**3. Pathophysiology**

severe epigastric or right upper quadrant pain that might radiate through to the back and right infrascapular regions, lasting for at least thirty minutes but less than 6 hours. It can be associated with symptoms of nausea and vomiting, and may awaken the patient from sleep [8]. Episodes are recurrent but usually in a sporadic and quite erratic frequency. Its functional nature should be supported by an absence of markers of organic disease: normal liver and pancreatic biochemistries, and negative diagnostic imaging. No structural basis should be

Functional biliary pain has also been termed: *gallbladder dyskinesia*, *chronic acalculous gallbladder dysfunction*, *acalculous biliary disease* an*d chronic acalculous cholecystitis [9]*. "Biliary dyskinesia" implies a motility disorder resulting from abnormal motor function of the gallbladder

Following removal of the gallbladder, biliary pain has been attributed to sphincter of Oddi dysfunction (SOD). SOD represents intermittent obstruction to the flow of biliopancreat‐ ic secretions through the sphincter of Oddi in the absence of biliary stones or a ductal stricture [11]. The Rome III Consensus has developed criteria for functional biliary-type

Dyspepsia overall is a common symptom in the general population with reported prevalence rates ranging between 10-45% [12]. Such estimates are confounded by the use of differing criteria for defining dyspepsia as well as a recurrent failure to exclude patients who primarily report heartburn symptoms12. Nevertheless, dyspepsia remains a common issue with annual incidence rates estimated between 1-6%[13]. In the United States, there were 4,007,198 outpatient visits for gastroenteritis or dyspepsia and 130,744 hospital admissions for functional or motility disorders in 2009 [14]. This represents a 26% increase from the year 2000, which

*Epidemiology of functional gallbladder disease* (i.e.; Frequency of biliary pain with a normal

The true prevalence of biliary dyspepsia is unknown. Estimates are generally based on the presence of non-specific clinical features and a lack of structural findings on ultrasonographic investigation of the biliary system. In large Italian population-based studies, 7.6% of men and 20.7% of women experienced biliary pain yet lacked gallstones on abdominal ultrasonography

With the advent of minimally invasive surgery, biliary dyskinesia has become a new indication for laparoscopic cholecystectomy increasing 348% in adults [17] and escalating 700% in pediatric patients over approximately a decade [18]. Large scale case series now list biliary

suggests an upsurge in the overall incidence of dyspepsia14.

appearing gallbladder e.g. without gallstones)

(manifest as impaired emptying) and/or sphincter of Oddi (increased tone)[10].

**1.3. Functional disorders of the biliary tract (Sphincter of Oddi dysfunction)**

evident to explain the pain.

112 Dyspepsia - Advances in Understanding and Management

pain (Table 1) [8].

**2. Epidemiology**

[15, 16].

#### **3.1. Acute biliary pain**

The biliary tract normally is a low-pressure conduit though which bile secreted from the liver reaches the duodenum. The gallbladder acts as a reservoir for decompression while storing bile in the interdigestive periods overnight and throughout the day [29]. Even in the digestive phase, gallbladder contraction does not elicit marked pressure spikes within the biliary tree because the sphincter of Oddi effectively relaxes. The hormone cholecystokinin (CCK) is primarily responsible for this reciprocity.

In the setting of cholelithiasis, biliary pain is assumed to originate from either an obstructive event (the gallbladder contracting on a closed cystic duct which is blocked by a gallstone) that increases intrabiliary pressure and/or inflammation (cholecystitis)10. Such obstruction also appears to stimulate the gallbladder mucosa to produce a phospholipase, which then hydrol‐ yses fatty acids off lecithin to yield lysolecithin in bile. Lysolecithin, acting as a biological detergent, might then initiate an inflammatory reaction (cholecystitis). Subsequently, inflam‐ matory mediators could trigger painful stimuli, while mechanoreceptor afferent fibers in the gallbladder and biliary tree conduct visceral pain information to the spinal cord and the brain. Thus, motor contraction, sensory afferents producing painful sensations and obstruction/ inflammation may all play a role in the perception of acute biliary-type pain.

