**4. Differential diagnoses**

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 diagnosis of a functional gallbladder disorder, other causes of impaired gallbladder emptying should be identified to obviate confounders (Table 3) [53].

**Primary gallbladder disease**

Pigment stones

Cholecystitis

**Metabolic disorders**

**Neuromuscular defects**

Myotonia dystrophic

Irritable bowel syndrome

Celiac disease, fasting/TPN

**5.1. Functional gallbladder disease**

**Table 3.** Causes of Impaired Gallbladder Emptying [52]

**Deficiency of cholecystokinin**

**Drugs**

**5. Diagnosis**

Cholesterol gallstones

following medical dissolution

Hemoglobinopathies

Acute or chronic, with or without stones

Denervation (spinal cord injury, vagotomy)

Obesity, diabetes, pregnancy, VIPoma, sickle hemoglobinopathy

**Functional gastrointestinal diseases: functional dyspepsia, functional abdominal pain**

A receptor antagonist, nitric oxide donors, female sex hormones (progestins)

Anticholinergic agents, calcium channel blockers, opioids, ursodeoxycholic acid, octreotide, cholecystokinin-

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117

The diagnosis of functional disorders of the gallbladder and sphincter of Oddi should be based on the Rome III criteria for functional gallbladder and sphincter of Oddi disorders (Table 1).

**1.** Preliminary investigations to rule out structural disease that might be the origin of the pain must include liver and pancreatic biochemistries and esophagogastroduodenoscopy. All should be normal in functional gallbladder disorder. The search for gallstones must be scrupulous. Transabdominal ultrasound is critical in being capable of detecting stones down to 3-5 mm in size. Endoscopic ultrasound (EUS) is more refined for microlithiasis: tiny stones < 3mm and biliary sludge [10]. Microscopic examination of gallbladder bile collected from the duodenum following IV CCK stimulation can detect deposits, either cholesterol as birefringent crystals (Figure 1) or pigment in the form of dark red-brown

Prior to stone formation as evidenced by microcrystals of cholesterol and

#### **Must include episodes of pain located in the epigastrium and/or right upper quadrant and all of the following:**


#### **Supportive criteria:**

The pain may present with 1 or more of the following:


**Table 1.** Rome III Diagnostic Criteria for Functional Gallbladder and Sphincter of Oddi Disorders [8]


**Table 2.** Organic Causes for Dyspepsia [12]

#### **Primary gallbladder disease**

diagnosis of a functional gallbladder disorder, other causes of impaired gallbladder emptying

**Must include episodes of pain located in the epigastrium and/or right upper quadrant and all of the following:**

should be identified to obviate confounders (Table 3) [53].

4. The pain is moderate to severe enough to interrupt the patient's daily activities or lead to

**Table 1.** Rome III Diagnostic Criteria for Functional Gallbladder and Sphincter of Oddi Disorders [8]

2. Recurrent symptoms occurring at different intervals (not daily)

8. Exclusion of other structural disease that would explain the symptoms

1. Episodes lasting 30 minutes or longer

116 Dyspepsia - Advances in Understanding and Management

3. The pain builds up to a steady level

5. The pain is not relieved by bowel movements 6. The pain is not relieved by postural change 7. The pain is not relieved by antacids

The pain may present with 1 or more of the following: 1. Pain is associated with nausea and vomiting

3. Pain awakens from sleep in the middle of the night

2. Pain radiates to the back and/or right infrasubscapular region

an emergency department visit

**Supportive criteria:**

**Gastrointestinal Disorders**

Gastric infections Gastroparesis

Pancreatitis

**Systemic Disorders** Adrenal insufficiency Diabetes mellitus Hyperparathyroidism Renal insufficiency Thyroid disease

Pancreatic neoplasms

Gastroesophageal reflux disease Gastric or esophageal cancer

Inflammatory bowel disease Irritable bowel syndrome Peptic ulcer disease Food intolerances Drug intolerances **Pancreaticobiliary Disorders**

Cholelithiasis, choledocholithiasis

**Table 2.** Organic Causes for Dyspepsia [12]

Cholesterol gallstones

Prior to stone formation as evidenced by microcrystals of cholesterol and

following medical dissolution

Pigment stones

Hemoglobinopathies

Cholecystitis

Acute or chronic, with or without stones

#### **Metabolic disorders**

Obesity, diabetes, pregnancy, VIPoma, sickle hemoglobinopathy

#### **Neuromuscular defects**

Myotonia dystrophic

Denervation (spinal cord injury, vagotomy)

**Functional gastrointestinal diseases: functional dyspepsia, functional abdominal pain**

Irritable bowel syndrome

#### **Deficiency of cholecystokinin**

Celiac disease, fasting/TPN

#### **Drugs**

Anticholinergic agents, calcium channel blockers, opioids, ursodeoxycholic acid, octreotide, cholecystokinin-A receptor antagonist, nitric oxide donors, female sex hormones (progestins)

**Table 3.** Causes of Impaired Gallbladder Emptying [52]

#### **5. Diagnosis**

The diagnosis of functional disorders of the gallbladder and sphincter of Oddi should be based on the Rome III criteria for functional gallbladder and sphincter of Oddi disorders (Table 1).

