We have previously found that BD and symptomatic CL are associated with a 9- to 12-fold increase in gallbladder wall MCs when compared to controls [7
]. In the current study, we confirmed that MCs are frequently present in the gallbladder wall at counts very similar to what was observed in our previous study. MCs have been implicated in other functional gastrointestinal disorders. Increased gastric MCs have been reported in adults with functional dyspepsia [8
]. Increased MCs have been found in the ileum and colon of adults with irritable bowel syndrome [9
]. Similar to our previous report, MC density was increased in the lamina propria and the muscularis mucosae in both CL and BD patients. For CL patients, this is similar to findings previously reported in adults with CL which demonstrated increased MC density and % of degranulated MCs in the muscular layer of adults with gallstones as compared to controls [16
]. Unlike our previous report, MCs in the lamina propria were significantly increased in patients with CL as compared to patients with BD. The significance of this finding is not known. Moreover, it is possible that this represents a reaction to the stone itself or to an abnormal bile acid pool which may be present in stone formers. As we only studied symptomatic CL patients, it is not known whether MCs are unique to patients experiencing pain or whether they are also found in asymptomatic patients.
While we diagnosed BD in the current study utilizing adult criteria for functional gallbladder disorder, it should be noted that 85% of the patients in this group demonstrated chronic cholecystitis on pathologic examination. Our findings are consistent with other reports of pathology in biliary dyskinesia in children where chronic cholecystitis has been reported in 44-93% of patients [6
]. This raises the question of whether these patients should be diagnosed with acalculous cholecystitis or whether chronic inflammation contributes to the pathogenesis or functional gallbladder disorders. This would be analogous to the increase in colonic lymphocytes reported in post-infectious irritable bowel syndrome [19
]. Whether chronic inflammation is important in symptom generation is also unclear. In two previous studies, the proportion of patients with chronic cholecystitis did not differ between patients experiencing positive benefit from cholecystectomy as compared to those who did not [17
A major focus of the current study was to define the degree of activation of gallbladder wall MCs by electron microscopy. The primary biologic and pathophysiologic actions of MCs result from the release of specific mediators which are often active in a concentration-dependent fashion. Thus the activity of MCs is defined by the density and degree of activation and degranulation [12
]. Although there are no established norms for intestinal mast cell degranulation indices in the gastrointestinal tract, we have demonstrated a moderate to high degree of activation comparable to that seen in other diseases where MCs are known to have a pathophysiologic role [14
]. MC products have the potential to result in pain through direct stimulation of sensory nerves or induction of visceral hyperalgesia. MC activation has been associated with pain severity and increased visceral sensitivity in adults with both functional dyspepsia and irritable bowel syndrome [11
]. MC degranulation results in a decreased threshold for the pain response with balloon distension and this hyperalgesic response can be prevented with MC-stabilizing medication [21
] MC may also create gallbladder symptoms through the generation of gallbladder spasm. Two MC products, histamine and leukotrienes, have been shown to increase the excitability of gallbladder smooth muscle and lead to contraction [22
]. We were unable to demonstrate a correlation between MC density or activation and the ejection fraction although this may be the result of the sensitivity of the method employed. The activation index is a general indicator of activation but may be limited in assessing specific pathophysiologic processes. MCs produce many mediators which may be selectively released with varying physiologic actions. Additionally, while EM activation has been described in conditions where MCs appear to play a role, there is no "gold standard" measure of MC activation which would allow assessment of the accuracy of degranulation indices. Further work is necessary to determine if specific mediators are responsible for the observed dysmotility.
Another focus of the current study was to prospectively evaluate global response, to determine which symptoms improve with cholecystectomy, and to evaluate whether there is a relationship between MC density or activation and clinical response. Consistent with previous reports, a complete or nearly complete clinical response was seen in all CL patients. Specific symptoms decreasing in frequency were abdominal pain, pain with eating, night waking with pain, nausea, and vomiting while lower tract symptoms (diarrhea, constipation, and pain improving with a stool) did not improve. Cholecystectomy resulted in a complete clinical response in 80% of BD patients, with an additional 15% experiencing clinical improvement. Specific symptoms decreasing in frequency were abdominal pain, pain with eating, night waking with pain, and nausea. Again, lower tract symptoms did not decrease in frequency postoperatively. Our response rate for BD is consistent with previous studies, most of which have been retrospective. As reviewed by Constantinou, et al, eleven previous studies reported postoperative response rates varying from 71-100% [17
]. Constantinou, et al, also reported outcomes following cholecystectomy in 100 children with BD where outcome data were collected prospectively [17
]. Similar to our patients, 77% reported resolution of symptoms at 6 months to 5 years postoperatively. The only randomized trial for BD was performed in adults [26
] This study found cholecystectomy to be more efficacious than observation. Siddiqui, et al, retrospectively evaluated the degree of response to cholecystectomy for BD in children [27
]. Similar to our patients, the overall response rate was 93% with 65% reporting resolution of symptoms and 28% reporting improvement with some residual symptoms. Overall, our study adds to the previous prospective study and confirms the clinical efficacy that has been reported in the previously cited retrospective studies.
The only relationship between MC activation or density and the clinical response grade for either patient group was demonstrated in the BD patients. A complete clinical response was associated with lower epithelial MC density when compared to a partial or non-response. The reason for this is not clear. It is possible that higher MC density may be associated with MCs in the gastrointestinal tract resulting in dyspepsia or irritable bowel syndrome. This could not be evaluated in the current study as only a few patients underwent endoscopic evaluation. There are insufficient data to determine whether there is clinical value to obtaining gastrointestinal biopsies prior to cholecystectomy. These data (both the positive findings in the epithelium and the negative findings in other layers) need to be interpreted with caution as there were so few partial or non-responders for comparison. The positive findings may simply represent a type II statistical error. Larger studies are necessary to evaluate the relationship between MCs and outcome.