#### **3.2. Chronic functional biliary pain**

The basis for chronic functional biliary pain appears to reside in visceral hypersensitivity, altered central processing, and/or abnormal gastrointestinal motility. Prolonged or intense noxious stimuli, particularly when repeated, lead to sensitization of visceral nociceptors. These peripheral sensory neurons respond to potentially damaging stimuli by sending nerve signals to the spinal cord (dorsal horn) and then projecting centrally to the brain – the thalamus and cortex, the site of pain perception. Chronic irritation might then influence afferent input and the release of neuroactive chemicals in the dorsal horn of the spinal cord. Even when the peripheral irritation ceases, synaptic changes in the spinal cord can persist, causing "pain memory". Thus, irritation to the biliary tract can potentially sensitize the nervous system. In some, the central nervous system becomes so sensitive that *hyperalgesia* results: severe pain evoked by only mildly painful stimuli. Persistent central excitability might subsequently result in *allodynia*: innocuous stimuli produce pain [30, 31]. Thus, the basis for abnormally heightened biliary sensations can reside at any level: either altered receptor sensitivity of the viscus, increased excitability of the neurons in the spinal cord dorsal horn, and/or altered central modulation of sensation, including psychological influences that affect the interpretation of these sensations. Further, central hyperexcitability can effect changes in the dorsal horn.

Hence, a smooth muscle defect producing gallbladder hypomotility is intrinsic to cholesterol gallstone formation and disease [35, 36] and also occurs in chronic acalculous disease [37]. Both conditions yield biliary pain, creating a potentially confusing scenario. Evidence of microli‐ thiasis in the gallbladder bile in some patients with biliary dyskinesia [38] may merely indicate that excessive cholesterol, likely a stage of stone formation in which macroscopic gallstones were not evident, compromised signal transduction in the gallbladder and was the mechanism for reduced emptying. Certainly any bile crystals or sludge may eventually result in calculous disease, causing obstruction of the gallbladder and symptoms of biliary pain, but this must be distinguished from functional gallbladder disease. The mechanism for chronic cholecystitis is unclear [39], while cholesterolosis with its accumulation of lipid products (triglycerides and cholesterol precursors and esters) is likely too common to have any clinical importance as a

Biliary Dyspepsia: Functional Gallbladder and Sphincter of Oddi Disorders

http://dx.doi.org/10.5772/56779

115

Gallbladder dysmotility is also associated with other conditions including functional gastro‐ intestinal disorders, pregnancy, diabetes mellitus, obesity, cirrhosis [40], and the use of various medications (including atropine, morphine, octreotide, nifedipine, and progesterone) [41]. Interestingly, gut smooth muscle in the irritable bowel syndrome (IBS) also exhibits altered sensitivity to regulatory peptides such as CCK [42]. It is, therefore, not surprising that the

Although in sphincter of Oddi dysfunction, pain has classically been attributed to abnormal smooth muscle motility, there may also be a component of visceral hypersensitivity. Here, the hypersensitivity might arise in a structure adjacent to the sphincter, the duodenum [46, 47].

Despite biliary dyspepsia suggesting impaired digestion, there is no consistent relationship to eating. Historically, the abdominal discomfort and bloating that follow a heavy, fatty meal has been termed "fatty food" intolerance, connoting an association between fat content in the diet and biliary dyspepsia [48, 49, 59]. Patients with biliary dyspepsia may eat fewer meals, perhaps because their symptoms onset after eating [51]. In some, the sensation of fullness experienced relates to the amount of fat consumed. The presumed basis is fat releasing CCK and peptide YY, which are gut hormones important in regulating hunger and satiety. Patients with biliary dyspepsia, particularly those experiencing higher scores for nausea and pain, have higher concentrations of fasting and postprandial CCK compared to healthy individuals50. However, just as dyspepsia is not a particular manifestation of gallstone disease, fatty foods do not

Structural causes affecting the gastrointestinal tract should be considered in any patient presenting with dyspepsia (Table 2) [12]. Gallstones, biliary sludge and microlithiasis must be eliminated [12]. As decreased gallbladder emptying is a key investigation leading to the

gallbladder empties abnormally in some patients with IBS [43-45].

**3.3. Biliary dyspepsia and fatty food intolerance**

necessarily precipitate attacks of biliary colic [3, 52].

**4. Differential diagnoses**

cause of biliary pain [38].