#### **5.1. Functional gallbladder disease**

**1.** Preliminary investigations to rule out structural disease that might be the origin of the pain must include liver and pancreatic biochemistries and esophagogastroduodenoscopy. All should be normal in functional gallbladder disorder. The search for gallstones must be scrupulous. Transabdominal ultrasound is critical in being capable of detecting stones down to 3-5 mm in size. Endoscopic ultrasound (EUS) is more refined for microlithiasis: tiny stones < 3mm and biliary sludge [10]. Microscopic examination of gallbladder bile collected from the duodenum following IV CCK stimulation can detect deposits, either cholesterol as birefringent crystals (Figure 1) or pigment in the form of dark red-brown calcium bilirubinate. Both techniques are fairly specific (in the order of 90%). Detection of microlithiasis by EUS however is more sensitive (96% versus 67%) than microscopic bile examination [54, 55], and also more available in most centres. Regardless, the use of these investigations in biliary dyskinesia is limited by their invasive nature.

Figure 1. Cholesterol<\$%&?>microcrystals<\$%&?>in<\$%&?>aspirated<\$%&?>duodenal<\$%&?>bile<\$%&?>following<\$%&?>CCK<\$%&?>stimulati on.<\$%&?>The<\$%&?>collected<\$%&?>golden<\$%&?>brown<\$%&?>duodenal<\$%&?>bile<\$%&?>is<\$%&?>first<\$%&?>centrifuged<\$%&?>and<\$ %&?>then<\$%&?>examined<\$%&?>under<\$%&?>polarizing<\$%&?>microscopy.<\$%&?>As<\$%&?>seen<\$%&?>here,<\$%&?>cholesterol<\$%&?>is<\$

cholescintigraphy<\$%&?>is<\$%&?>currently<\$%&?>the<\$%&?>key<\$%&?>to<\$%&?>diagnosing<\$%&?>functional<\$%&?>gallblad der<\$%&?>disorder.<\$%&?>The<\$%&?>gallbladder<\$%&?>ejection<\$%&?>fraction<\$%&?>(GBEF)<\$%&?>is<\$%&?>best<\$%&?>m easured<\$%&?>via<\$%&?>a<\$%&?>nuclear<\$%&?>medicine<\$%&?>hepatobiliary<\$%&?>scan.<\$%&?>The<\$%&?>radiopharmace

labelled<\$%&?>iminodiacetic<\$%&?>acid<\$%&?>(HIDA),<\$%&?>when<\$%&?>infused<\$%&?>intravenously,<\$%&?>is<\$%&?>rea dily<\$%&?>taken<\$%&?>up<\$%&?>by<\$%&?>hepatocytes,<\$%&?>excreted<\$%&?>into<\$%&?>the<\$%&?>bile,<\$%&?>and<\$%&?> accumulates<\$%&?>in<\$%&?>the<\$%&?>gallbladder<\$%&?>[37,<\$%&?>56,<\$%&?>57]<\$%&?>.<\$%&?>Infusion<\$%&?>of<\$%&?>t

8),<\$%&?>then<\$%&?>initiates<\$%&?>gallbladder<\$%&?>evacuation<\$%&?>(Figure<\$%&?>2).<\$%&?>There<\$%&?>has<\$%&?>be en<\$%&?>a<\$%&?>wide<\$%&?>variation<\$%&?>in<\$%&?>methodology,<\$%&?>leading<\$%&?>to<\$%&?>a<\$%&?>consensus<\$% &?>recommendation:<\$%&?>Sincalide™<\$%&?>should<\$%&?>be<\$%&?>infused<\$%&?>at<\$%&?>0.02μg/kg<\$%&?>over<\$%&?>6 0<\$%&?>minutes.<\$%&?>Normal<\$%&?>gallbladder<\$%&?>ejection<\$%&?>fraction<\$%&?>should<\$%&?>be<\$%&?>≥<\$%&?>38% ,<\$%&?>according<\$%&?>to<\$%&?>a<\$%&?>recent<\$%&?>consensus<\$%&?>conference<\$%&?>[58].<\$%&?>In<\$%&?>selected<\$ %&?>cases<\$%&?>of<\$%&?>recurrent<\$%&?>biliary<\$%&?>pain<\$%&?>in<\$%&?>which<\$%&?>no<\$%&?>structural<\$%&?>caus e<\$%&?>is<\$%&?>evident,<\$%&?>no<\$%&?>stone<\$%&?>disease<\$%&?>is<\$%&?>apparent<\$%&?>and<\$%&?>there<\$%&?>exist s<\$%&?>no<\$%&?>other<\$%&?>associated<\$%&?>cause<\$%&?>for<\$%&?>impaired<\$%&?>gallbladder<\$%&?>emptying,<\$%&?> cholecystectomy<\$%&?>is<\$%&?>a<\$%&?>reasonable<\$%&?>consideration<\$%&?>when<\$%&?>the<\$%&?>gallbladder<\$%&?>eje

