One reason for the development of post-cholecystectomy diarrhoea is from disruption to the enterohepatic circulation, causing hepatic overproduction of bile acids. This is known as bile acid diarrhoea (BAD) of which there are three types: type one occurs secondary to ileal inflammation, thus interfering with bile acid absorption; type two is primary or idiopathic; and type three occurs secondary to other conditions where the ileum appears normal. In the latter, one of these conditions is following cholecystectomy [11, 12].
The mechanism of action to balance bile acid secretion is a negative feedback loop. Bile acid reabsorption in the ileum leads to activation of ileal FXR (farnesoid × receptor), thus inducing transcription of FGF19 (fibroblast growth factor 19) which then activates hepatic FXR. This inhibits CYP7A1 (cholesterol 7-αhydroxylase), which is the rate-limiting enzyme in bile acid synthesis, thus decreasing bile acid formation. When this is disrupted, as in BAD, there is overproduction of FGF19 leading to higher concentrations of bile acids which, in turn, leads to diarrhoea [12, 13].
In this study involving collaboration from five tertiary centres, only a small number of patients (2.1%) were investigated for diarrhoea following laparoscopic cholecystectomy. This may imply either that the rest of the patients did not require any investigation as they did not develop diarrhoea, or that their symptoms were short term and settled spontaneously without warranting medical investigation. The published literature reveals a large variation in the quoted incidence of post-cholecystectomy diarrhoea. This ranges from 2.1 to 57.2% [2,3,4,5,6, 14]. Our own review of the literature showed a post-cholecystectomy diarrhoea rate of 13% (Farrugia et al., Post-Cholecystectomy diarrhoea rate and predictive factors—a systematic review of the literature). Despite this, the true rate of post-cholecystectomy diarrhoea due to altered bile acid physiology has not been determined. C4 (7α-hydroxy-4-cholesten-3-one) levels, which directly correlate with bile acid synthesis, have been shown to increase following cholecystectomy, while FGF19 levels decrease [5, 15]. Despite this, the increase in C4 levels has not been shown to be related to increased frequency of bowel movements or type of stool .
Thus, the number of patients being investigated does not necessarily correlate with the presumed rate of post-cholecystectomy diarrhoea that is reported in the literature. This may be due to a lack of awareness that diarrhoea may develop after cholecystectomy due to faults in the pre-operative consent process. Indeed, up to 70.3% of patients are not being consented for the possibility of developing diarrhoea after laparoscopic cholecystectomy .
There is a clear delay in initiating investigations, with a median of 672 days between surgery and 75SeHCAT testing found in this study, implying that there is poor awareness within the medical community of the possibility of developing BAD after cholecystectomy. There was a difference in time to investigation between women and men, with median time to testing for female patients being 726 days while median time to testing for male patients, 539 days. While not statistically significant (p = 0.139), there is a median difference of 187 days. This may imply that complaints are not well regarded and in indeed one study suggests that there is a perceived reduction in constipation in women after cholecystectomy, but no real diarrhoea . However, we can see from our results that it is not simply perception as patients have had positive 75SeHCAT tests after developing diarrhoea post-cholecystectomy.
Furthermore, we have noted that not all patients underwent endoscopic investigation in addition to 75SeHCAT testing, as is recommended by the British Society of Gastroenterology guidelines . This could also imply that inflammatory bowel disease (IBD) was not excluded in all patients. As IBD (ileal Crohn’s) can be a cause of BAD, this is a confounding factor in our study. Another confounding factor is that some patients were known to have Crohn’s disease prior to laparoscopic cholecystectomy and others had had a previous right hemicolectomy for other conditions. As both of these factors affect the terminal ileum and may lead to bile acid malabsorption, it is unclear, for these patients, whether the BAD that developed was a consequence of malabsorption from the terminal ileum, or from bile acid overproduction following cholecystectomy, or perhaps a mixture of both. With endoscopic investigations there was an added delay of 178 days between women and men (median of 723 days for women and 545 days for men). Whilst failing to reach statistical significance (p = 0.29), it does represent an extra period of time with a reduced quality of life .
Despite CT scan being more useful in the investigation of structural rather than functional disorders, a large number of patients still had a CT scan as part of their initial investigation. In this there was a significant difference between referral time for women and men (p = 0.022), 938 days for women and 388 days for men. For all investigations, the median time to investigation of female patients was longer. This is a pattern that has been previously reported in other aspects of healthcare, resulting in higher morbidity and mortality for female patients [19, 20]. It is also interesting as CT scan is not recommended by the BSG guidelines for the investigation of chronic diarrhoea. However, there may have been other aspect if the clinical history led to a referral for CT scan.
Despite men being investigated (75SeHCAT, endoscopy and CT scan) more rapidly from initial presentation compared to women, we can still see that there is a significant delay in initiating investigations after laparoscopic cholecystectomy with a median time to investigation longer than 18 months for each investigation. Symptoms tend to develop within the first 3 months after cholecystectomy, and it is therefore apparent that these patients are not being investigated in a timely manner  and to the detriment of their quality of life . However, there may be other issues at play such as social factors preventing some patients from seeking help or attending for tests, delays resulting from local processes such as referral practices and waiting list times for tests such as 75SeHCAT (which is not found in all centres) and endoscopy waiting times. As such, it is difficult to say what effect this has on time from cholecystectomy to testing. As this is a multicentre study there may also be differences in practice between regions to take into account.
This study has confirmed that the degree of BAD, as seen on the 75SeHCAT result, does not necessarily correlate with patient symptoms (p = 0.382), which is in keeping with previous work on the subject . However, all patients were investigated after having diarrhoea for 4 weeks and the majority had a up to 10 episodes per day, which is congruent with the BSG guidelines for the investigation of chronic diarrhoea . It is also interesting to note that whilst 62.8% of the cohort was diagnosed with BAD and 18.4% had another diagnosis, in 18.8% of patients a definitive diagnosis was not secured. This highlights that further work is required in this area to benefit this large group of patients with clinical symptoms.
We found that patients younger than 35 years of age were all females and there are generally fewer males in each age group under the age of 50. This seems to imply that younger women are at higher risk of developing PCD in our dataset. This correlates with some studies  but not with others that suggest younger males to be more at risk [4, 24, 25].
This study is based upon real-time linked clinical data, thus showing the true perspective of patients who were investigated post-laparoscopic cholecystectomy for diarrhoea. Patients who were empirically started on bile acid sequestrants rather than being investigated via 75SeHCAT would not have been captured in the present study. Another possible limitation is that not all patients who develop diarrhoea are investigated via 75SeHCAT; thus, the true numerator remains unknown. BAD is not a well-known condition, and therefore, the only patients who were referred for 75SeHCAT testing were those seen by GPs, physicians, and surgeons who are aware of the condition. We also have no data regarding response to treatment in these patients identified here who were diagnosed with BAD. We have identified a large discrepancy between the number of male and female patients within our dataset, as such there may be an element of selection bias. However, the advantage of this study is that it is a multicentre study using 75SeCHAT as the investigation of choice with defined cut-off values for diagnosis of BAD. It also benchmarks the current clinical scenario when it comes to the investigation of chronic diarrhoea after cholecystectomy. While this is the largest study of its kind to date, further studies involving direct comparison between those patients investigated, and those who are not, for diarrhoea following cholecystectomy would present a more comprehensive picture of this difficult condition and would not only improve our understanding but allow for improved patient care.