Acalculous biliary pain may represent a generalised motor disorder of the duct: the irritable gallbladder/sphincter of Oddi10. The abnormalities identified by impaired gallbladder emptying or increased tone in the sphincter of Oddi, for example, may reflect a more gener‐ alised motility disorder of the gut [32]. Moreover, biliary-type pain could originate from a neighbouring structure: for example, abnormal small intestinal motility. Gut smooth muscle in functional gut disorders exhibits altered sensitivity to regulatory peptides such as CCK, precipitating abdominal pain in some patients and confounding the interpretation of intestinal versus biliary pain.

Functional biliary disorders have been most prominently linked to abnormal motility of the gallbladder and/or sphincter of Oddi, in part because techniques exist to detect them in clinical practice. Biliary pain is construed to result in most instances from increased gallbladder pressure from either abnormal gallbladder contraction ("dyskinesia") and/or structural or functional outlet obstruction either at the exit from the gallbladder (e.g.; abnormal cystic duct) or at the sphincter of Oddi ("the fighting gallbladder"). Reduced emptying and pain however may also reflect diminished gallbladder contractility ("hypokinesia"). Decreased gallbladder emptying has been attributed to abnormal CCK release, decreased gallbladder CCK receptor sensitivity or density, or increased cystic duct receptor sensitivity to CCK with impaired smooth-muscle contractility producing outlet obstruction [33].

Impaired gallbladder emptying, however, is also an important pathogenetic component in cholesterol gallstones. Cholesterol gallstone formation begins when the liver produces bile supersaturated with cholesterol, in excess of the solubilizing agents, bile salts and leci‐ thin. In this first stage, the liver secretes excess cholesterol into bile canaliculi that is accompanied by lecithin as small, unilamellar vesicles. These fuse in this supersaturated bile to become cholesterol-rich, multilamellar vesicles (liquid crystals). Aided by nucleat‐ ing factors (biliary proteins), cholesterol microcrystals precipitate out of solution. Mucin, a glycoprotein, secreted by the gallbladder mucosa, then acts as a matrix scaffold to retain these cholesterol microcrystals. Diminished gallbladder contractility facilitates retention, providing the residence time that is necessary for these microcrystals to agglomerate and grow into overt gallstones. Cholesterol constitutes the vast majority (>85%) of gallstones. A minority of gallstones are black pigment stones. These are composed of calcium bilirubinate polymers that result from abnormal bilirubin metabolism. Such black pig‐ ment stones tend to develop in advanced age, Crohn's disease, extensive ileal resection, cirrhosis, cystic fibrosis, and chronic hemolytic states [34].

Hence, a smooth muscle defect producing gallbladder hypomotility is intrinsic to cholesterol gallstone formation and disease [35, 36] and also occurs in chronic acalculous disease [37]. Both conditions yield biliary pain, creating a potentially confusing scenario. Evidence of microli‐ thiasis in the gallbladder bile in some patients with biliary dyskinesia [38] may merely indicate that excessive cholesterol, likely a stage of stone formation in which macroscopic gallstones were not evident, compromised signal transduction in the gallbladder and was the mechanism for reduced emptying. Certainly any bile crystals or sludge may eventually result in calculous disease, causing obstruction of the gallbladder and symptoms of biliary pain, but this must be distinguished from functional gallbladder disease. The mechanism for chronic cholecystitis is unclear [39], while cholesterolosis with its accumulation of lipid products (triglycerides and cholesterol precursors and esters) is likely too common to have any clinical importance as a cause of biliary pain [38].

Gallbladder dysmotility is also associated with other conditions including functional gastro‐ intestinal disorders, pregnancy, diabetes mellitus, obesity, cirrhosis [40], and the use of various medications (including atropine, morphine, octreotide, nifedipine, and progesterone) [41]. Interestingly, gut smooth muscle in the irritable bowel syndrome (IBS) also exhibits altered sensitivity to regulatory peptides such as CCK [42]. It is, therefore, not surprising that the gallbladder empties abnormally in some patients with IBS [43-45].

Although in sphincter of Oddi dysfunction, pain has classically been attributed to abnormal smooth muscle motility, there may also be a component of visceral hypersensitivity. Here, the hypersensitivity might arise in a structure adjacent to the sphincter, the duodenum [46, 47].