Biliary Dyspepsia: Functional Gallbladder and Sphincter of Oddi Disorders

(a)

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(b)

cholescintigraphy.<\$%&?>The<\$%&?>gallbladder<\$%&?>is<\$%&?>visualized<\$%&?>30<\$%&?>minutes<\$%&?>after<\$%&?>the<\$%&?>injection<\$

labelled<\$%&?>technetium<\$%&?>iminodiacetic<\$%&?>acid<\$%&?>radiopharmaceutical<\$%&?>(HIDA<\$%&?>scan).<\$%&?>Cholecystokinin<\$% &?>is<\$%&?>then<\$%&?>infused<\$%&?>(shown<\$%&?>as<\$%&?>arrow).<\$%&?>Prompt<\$%&?>gallbladder<\$%&?>emptying<\$%&?>(70%<\$%&? >here)<\$%&?>then<\$%&?>ensues<\$%&?>with<\$%&?>the<\$%&?>radiolabel<\$%&?>ejected<\$%&?>into<\$%&?>the<\$%&?>small<\$%&?>intestine.<\$ %&?>The<\$%&?>gallbladder<\$%&?>is<\$%&?>depicted<\$%&?>as<\$%&?>GB,<\$%&?>before<\$%&?>and<\$%&?>after<\$%&?>the<\$%&?>CCK<\$%&? >infusion.<\$%&?>[52],<\$%&?>B.<\$%&?>Abnormal<\$%&?>gallbladder<\$%&?>emptying.<\$%&?>Although<\$%&?>the<\$%&?>gallbladder<\$%&?>fill s,<\$%&?>becoming<\$%&?>well<\$%&?>visualized<\$%&?>at<\$%&?>30<\$%&?>minutes,<\$%&?>the<\$%&?>CCK<\$%&?>infusion<\$%&?>(arrow)<\$% &?>has<\$%&?>little<\$%&?>effect<\$%&?>thirty<\$%&?>minutes<\$%&?>later<\$%&?>at<\$%&?>60<\$%&?>minutes<\$%&?>into<\$%&?>the<\$%&?>stud y<\$%&?>or<\$%&?>even<\$%&?>with<\$%&?>an<\$%&?>additional<\$%&?>thirty<\$%&?>minutes<\$%&?>at<\$%&?>90<\$%&?>minutes.<\$%&?>The<\$

cholescintigraphy<\$%&?>in<\$%&?>those<\$%&?>with<\$%&?>established<\$%&?>yet<\$%&?>uncomplicated<\$%&?>('silent")<\$%&? >gallstones.<\$%&?>The<\$%&?>influence<\$%&?>of<\$%&?>gallbladder<\$%&?>evacuation<\$%&?>on<\$%&?>the<\$%&?>developme nt<\$%&?>of<\$%&?>biliary<\$%&?>symptoms<\$%&?>and<\$%&?>on<\$%&?>the<\$%&?>severity<\$%&?>of<\$%&?>disease<\$%&?>re mains<\$%&?>unclear<\$%&?>[56].<\$%&?>The<\$%&?>sluggish<\$%&?>gallbladder<\$%&?>does<\$%&?>not<\$%&?>protect<\$%&?>an

shaped<\$%&?>crystals,<\$%&?>characteristically<\$%&?>with<\$%&?>a<\$%&?>notch<\$%&?>in<\$%&?>one<\$%&?>corner.

