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Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder (FGID) characterized by abdominal pain or discomfort associated with changes in bowel habit. According to the Rome III bowel habit subclassification, IBS is subtyped into four categories based on stool form alone: IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), IBS with a mixed pattern (IBS-M), and unsubtyped (IBS-U). Studies demonstrate that IBS-M is the most common clinical subtype with a prevalence of 30–63%.[2-5] A recent meta-analysis suggested that the three main IBS subtypes have equal distribution, however, it should be noted that these results were drawn from only a small subset of the meta-analysis studies and subtypes were defined using different criteria including Manning, Rome I, Rome II, or Rome III.
Prior to the Rome III subclassification criteria, IBS was usually subgrouped into only IBS-C or IBS-D using a more complicated combination of bowel-related symptoms including stool form, stool frequency, urgency, and straining. Patients who did not meet criteria for either were typically defined as non-C, non-D IBS or IBS with alternating bowel habits (IBS-A). In 2006, the Rome III Functional Bowel Disorders committee redefined the IBS bowel habit subgroups and defined IBS-M as having mixed stool forms (i.e., both hard/lumpy and loose/watery at least 25% of evacuations). The current Rome III subclassification is easier to use, as it is based solely on the prevalence of stool form, which correlates with colonic transit time,[8, 9] and has been shown to be the most reliable and sensitive criteria for subtype differentiation.
However, IBS-M remains a heterogeneous group and is characterized by varying symptoms commonly associated with IBS-C and IBS-D, thus posing challenges both in clinical practice and research. While many studies have characterized bowel habits in IBS-C and IBS-D, there are few that have evaluated IBS-M, particularly in those classified by Rome III criteria in a U.S. population. Previous studies using the Rome III criteria have been performed in non-U.S.-based populations and mostly at larger tertiary care centers.[11-13]
While new IBS-specific drugs continue to emerge, most clinical trials have focused primarily on IBS-C or IBS-D. There remains a paucity of treatments specifically for IBS-M given its heterogeneous nature and lack of accepted and valid patient reported outcome measures (PROs) for this group. There are only a few published clinical trials that specifically evaluated pharmaceutical treatments in the IBS-M subtype.[5, 14] However, these studies only used a binary primary endpoint, which is no longer recommended by regulatory agencies including the Food and Drug Administration (FDA). A lack of understanding of the IBS-M subgroup is further demonstrated by the exclusion of enrollment and responder criteria for IBS-M in the recent FDA guidance for IBS clinical trials.
Thus, the main aims of this study were (i) to characterize the IBS-M subtype based on the Rome III criteria in patients recruited from a U.S. community, and (ii) to compare clinical characteristics of IBS-M with IBS-C and IBS-D.
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- Author Contribution
- Supporting Information
IBS-M by nature is a highly heterogeneous subgroup due to a range of symptoms that are similar to those associated with IBS-C and IBS-D. Our main study findings were: (i) IBS-M is the most common subtype (44.1%) in our patient population using Rome III criteria, (ii) About a third of IBS-M patients may be potentially misclassified due to medication effects causing loose or hard stools, (iii) The IBS-M medication group tends to have more severe and prolonged symptoms than the remaining two thirds of IBS-M patients (iv) The majority of IBS-M flares and remissions are relatively short, (v) Upper and lower GI symptoms and psychological symptoms reported by IBS-M are similar to that in IBS-C and IBS-D, (vi) The most commonly reported most bothersome symptoms in IBS-M are irregular bowel habits, bloating, and abdominal pain, and (vii) Two thirds of IBS-M patients report abnormal BM frequencies at least 25% of the time, while about one third have normal BM frequencies.
A surprising and important finding in our study was that up to a third of IBS-M patients could be potentially misclassified due to medication effects on stool form. Unlike the other subtypes, IBS-M patients responded to answers suggesting that they only experienced both extremes of stool form due to a laxative or antidiarrheal agent. Both of these medication types are commonly used and available over-the-counter. Thus, a significant proportion of IBS-M patients defined by the Rome III subclassification criteria may be potentially misclassified, which is important to know for clinical management and research. However, in our study medical histories provided more information to reclassify only a subgroup of these patients. Therefore, we do not know if the majority of these patients were misclassified. Regardless, this IBS-M medication group tended to have more severe and prolonged bowel symptoms than the remaining IBS-M group. This suggests that a group of IBS patients with more severe symptoms use medications to the point where they may overshoot a targeted normal stool form. It is possible that these patients have IBS-M but the greater severity and longer duration of symptoms provoke use of medications to regulate bowel habits. Alternatively, the use of medications can be associated with extremes of stool form and therefore lead to more severe and prolonged symptoms. With the notable rate of medication usage in IBS-M, and the increased severity in this group, our results emphasize the importance of accurate documentation of medication effects on stool form for improved clinical management and accurate establishment of IBS bowel habit subclassification.