#### **3.3. Biliary dyspepsia and fatty food intolerance**

peripheral irritation ceases, synaptic changes in the spinal cord can persist, causing "pain memory". Thus, irritation to the biliary tract can potentially sensitize the nervous system. In some, the central nervous system becomes so sensitive that *hyperalgesia* results: severe pain evoked by only mildly painful stimuli. Persistent central excitability might subsequently result in *allodynia*: innocuous stimuli produce pain [30, 31]. Thus, the basis for abnormally heightened biliary sensations can reside at any level: either altered receptor sensitivity of the viscus, increased excitability of the neurons in the spinal cord dorsal horn, and/or altered central modulation of sensation, including psychological influences that affect the interpretation of these sensations. Further, central hyperexcitability can effect changes in the dorsal horn.

Acalculous biliary pain may represent a generalised motor disorder of the duct: the irritable gallbladder/sphincter of Oddi10. The abnormalities identified by impaired gallbladder emptying or increased tone in the sphincter of Oddi, for example, may reflect a more gener‐ alised motility disorder of the gut [32]. Moreover, biliary-type pain could originate from a neighbouring structure: for example, abnormal small intestinal motility. Gut smooth muscle in functional gut disorders exhibits altered sensitivity to regulatory peptides such as CCK, precipitating abdominal pain in some patients and confounding the interpretation of intestinal

Functional biliary disorders have been most prominently linked to abnormal motility of the gallbladder and/or sphincter of Oddi, in part because techniques exist to detect them in clinical practice. Biliary pain is construed to result in most instances from increased gallbladder pressure from either abnormal gallbladder contraction ("dyskinesia") and/or structural or functional outlet obstruction either at the exit from the gallbladder (e.g.; abnormal cystic duct) or at the sphincter of Oddi ("the fighting gallbladder"). Reduced emptying and pain however may also reflect diminished gallbladder contractility ("hypokinesia"). Decreased gallbladder emptying has been attributed to abnormal CCK release, decreased gallbladder CCK receptor sensitivity or density, or increased cystic duct receptor sensitivity to CCK with impaired

Impaired gallbladder emptying, however, is also an important pathogenetic component in cholesterol gallstones. Cholesterol gallstone formation begins when the liver produces bile supersaturated with cholesterol, in excess of the solubilizing agents, bile salts and leci‐ thin. In this first stage, the liver secretes excess cholesterol into bile canaliculi that is accompanied by lecithin as small, unilamellar vesicles. These fuse in this supersaturated bile to become cholesterol-rich, multilamellar vesicles (liquid crystals). Aided by nucleat‐ ing factors (biliary proteins), cholesterol microcrystals precipitate out of solution. Mucin, a glycoprotein, secreted by the gallbladder mucosa, then acts as a matrix scaffold to retain these cholesterol microcrystals. Diminished gallbladder contractility facilitates retention, providing the residence time that is necessary for these microcrystals to agglomerate and grow into overt gallstones. Cholesterol constitutes the vast majority (>85%) of gallstones. A minority of gallstones are black pigment stones. These are composed of calcium bilirubinate polymers that result from abnormal bilirubin metabolism. Such black pig‐ ment stones tend to develop in advanced age, Crohn's disease, extensive ileal resection,

smooth-muscle contractility producing outlet obstruction [33].

cirrhosis, cystic fibrosis, and chronic hemolytic states [34].

versus biliary pain.

114 Dyspepsia - Advances in Understanding and Management

Despite biliary dyspepsia suggesting impaired digestion, there is no consistent relationship to eating. Historically, the abdominal discomfort and bloating that follow a heavy, fatty meal has been termed "fatty food" intolerance, connoting an association between fat content in the diet and biliary dyspepsia [48, 49, 59]. Patients with biliary dyspepsia may eat fewer meals, perhaps because their symptoms onset after eating [51]. In some, the sensation of fullness experienced relates to the amount of fat consumed. The presumed basis is fat releasing CCK and peptide YY, which are gut hormones important in regulating hunger and satiety. Patients with biliary dyspepsia, particularly those experiencing higher scores for nausea and pain, have higher concentrations of fasting and postprandial CCK compared to healthy individuals50. However, just as dyspepsia is not a particular manifestation of gallstone disease, fatty foods do not necessarily precipitate attacks of biliary colic [3, 52].
