Although international consensus-derived criteria recommend that patients can be diagnosed with irritable bowel syndrome (IBS) if they have specific symptoms, ‘red flags’ are absent. There is no serological evidence of inflammation or coeliac disease, many studies suggest that an alternative gastrointestinal (GI) disorder can frequently be identified in patients confidently diagnosed with IBS. These include bile acid diarrhea (BAD), cancer, carbohydrate malabsorption, coeliac disease, infectious diarrhea, inflammatory bowel disease, microscopic colitis, pancreatic exocrine insufficiency (PEI), and small intestinal bacterial overgrowth (SIBO). However, studies report widely differing prevalences of these conditions [¹].

There are no published studies on people whose symptoms meet diagnostic criteria for IBS that investigate participants for all the conditions listed above and report the change in symptoms using patient-reported outcome measures when such a condition is diagnosed and treated.

In this study, we recorded the alternative diagnoses detected in a consecutive series of patients with diarrhea-predominant IBS (IBS-D) and functional diarrhea (FD) following comprehensive investigations. We also measured changes in their symptoms and quality of life, prospectively following lifestyle advice when necessary and standard treatment of all alternative conditions detected.

Our Clinical Governance and Research and Innovation Departments of the United Lincolnshire Hospitals National Health Service Trust approved this study as a prospective clinical service evaluation. It was not considered to require written informed consent by the patients as all tests conducted fall within the standard investigative pathway comprehensively to look for potential aetiologies in chronic diarrhea in these patients.

We recorded investigation results and outcomes following intervention in patients newly referred to our “diarrhea clinic” by their GPs for secondary care management of persistent GI symptoms.

Between April 2019 and March 2020, we identified consecutive adults prospectively aged \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\ge$\end{document}≥ 18 and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\le$\end{document}≤ 50 years old who had symptoms fulfilling the Rome IV criteria for IBS-D or FD but no “red flag” symptoms at the time of their first clinic visit in Lincoln County Hospital, UK. Patients were excluded from this study if they had undergone any previous abdominal surgery (except appendicectomy, inguinal/femoral hernia repair, or Caesarean section). Patients were also excluded if they were pregnant or breastfeeding or had a history of coeliac disease, cancer, inflammatory bowel disease, or pancreatic disease.

All clinic patients were investigated similarly, so this study did not reflect a change in clinical practice. If the physical examination was unremarkable, first and second-line investigations were arranged accordingly .

Before each appointment, all patients completed a Patient Reported Questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS), (Supplemental material). This questionnaire is validated for patients with functional bowel symptoms [²,³,⁴]. In this study, a \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\ge$\end{document}≥30% reduction in the overall GSRS score is considered a good response to treatment with significant symptom improvement [⁵]. The GSRS questionnaire was modified by adding two 11-point visual analog scales evaluating the quality of life and the impact of GI symptoms on quality of life and a Bristol Stool Chart assessing the patient’s ‘best’ and ‘worst’ bowel frequencies and stool forms. In addition, to avoid missing relapsing and remitting symptoms [⁶], we asked patients to complete the questionnaire based on their symptoms over the preceding month rather than the two weeks originally specified. Some questions were shortened, and 17 additional symptoms were added to allow for a more holistic assessment. All these additional items were deemed clinically relevant, and their inclusion allowed a more holistic assessment of the patient’s overall symptom burden. They can be categorized into three major domains – upper GI, lower GI, and perianal symptoms. In addition, two visual analog scales evaluating the quality of life and the impact of GI symptoms on quality of life and a Bristol Stool Chart assessing the patient’s ‘best’ and ‘worst’ bowel frequencies and stool forms were included in the questionnaire. All these modifications made to the original questionnaire give a better reflection of patients’ overall GI burden and have been adopted in clinical practice by Professor Andreyev, an experienced clinician and Professor in gastroenterology.

This study demonstrates that a significant proportion of patients who fit the Rome IV diagnostic criteria for IBS-D or FD referred to a secondary care “diarrhea clinic” have at least one alternative diagnosis potentially accounting for their symptoms. Standard first-line therapies led to the alleviation or abolition of symptoms in many patients. Treating all identified alternative diagnoses was often required to achieve clinical improvement.

