Assessing the clinical utility of a new assay for bile acid diarrhoea

Graham Johnson, Managing Director at BIOHIT HealthCare Ltd

Bile acid diarrhoea (BAD) is an unpleasant condition that affects approximately one in every 100 people in the UK, and results in debilitating and embarrassing symptoms, including chronic diarrhoea, faecal incontinence and excessive flatulence.¹ Bile acid sequestrants and dietary changes can help to manage the condition, but diagnosis is much more challenging, and it can often take more than five years to reach a conclusion.² This is largely owing to the unclear and inconsistent patient care pathway, and a noticeable lack of access to suitable diagnostic tests. Consequently, researchers at the University of Wolverhampton NHS Trust undertook a study to evaluate the validity of measuring faecal bile acids in a single stool sample using the IDK^® Faecal Bile Acids assay, with promising results for diagnosing BAD in Crohn’s patients.³ Here, we look at the discrepancies in diagnosing these patients, and summarise the result of this study and what this could mean for the future of BAD investigations.

Why is BAD often overlooked?

BAD is caused by either the malabsorption or excessive secretion of bile acids in the small intestine. These bile salts then travel into the colon, stimulating abnormally high water and salt secretions into the bowel and result in watery diarrhoea.¹ However, the underlying pathology of BAD can vary, occurring as either a primary condition or secondary to an existing illness, creating three distinct types classified by their disease pathways. Type 1 BAD occurs as a result of ileal dysfunction or resection – in Crohn’s disease, for example – Type 2 (idiopathic) BAD develops in an intact colon, and Type 3 can stem from various gastrointestinal diseases or removal of the gall bladder (cholecystectomy).⁴

The crossover with similar diseases, together with a general lack of awareness amongst doctors and patients, means that investigating BAD is not always the first port of call when assessing symptoms in primary care. The condition is often misdiagnosed as more well-known conditions, with reports suggesting that up to one third of patients diagnosed with diarrhoea-predominant irritable bowel syndrome (D-IBS) have undiagnosed BAD.⁵ Consequently, the British Society of Gastroenterology (BSG) recommends referring patients with persistent diarrhoea to investigate BAD in secondary care, regardless of normal first-line investigations.⁶ Unfortunately, the picture in secondary care is not much clearer, and gastroenterologists are often unable to access the appropriate tools for investigating BAD, even in specialist clinics.

Limitations in diagnosing BAD

Currently, there are three methods for investigating BAD, each with their own limitations:

⁷⁵Selenium taurocholic acid (SeHCAT) scan

A SeHCAT scan is used to determine bile acid malabsorption, by assessing the retention of SeHCAT – containing ⁷⁵Se gamma-emitter and a taurine-conjugated bile acid analogue – after seven days. The greatest downside of this method is that is not widely available; even in the UK, where it is considered gold standard, the scans are only available in tertiary centres, and the method is not licensed in the United States for measuring bile acids. This often means that patients referred for a SeHCAT scan in the UK must make time to visit a nuclear medicine department – which are few and far between –twice over seven days. SeHCAT scans are also often expensive, and there are always concerns when exposing patients to radioactive pharmaceuticals unnecessarily.

Tests for serum biomarkers of hepatic BA synthesis

Tests for serum C4 (7-alpha-hydrooxy-4-cholesten-3-one) and fibroblast growth factor 19 (FGF-19) have also been proposed as potential screening methods, as elevated C4 levels in combination with a decrease in FGF-19 can be indicative of BAD. However, these tests are also not widely available, and measurements can be subject to diurnal variation or altered by meal ingestion.⁷

Liquid chromatography with mass spectrometry (LC-MS and LC-MS/MS)

LC-MS and LC-MS/MS can be used to reliably quantify bile acids in biological fluids. However, the high running costs, requirement for technical expertise, and lack of accessibility are frequent issues that make it challenging to implement them for routine use.⁸

A clinical void

The lack of appropriate diagnostic tests for BAD is felt across the healthcare sector, with the National Institute for Health and Care Excellence (NICE) declaring that more needs to be done to establish the validity and accuracy of diagnostic methods.⁹ This clinical void often leaves gastroenterologists to arduously rule out any other potential conditions first, in order to whittle down the possible causes of symptoms. When left with no other choice, some doctors will even try an empirical trial of treatment, and assume a positive diagnosis from an improvement in symptoms. This is not recommended by the BSG, which states that there is not enough evidence to support the benefits of this method over a positive diagnosis, due to low patient adherence to treament.⁶ The gruelling process of putting patients through test upon test, and potentially subjecting them to unnecessary investigations and medications, only delays appropriate diagnoses, often leaving individuals to live with uncertainty and debilitating symptoms for years.

A potential one-step solution

The IDK Faecal Bile Acids test is a photometric assay that quantifies faecal bile acids for the diagnosis of BAD in patients with D-IBS, or to support differential diagnosis. This assay can rapidly determine the concentration of faecal bile acids from a single stool sample, demonstrating excessive secretion or malabsorption. This test can therefore help to accelerate and streamline the journey to diagnosis for the patient, allowing them to access methods to manage this incapacitating condition sooner.