2. Assessment<\$%&?>of<\$%&?>gallbladder<\$%&?>emptying<\$%&?>by<\$%&?>cholecystokinin-

he<\$%&?>CCK<\$%&?>analogue,<\$%&?>Sincalide™<\$%&?>(the<\$%&?>8-amino<\$%&?>acid<\$%&?>C-

ction<\$%&?>fraction<\$%&?>is<\$%&?>reduced<\$%&?>at<\$%&?>less<\$%&?>than<\$%&?>35-40%<\$%&?>[59].

terminal<\$%&?>fragment<\$%&?>of<\$%&?>cholecystokinin,<\$%&?>CCK-

Figure 2. A.<\$%&?>Normal<\$%&?>gallbladder<\$%&?>emptying<\$%&?>on<\$%&?>CCK-

gallbladder does not protect an individual with stones from developing pain.

gastroparesis often accompanies functional gastrointestinal disorders [58].

**Figure 2.** A. Normal gallbladder emptying on CCK-cholescintigraphy. The gallbladder is visualized 30 minutes after the injection of the 99m-labelled technetium iminodiacetic acid radiopharmaceutical (HIDA scan). Cholecystokinin is then infused (shown as arrow). Prompt gallbladder emptying (70% here) then ensues with the radiolabel ejected into the small intestine. The gallbladder is depicted as GB, before and after the CCK infusion. [52], B. Abnormal gallbladder emptying. Although the gallbladder fills, becoming well visualized at 30 minutes, the CCK infusion (arrow) has little effect thirty minutes later at 60 minutes into the study or even with an additional thirty minutes at 90 minutes. The

There is as yet no predictive value for CCK-cholescintigraphy in those with established yet uncomplicated ('silent") gallstones. The influence of gallbladder evacuation on the develop‐ ment of biliary symptoms and on the severity of disease remains unclear [56]. The sluggish

%&?>liver<\$%&?>washes<\$%&?>out<\$%&?>during<\$%&?>this<\$%&?>period<\$%&?>of<\$%&?>time.<\$%&?>[52]

There<\$%&?>is<\$%&?>as<\$%&?>yet<\$%&?>no<\$%&?>predictive<\$%&?>value<\$%&?>for<\$%&?>CCK-

<\$%&?>individual<\$%&?>with<\$%&?>stones<\$%&?>from<\$%&?>developing<\$%&?>pain.

Real-time ultrasound has also been used to measure volume changes as the gallbladder empties. Its advantage over a nuclear medicine scan obviates exposing the patient to ionizing radiation. Quantitative ultrasonography, based on geometric assumptions, however is operator-dependent, limiting its accuracy. Although 3-dimensional and 4-dimensional ultrasounds appear to correlate reasonably well with HIDA scans in identifying reduced gallbladder ejection fractions [60], CCK-cholescintigraphy is more precise and remains the

The CCK-provocation test aimed to reproduce the biliary pain following an infusion of CCK, implicating the gallbladder as the culprit. This test has fallen out of favor due to lack of objectivity and specificity for biliary dyskinesia [42, 61]. Rapid infusion of CCK can elicit

The algorithm for diagnosing and managing functional gallbladder disorder is outlined in

The use of a fatty meal to stimulate gallbladder contraction may be more physiological and cheaper than CCK but does not enjoy an established protocol with normal values. Another limitation is that endogenous CCK release depends upon gastric emptying of the meal;

%&?>of<\$%&?>the<\$%&?>99m-

liver washes out during this period of time. [52]

standard [56, 58, 60].

Figure 3 [8].

abdominal pain even in normal individuals [10].

%&?>evident<\$%&?>as<\$%&?>birefringent,<\$%&?>rhomboid-

utical,<\$%&?>technetium<\$%&?>99m-

**Figure 1.** Cholesterol microcrystals in aspirated duodenal bile following CCK stimulation. The collected golden brown duodenal bile is first centrifuged and then examined under polarizing microscopy. As seen here, cholesterol is evident as birefringent, rhomboid-shaped crystals, characteristically with a notch in one corner.

**2.** Assessment of gallbladder emptying by cholecystokinin-cholescintigraphy is currently the key to diagnosing functional gallbladder disorder. The gallbladder ejection fraction (GBEF) is best measured via a nuclear medicine hepatobiliary scan. The radiopharma‐ ceutical, technetium 99m-labelled iminodiacetic acid (HIDA), when infused intravenous‐ ly, is readily taken up by hepatocytes, excreted into the bile, and accumulates in the gallbladder [37, 56, 57]. Infusion of the CCK analogue, Sincalide™ (the 8-amino acid Cterminal fragment of cholecystokinin, CCK-8), then initiates gallbladder evacuation (Figure 2). There has been a wide variation in methodology, leading to a consensus recommendation: Sincalide™ should be infused at 0.02μg/kg over 60 minutes. Normal gallbladder ejection fraction should be ≥ 38%, according to a recent consensus conference [58]. In selected cases of recurrent biliary pain in which no structural cause is evident, no stone disease is apparent and there exists no other associated cause for impaired gall‐ bladder emptying, cholecystectomy is a reasonable consideration when the gallbladder ejection fraction is reduced at less than 35-40% [59].