Many previous studies have examined the co-existence of one specific organic GI condition in patients with IBS-type symptoms, predominantly BAD and SIBO [¹]. However, this is the first study that looks for a wide range of potential diagnoses. Our study has also considered the role of significant dietary indiscretion in contributing to symptoms, be it fiber, caffeine, or alcohol. In addition, our study is unique in objectively assessing treatment outcomes using patient-reported measures if any of these new diagnoses are made.

The prevalence of most of the conditions we identified is similar to data reported elsewhere in studies that have looked for the co-existence of one specific organic GI condition in patients with IBS-type symptoms [¹]. The fact that the majority of patients reported a clinical response after appropriate treatments also suggests that the conditions were correctly identified. Thirdly, the response rates we saw are similar to other large studies that have looked at the response of these individual conditions to treatment [¹⁰,¹³,¹²,¹⁴].

An important finding was a relatively high response rate to treatment in patients with “borderline” SeHCAT results (between 15-20% 7-day retention) and in almost half of patients with a pancreatic FE-1, which lies between 200-500 µg/g. Many clinicians would consider these a normal result; however, these response rates support previously published data challenging the view that a SeHCAT scan is significant only if the level is below 10% or 15% 7-day retention [¹⁰,¹⁵,⁹]. Also, a recent study has confirmed that a significant proportion of patients with a FE-1 level of between 200-500 µg/g may also respond to pancreatic enzyme replacement therapy[¹⁶]; however, while experts do acknowledge that this is possible, clinical data are lacking [¹⁷].

One limitation of our findings is that this was a non-randomized study, and symptom scores were compared to baseline in the same individual. There were no matched controls. Therefore, improvements may be related to placebo effects, although many patients had had a variety of previous treatments in primary care that had no benefit. The patient population captured in this study likely represents more complex cases and may not represent the broader IBS population.

A second limitation was that the coronavirus outbreak in March 2020 caused major disruptions to clinics and non-urgent investigations, resulting in some patients in this study not having complete investigations. It is, therefore, likely that GI diagnoses were missed in some. Lockdowns may also have minimized symptoms for other patients as they stayed home. Others may not have received full or appropriate treatment due to delayed or telephone follow-up. Therefore, the findings generated from this study with a small sample size should be interpreted cautiously.

A third limitation is that a number of patients received multiple interventions, particularly with respect to any detected dietary indiscretion, and this study did not assess specifically the impact of advice given to correct these, particularly when another cause was also treated. So, some of the measured improvements in outcomes may have been related to wider lifestyle changes than just a specific prescribed medication.

The follow-up period varied and ideally would have been longer – those with only one alternative GI condition identified and reporting an excellent treatment response stayed in this study for a much shorter period than those who required more than one form of treatment for multiple GI diagnoses.

After first-line antibiotic therapy for SIBO, improvement was only seen in four in ten treated patients. Our normal practice in people with a positive HBT is to try a first-line treatment and then, if there is no response, a second-line treatment. If HBT is still positive and the patient remains symptomatic, a small bowel aspirate is performed to attempt to grow the organisms causing SIBO and obtain antibiotic sensitivities. This meticulous approach was discarded as a result of the pandemic. Important data suggest that normalization of a HBT following antibiotics correlates with good treatment outcome [¹⁸], so appropriate treatment for SIBO should be the goal. Our data also show that it is essential to measure both H2 and CH4 during the HBT.

Our three patients diagnosed with overflow diarrhea did well after treatment. However, fecal loading is a subjective diagnosis with no clearly defined X-ray features, and it remains unclear whether the presence of fecal loading captured on a single abdominal film correlates well with symptoms.

Finally, although the validity of the GSRS is well-documented, we used a modified version which has not been validated. Nonetheless, the modified GSRS was repeated to assess all patients at baseline and following treatment, and this uniform assessment provides an objective short-term trajectory for each patient’s symptoms.

Despite these limitations, our data suggest that organic GI conditions can be detected in a large proportion of patients who could be easily misdiagnosed as having IBS. This can be detrimental not only to the patients but also to healthcare and society. If our data are reproduced by others, this would require a fundamental reappraisal of clinicians’ use of symptom-based diagnostic criteria.