faecal bile acids early in the care pathway offers a cost-effective solution to help signpost patients for further investigation and get diagnosed sooner, improving their quality of life and reducing healthcare costs.

The take home message

The value of testing for BAD is underlined by an uncontrolled open label study at the Mayo Clinic. This study showed that the success rate for treatment with bile acid sequestrants – currently the only available treatment – in patients with a formal diagnosis of BAD was about 75 %, compared to around 25 % for patients who had a therapeutic trial without a formal diagnosis.²

There are a number of crucial factors to be aware of when patients present with chronic functional diarrhoea:

• Iatrogenic causes, such as radiotherapy and metformin medication, should always be considered.
• New tests are being developed to diagnose BAD – including serum C4, serum FGF19 and total faecal bile acid excretion – which have the potential to be simpler, less costly and more widely available.
• A combination of tests – for example, fasting serum C4 and a random faecal bile acid test – could help provide a definitive diagnosis.
• Promising new treatments are in the pipeline – such the FXR agonists obeticholic acid and tropifexor,^2,6 and an FGF 19 analogue, aldafermin – that reduces hepatic bile acid synthesis.²
• BAD may be idiopathic, but other gastrointestinal disorders can have a bile acid malabsorption component.
• Identification of BAD helps select patients for treatment with bile acid sequestrants.
• It is important to consider the effect of diet; as bile is secreted in response to fat intake, following a low fat diet may help.²

Undoubtedly, identifying the cause of a patient’s functional disease at the earliest opportunity – so that they can start treatment sooner – will have a significant impact on their quality of life, simultaneously reducing the burden on healthcare providers.

You can find out more about BIOHIT IDK bile acids test here.

To watch to the webinar, go to https://www.bsg.org.uk/web-education/ggr-bile-salt-malabsorption

References

1. Walters JR, Pattni SS. Managing bile acid diarrhoea. Therap Adv Gastroenterol. 2010;3(6):349-357. doi.org/10.1177/1756283X10377126
2. BSG Global Grand Rounds Episode 1: Bile Salt Malabsorption with Professor Camilleri https://www.bsg.org.uk/videos/grand-rounds/bile-salt-malabsorption
3. Valentin N, Camilleri M, et al. Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-analysis. Gut 2016;65:1951-1959. doi.org/10.1136/gutjnl-2015-309889
4. BouSaba J, Sannaa W, et al. Impact of Bile Acid Diarrhea in Patients With Diarrhea-Predominant Irritable Bowel Syndrome on Symptoms and Quality of Life. Clin Gastroenterol Hepatol. 2022;20(9):2083-2090.e1. doi.org/10.1016/j.cgh.2021.11.035
5. Arasaradnam R, Brown S, et al. Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition. Gut 2018;67(8):1380-1399. doi.org/10.1136/gutjnl-2017-315909
6. Camilleri M, Nurko S. Bile Acid Diarrhea in Adults and Adolescents. Neurogastroenterol Motil 2022;34(4), e14287. doi.org/10.1111/nmo.14287
7. Kumar A, Al-Hassi HO, et al. A single faecal bile acid stool test demonstrates potential efficacy in replacing SeHCAT testing for bile acid diarrhoea in selected patients. Sci Rep 2022;12:8313. doi.org/10.1038/s41598-022-12003-z