Figure 1. Cholesterol<\$%&?>microcrystals<\$%&?>in<\$%&?>aspirated<\$%&?>duodenal<\$%&?>bile<\$%&?>following<\$%&?>CCK<\$%&?>stimulati on.<\$%&?>The<\$%&?>collected<\$%&?>golden<\$%&?>brown<\$%&?>duodenal<\$%&?>bile<\$%&?>is<\$%&?>first<\$%&?>centrifuged<\$%&?>and<\$ %&?>then<\$%&?>examined<\$%&?>under<\$%&?>polarizing<\$%&?>microscopy.<\$%&?>As<\$%&?>seen<\$%&?>here,<\$%&?>cholesterol<\$%&?>is<\$

cholescintigraphy<\$%&?>is<\$%&?>currently<\$%&?>the<\$%&?>key<\$%&?>to<\$%&?>diagnosing<\$%&?>functional<\$%&?>gallblad der<\$%&?>disorder.<\$%&?>The<\$%&?>gallbladder<\$%&?>ejection<\$%&?>fraction<\$%&?>(GBEF)<\$%&?>is<\$%&?>best<\$%&?>m easured<\$%&?>via<\$%&?>a<\$%&?>nuclear<\$%&?>medicine<\$%&?>hepatobiliary<\$%&?>scan.<\$%&?>The<\$%&?>radiopharmace

labelled<\$%&?>iminodiacetic<\$%&?>acid<\$%&?>(HIDA),<\$%&?>when<\$%&?>infused<\$%&?>intravenously,<\$%&?>is<\$%&?>rea dily<\$%&?>taken<\$%&?>up<\$%&?>by<\$%&?>hepatocytes,<\$%&?>excreted<\$%&?>into<\$%&?>the<\$%&?>bile,<\$%&?>and<\$%&?> accumulates<\$%&?>in<\$%&?>the<\$%&?>gallbladder<\$%&?>[37,<\$%&?>56,<\$%&?>57]<\$%&?>.<\$%&?>Infusion<\$%&?>of<\$%&?>t

8),<\$%&?>then<\$%&?>initiates<\$%&?>gallbladder<\$%&?>evacuation<\$%&?>(Figure<\$%&?>2).<\$%&?>There<\$%&?>has<\$%&?>be en<\$%&?>a<\$%&?>wide<\$%&?>variation<\$%&?>in<\$%&?>methodology,<\$%&?>leading<\$%&?>to<\$%&?>a<\$%&?>consensus<\$% &?>recommendation:<\$%&?>Sincalide™<\$%&?>should<\$%&?>be<\$%&?>infused<\$%&?>at<\$%&?>0.02μg/kg<\$%&?>over<\$%&?>6 0<\$%&?>minutes.<\$%&?>Normal<\$%&?>gallbladder<\$%&?>ejection<\$%&?>fraction<\$%&?>should<\$%&?>be<\$%&?>≥<\$%&?>38% ,<\$%&?>according<\$%&?>to<\$%&?>a<\$%&?>recent<\$%&?>consensus<\$%&?>conference<\$%&?>[58].<\$%&?>In<\$%&?>selected<\$ %&?>cases<\$%&?>of<\$%&?>recurrent<\$%&?>biliary<\$%&?>pain<\$%&?>in<\$%&?>which<\$%&?>no<\$%&?>structural<\$%&?>caus

cholecystectomy<\$%&?>is<\$%&?>a<\$%&?>reasonable<\$%&?>consideration<\$%&?>when<\$%&?>the<\$%&?>gallbladder<\$%&?>eje

>infusion.<\$%&?>[52],<\$%&?>B.<\$%&?>Abnormal<\$%&?>gallbladder<\$%&?>emptying.<\$%&?>Although<\$%&?>the<\$%&?>gallbladder<\$%&?>fill

shaped<\$%&?>crystals,<\$%&?>characteristically<\$%&?>with<\$%&?>a<\$%&?>notch<\$%&?>in<\$%&?>one<\$%&?>corner.