With regard to the comparisons with the other IBS subtypes, IBS-M patients reported symptoms commonly endorsed by both IBS-C (straining, incomplete evacuation, manual evacuation) and IBS-D (urgency). This mixed pattern of constipation symptoms with the addition of urgency in IBS-M is consistent with past Rome II studies.[3, 10] However, due to other variables, certain studies in the past have shown IBS-M to be more similar to IBS-C based on similarities in stool frequency, consistency, psychological symptoms, and a higher likelihood of transition between these two subtypes longitudinally.[2, 10] The recent study by Weinland et al. following episodes over 14 days also found IBS-M to be more similar to IBS-C.
However, during our further analysis, IBS-M tended to be more similar to IBS-D. IBS-M patients reported a greater proportion of diarrhea, and they also showed greater similarities in the most bothersome symptoms with IBS-D than with IBS-C. This may be different from previous studies because we excluded patients who had mostly loose stools with laxatives and thus could have IBS-C rather than IBS-M.
Aside from symptoms shared with IBS-C and IBS-D, we also found that IBS-M showed a trend for having a higher occurrence of nausea. While nausea has not historically been a common finding within IBS, Schmulson et al. also reported a higher frequency of dyspeptic symptoms of halitosis and vomiting within Rome III IBS-M patients compared to other subtypes. We further evaluated the prevalence of Rome III dyspepsia across IBS subtypes, but did not find any differences in distribution. We did not specifically confirm whether patients had functional dyspepsia, which would require exclusion of organic upper GI conditions, nor did we assess symptom criteria for the two subtypes of functional dyspepsia.
While it is clear that IBS patients experience multiple symptoms, determining the typical symptoms and most bothersome symptom can help determine if subgroups exist within each subtype and help guide future clinical research studies and treatment. When asked to choose a single most bothersome symptom, it was not surprising that the three most prevalent ones in IBS-M were irregular bowel habits, abdominal pain, and bloating.[10, 24] The prevalence of irregular bowel habits and abdominal pain are likely inherently high due to being part of the diagnostic criteria for IBS, but, previous studies have shown that bloating is highly prevalent[25-27] and can be the most bothersome symptom.[26, 27] However, because bloating is a common symptom in many FGIDs including IBS, it has not been used as a diagnostic symptom as its discriminative value would be low, but it is clearly a common and bothersome symptom that requires attention in clinical management and clinical trials.
Interestingly, over a third of all IBS-M patients do not experience any extremes of stool frequency at least 25% of the time. With regard to stool form, there are fairly evenly distributed groups within IBS-M of having predominantly diarrhea, constipation, or equal prevalence. Greater characterization of bowel habits in IBS-M would help in better defining this IBS subtype. In fact, recent studies have shown that prospective daily assessment of bowel habits would reclassify many IBS-M patients into IBS-U due to the lower actual prevalence of stool form extremes.
Study limitations include the fact that this study is a cross-sectional assessment of IBS-M symptoms and does not address prospective fluctuations. Furthermore, our use of a questionnaire for subtyping and symptom reporting has its own limitations, such as recall bias. However, a recent study postulated that it is likely that patients can overestimate their bowel habits on questionnaires. To mitigate this issue, our questionnaire used answer options with numbers (e.g., ‘about 25% of the time’) as opposed to just words (e.g., ‘sometimes’). Another source of bias can come from the nature of patient recruitment through advertisements. Recruiting was also only carried out in a single region, the Western United States, and may not be indicative of patients from other regions. Lastly, this study is exploratory in nature. Due to the small sample sizes within subtypes and the multiple questions explored, the statistical significance of our findings should be interpreted with caution. Further studies are needed to validate our findings.
In summary, IBS-M patients continue to be the most common subtype based on Rome III criteria. More emphasis and attention should be placed on properly obtaining information regarding medication impact on stool form as we have shown that up to a third of IBS-M patients may otherwise be misclassified and may only have mixed stool forms due to medications. Furthermore, this medication group may represent a more severe and difficult to manage subgroup of IBS. IBS-M continues to share symptoms of both constipation and diarrhea with the addition of a higher occurrence of nausea. However, in this study IBS-M appeared to report most bothersome symptoms more similarly to IBS-D. These study results will help provide supportive information when considering symptom management, development of PROs, and design of treatment trials for IBS-M.