A study group based at the Royal Wolverhampton NHS Trust recently embarked on a project to evaluate the efficacy of the IDK Faecal Bile Acids test as an alternative to SeHCAT for the diagnosis and monitoring of BAD with minimal disruption to the patient’s life. 113 patients from four hospitals across the West Midlands were divided into four groups: idiopathic bile acid diarrhoea as confirmed by SeHCAT scans, post-operative terminal ileal resected Crohn’s disease, post-cholecystectomy and a SeHCAT-negative control group. For each patient, the baseline faecal bile acid concentration was determined using the IDK Faecal Bile Acids test, and the results were compared to SeHCAT scan results. Based on NICE guidelines, SeHCAT results (% retention of bile acids) were used to divide patients into groups of severe (<5 %), moderate (5-10 %) or mild (10-15 %) BAD, as well as negative (>15 %). For those in the three positive groups, further stool samples were also taken after four and/or eight weeks of treatment with Colesevelam, to determine whether this test was a reliable indicator of therapeutic efficacy.

A promising first step

The results from this study demonstrated that faecal bile acid concentrations were significantly increased in post-operative terminal ileal resected Crohn’s patients with confirmed BAD, and those with severe BAD. Given the process of ileal resection – the removal of the end of the small intestines – it is unsurprising that these patients will have excess faecal bile acid concentrations and severe BAD. Therefore, these results are promising for showing the potential efficacy of the IDK Faecal Bile Acids test in diagnosing severe BAD or patients with post-operative Crohn’s disease. This could potentially help to accelerate the time to diagnosis, by providing a cost-effective and accessible test that can determine results from a single stool sample, allowing patients to access treatment sooner.

Although the results for the three remaining patient groups were less conclusive, and no significant difference was found pre- and post-treatment, this first report provides us with the perfect grounding to evaluate the validity of this test further. There are a number of considerations and areas of improvement that we can build on in order to better evaluate its diagnostic utility, including standardising the process of sample preparation, increasing the size and diversity of patient cohorts, and monitoring external factors, such as the dietary modifications used for the 48 hour faecal stool tests. The authors themselves deduced that the study was not adequately powered, but was a much-needed springboard to give larger studies the momentum to confirm the validity of this test, establish a normal range, and determine appropriate cut off values.

This also gives us the first step to determine where – and how – this test might fit into patient care pathways, with the potential for it to be used as an adjunct to SeHCAT scans or serum testing. The receiver operator characteristic (ROC) curve from this study demonstrated that the assay provided some utility in diagnosing BAD, which allowed the researchers to explore the possibility of using FBA tests to stratify patients for SeHCAT referral, but an appropriate cut off with the required specificity and sensitivity was not determined. Further research could provide greater insights into the clinical utility of this test, and suggest where it is best placed in the patient care pathway.

Summary

There is a clear-cut need for an effective and rapid diagnostic test for BAD to help reduce the burden of this condition on both patients and healthcare resources. Current diagnostic testing methods are not readily available, leaving clinicians at an impasse with no choice but to administer drugs without a positive diagnosis. That’s why we are excited to hear about the promising results from this latest study, which shows the potential for a faecal bile acid test from a single stool sample, reinforcing the need for progression in BAD diagnostic methods.

To find out more about BIOHIT HealthCare’s IDK Bile Acids test, visit:

www.biohithealthcare.co.uk/biohit-product/faecal-bile-acids-assay-idk/

References

1. BAD UK. 2016. Bile Acid Diarrhoea (BAD). [online] Available at: https://www.bad-uk.org/bile-acid-diarrhoea-bad [Accessed 12 September 2022].
2. Fernandes, DCR. et al. What is the cost of delayed diagnosis of bile acid malabsorption and bile acid diarrhoea?. Frontline Gastroenterol. 2019, 10(1), 72-76. doi:10.1136/flgastro-2018-101011
3. Kumar, A. 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. https://doi.org/10.1038/s41598-022-12003-z
4. Camilleri, M. Bile Acid diarrhea: prevalence, pathogenesis, and therapy. Gut Liver, 2015, 9(3), 332-9. doi: 10.5009/gnl14397. PMID: 25918262; PMCID: PMC4413966.
5. Walters, JR; Pattni, SS. Managing bile acid diarrhoea. Therap Adv Gastroenterol. 2010, 3(6), 349-357. doi:10.1177/1756283X10377126
6. Arasaradnam, RP. et al. Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3^rd Gut, 2018, 67(8), 1380-1399.
7. Vijayvargiya, P. et al. Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea in IBS-diarrhoea and functional diarrhoea. Aliment Pharmacol Ter, 2017, 46(6), 581-588.
8. Kakiyama, G. et al. A simple and accurate HPLC method for fecal bile acid profile in healthy and cirrhotic subjects: validation by GC-MS and LC-MS [S]. Journal of lipid research, (2014) 55(5), 978-990.