2. Assessment<\$%&?>of<\$%&?>gallbladder<\$%&?>emptying<\$%&?>by<\$%&?>cholecystokinin-

he<\$%&?>CCK<\$%&?>analogue,<\$%&?>Sincalide™<\$%&?>(the<\$%&?>8-amino<\$%&?>acid<\$%&?>C-

ction<\$%&?>fraction<\$%&?>is<\$%&?>reduced<\$%&?>at<\$%&?>less<\$%&?>than<\$%&?>35-40%<\$%&?>[59].

terminal<\$%&?>fragment<\$%&?>of<\$%&?>cholecystokinin,<\$%&?>CCK-

%&?>evident<\$%&?>as<\$%&?>birefringent,<\$%&?>rhomboid-

utical,<\$%&?>technetium<\$%&?>99m-

calcium bilirubinate. Both techniques are fairly specific (in the order of 90%). Detection of microlithiasis by EUS however is more sensitive (96% versus 67%) than microscopic bile examination [54, 55], and also more available in most centres. Regardless, the use of these

**Figure 1.** Cholesterol microcrystals in aspirated duodenal bile following CCK stimulation. The collected golden brown duodenal bile is first centrifuged and then examined under polarizing microscopy. As seen here, cholesterol is evident

**2.** Assessment of gallbladder emptying by cholecystokinin-cholescintigraphy is currently the key to diagnosing functional gallbladder disorder. The gallbladder ejection fraction (GBEF) is best measured via a nuclear medicine hepatobiliary scan. The radiopharma‐ ceutical, technetium 99m-labelled iminodiacetic acid (HIDA), when infused intravenous‐ ly, is readily taken up by hepatocytes, excreted into the bile, and accumulates in the gallbladder [37, 56, 57]. Infusion of the CCK analogue, Sincalide™ (the 8-amino acid Cterminal fragment of cholecystokinin, CCK-8), then initiates gallbladder evacuation (Figure 2). There has been a wide variation in methodology, leading to a consensus recommendation: Sincalide™ should be infused at 0.02μg/kg over 60 minutes. Normal gallbladder ejection fraction should be ≥ 38%, according to a recent consensus conference [58]. In selected cases of recurrent biliary pain in which no structural cause is evident, no stone disease is apparent and there exists no other associated cause for impaired gall‐ bladder emptying, cholecystectomy is a reasonable consideration when the gallbladder

as birefringent, rhomboid-shaped crystals, characteristically with a notch in one corner.

ejection fraction is reduced at less than 35-40% [59].

investigations in biliary dyskinesia is limited by their invasive nature.

118 Dyspepsia - Advances in Understanding and Management

Figure 2. A.<\$%&?>Normal<\$%&?>gallbladder<\$%&?>emptying<\$%&?>on<\$%&?>CCKcholescintigraphy.<\$%&?>The<\$%&?>gallbladder<\$%&?>is<\$%&?>visualized<\$%&?>30<\$%&?>minutes<\$%&?>after<\$%&?>the<\$%&?>injection<\$ %&?>of<\$%&?>the<\$%&?>99mlabelled<\$%&?>technetium<\$%&?>iminodiacetic<\$%&?>acid<\$%&?>radiopharmaceutical<\$%&?>(HIDA<\$%&?>scan).<\$%&?>Cholecystokinin<\$% &?>is<\$%&?>then<\$%&?>infused<\$%&?>(shown<\$%&?>as<\$%&?>arrow).<\$%&?>Prompt<\$%&?>gallbladder<\$%&?>emptying<\$%&?>(70%<\$%&? >here)<\$%&?>then<\$%&?>ensues<\$%&?>with<\$%&?>the<\$%&?>radiolabel<\$%&?>ejected<\$%&?>into<\$%&?>the<\$%&?>small<\$%&?>intestine.<\$ %&?>The<\$%&?>gallbladder<\$%&?>is<\$%&?>depicted<\$%&?>as<\$%&?>GB,<\$%&?>before<\$%&?>and<\$%&?>after<\$%&?>the<\$%&?>CCK<\$%&? **Figure 2.** A. Normal gallbladder emptying on CCK-cholescintigraphy. The gallbladder is visualized 30 minutes after the injection of the 99m-labelled technetium iminodiacetic acid radiopharmaceutical (HIDA scan). Cholecystokinin is then infused (shown as arrow). Prompt gallbladder emptying (70% here) then ensues with the radiolabel ejected into the small intestine. The gallbladder is depicted as GB, before and after the CCK infusion. [52], B. Abnormal gallbladder emptying. Although the gallbladder fills, becoming well visualized at 30 minutes, the CCK infusion (arrow) has little effect thirty minutes later at 60 minutes into the study or even with an additional thirty minutes at 90 minutes. The liver washes out during this period of time. [52]

s,<\$%&?>becoming<\$%&?>well<\$%&?>visualized<\$%&?>at<\$%&?>30<\$%&?>minutes,<\$%&?>the<\$%&?>CCK<\$%&?>infusion<\$%&?>(arrow)<\$% &?>has<\$%&?>little<\$%&?>effect<\$%&?>thirty<\$%&?>minutes<\$%&?>later<\$%&?>at<\$%&?>60<\$%&?>minutes<\$%&?>into<\$%&?>the<\$%&?>stud y<\$%&?>or<\$%&?>even<\$%&?>with<\$%&?>an<\$%&?>additional<\$%&?>thirty<\$%&?>minutes<\$%&?>at<\$%&?>90<\$%&?>minutes.<\$%&?>The<\$ %&?>liver<\$%&?>washes<\$%&?>out<\$%&?>during<\$%&?>this<\$%&?>period<\$%&?>of<\$%&?>time.<\$%&?>[52] There<\$%&?>is<\$%&?>as<\$%&?>yet<\$%&?>no<\$%&?>predictive<\$%&?>value<\$%&?>for<\$%&?>CCK-There is as yet no predictive value for CCK-cholescintigraphy in those with established yet uncomplicated ('silent") gallstones. The influence of gallbladder evacuation on the develop‐ ment of biliary symptoms and on the severity of disease remains unclear [56]. The sluggish gallbladder does not protect an individual with stones from developing pain.

cholescintigraphy<\$%&?>in<\$%&?>those<\$%&?>with<\$%&?>established<\$%&?>yet<\$%&?>uncomplicated<\$%&?>('silent")<\$%&? >gallstones.<\$%&?>The<\$%&?>influence<\$%&?>of<\$%&?>gallbladder<\$%&?>evacuation<\$%&?>on<\$%&?>the<\$%&?>developme nt<\$%&?>of<\$%&?>biliary<\$%&?>symptoms<\$%&?>and<\$%&?>on<\$%&?>the<\$%&?>severity<\$%&?>of<\$%&?>disease<\$%&?>re mains<\$%&?>unclear<\$%&?>[56].<\$%&?>The<\$%&?>sluggish<\$%&?>gallbladder<\$%&?>does<\$%&?>not<\$%&?>protect<\$%&?>an <\$%&?>individual<\$%&?>with<\$%&?>stones<\$%&?>from<\$%&?>developing<\$%&?>pain. The use of a fatty meal to stimulate gallbladder contraction may be more physiological and cheaper than CCK but does not enjoy an established protocol with normal values. Another limitation is that endogenous CCK release depends upon gastric emptying of the meal; gastroparesis often accompanies functional gastrointestinal disorders [58].

Real-time ultrasound has also been used to measure volume changes as the gallbladder empties. Its advantage over a nuclear medicine scan obviates exposing the patient to ionizing radiation. Quantitative ultrasonography, based on geometric assumptions, however is operator-dependent, limiting its accuracy. Although 3-dimensional and 4-dimensional ultrasounds appear to correlate reasonably well with HIDA scans in identifying reduced gallbladder ejection fractions [60], CCK-cholescintigraphy is more precise and remains the standard [56, 58, 60].

The CCK-provocation test aimed to reproduce the biliary pain following an infusion of CCK, implicating the gallbladder as the culprit. This test has fallen out of favor due to lack of objectivity and specificity for biliary dyskinesia [42, 61]. Rapid infusion of CCK can elicit abdominal pain even in normal individuals [10].

The algorithm for diagnosing and managing functional gallbladder disorder is outlined in Figure 3 [8].

**Biliary type Type I:**

**Type II:**

**Type III:**

**Type I:**

**Type II:**

**Type III:**

Biliary type pain only Pancreatic type SOD

Pancreatic type pain

Pancreatic type pain only

Typical biliary type pain

Dilated CBD > 8 mm in diameter

Positive manometry for biliary SOD (seen in 65-95% of patients)

Dilated pancreatic duct (head > 6 mm, body > 5 mm)

Biliary type pain and one of the above criteria (laboratory or imaging)

Pancreatic type pain, and one of the above criteria (laboratory or imaging)

Liver enzymes (AST, ALT or ALP) > 2 times normal limit documented on at least 2 occasions during episodes of pain

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Amylase and/or lipase > 2 times upper normal limit on at least 2 occasions during episodes of pain

**Table 4.** Modified Milwaukee Classification of Sphincter of Oddi dysfunction [8, 61, 62, 64-66].

versus pancreatic sphincters or both (e.g.; occurring simultaneously).

**a.** Functional Biliary Sphincter of Oddi Disorder

one of either the laboratory or the imaging abnormalities.

causing structural outflow obstruction.

As in biliary dyspepsia due to gallbladder dysfunction, patients with suspected SOD should undergo evaluation with serum liver and pancreas biochemical tests, abdominal ultrasound, and esophagogastroduodenoscopy to rule out underlying structural disease as a cause for their abdominal symptoms. Consideration should also be given to magnetic resonance cholangio‐ pancreatography (MRCP) to eliminate structural lesions such as stones, strictures and tumors. Dysfunction potentially might affect either or both segments of the sphincter of Oddi: biliary

Type I manifest biliary pain; abnormal liver biochemistries (elevated aminotransferases, alkaline phosphatase and/or bilirubin) >2 times normal on two or more occasions; plus a dilated common bile duct > 8mm on abdominal ultrasound. Most will exhibit biliary SO dysfunction on formal manometry. They are considered to have stenosis of the sphincter

Type II patients with biliary sphincter dysfunction experience the biliary-type pain plus exhibit

**Figure 3.** Algorithm for the diagnostic workup and management for biliary dyspepsia due to functional gallbladder disorder [8]. Patients with biliary type abdominal pain should initially undergo non-invasive investigations including relevant laboratory work and an abdominal ultrasound. An endogastroduodenoscopy (EGD) should then be per‐ formed and if any structural abnormalities, should be treated by medical, endoscopic or surgical management. A gall‐ bladder cholecystokinin (GB CCK) cholescintigraphy can be subsequently performed. If there is abnormal ejection, EUS (endoscopic ultrasound) or bile microscopy can be used to further investigate for microlithiasis. Even in the absence of microlithiasis, if the ejection fraction is abnormal on GB CCK cholescintigraphy and no obvious confounding factor identified, consider referring the patient for a cholecystectomy.

#### **5.2. Functional Sphincter of Oddi Disorder (SOD)**

Sphincter of Oddi dysfunction implies that the basis is a motility disorder of the sphincter that intermittently results in pain, elevated liver and/or pancreatic enzymes, a dilated common duct and potentially pancreatitis. The Milwaukee classification originally categorizes SOD into three types, separating functional biliary and pancreatic sphincter of Oddi disorders on the basis of symptoms, laboratory tests and radiological imaging [8, 62-65] (Table 4). As these require an invasive procedure, endoscopic cholangiopancreatography (ERCP), to measure common duct size and biliary drainage, the criteria have been revised to use non-invasive imaging for estimating duct size of on an abdominal ultrasound [64].

#### **Biliary type**

#### **Type I:**

**Figure 3.** Algorithm for the diagnostic workup and management for biliary dyspepsia due to functional gallbladder disorder [8]. Patients with biliary type abdominal pain should initially undergo non-invasive investigations including relevant laboratory work and an abdominal ultrasound. An endogastroduodenoscopy (EGD) should then be per‐ formed and if any structural abnormalities, should be treated by medical, endoscopic or surgical management. A gall‐ bladder cholecystokinin (GB CCK) cholescintigraphy can be subsequently performed. If there is abnormal ejection, EUS (endoscopic ultrasound) or bile microscopy can be used to further investigate for microlithiasis. Even in the absence of microlithiasis, if the ejection fraction is abnormal on GB CCK cholescintigraphy and no obvious confounding factor

Sphincter of Oddi dysfunction implies that the basis is a motility disorder of the sphincter that intermittently results in pain, elevated liver and/or pancreatic enzymes, a dilated common duct and potentially pancreatitis. The Milwaukee classification originally categorizes SOD into three types, separating functional biliary and pancreatic sphincter of Oddi disorders on the basis of symptoms, laboratory tests and radiological imaging [8, 62-65] (Table 4). As these require an invasive procedure, endoscopic cholangiopancreatography (ERCP), to measure common duct size and biliary drainage, the criteria have been revised to use non-invasive

identified, consider referring the patient for a cholecystectomy.

120 Dyspepsia - Advances in Understanding and Management

**5.2. Functional Sphincter of Oddi Disorder (SOD)**

imaging for estimating duct size of on an abdominal ultrasound [64].

Typical biliary type pain

Liver enzymes (AST, ALT or ALP) > 2 times normal limit documented on at least 2 occasions during episodes of pain Dilated CBD > 8 mm in diameter

Positive manometry for biliary SOD (seen in 65-95% of patients)


**Table 4.** Modified Milwaukee Classification of Sphincter of Oddi dysfunction [8, 61, 62, 64-66].

As in biliary dyspepsia due to gallbladder dysfunction, patients with suspected SOD should undergo evaluation with serum liver and pancreas biochemical tests, abdominal ultrasound, and esophagogastroduodenoscopy to rule out underlying structural disease as a cause for their abdominal symptoms. Consideration should also be given to magnetic resonance cholangio‐ pancreatography (MRCP) to eliminate structural lesions such as stones, strictures and tumors. Dysfunction potentially might affect either or both segments of the sphincter of Oddi: biliary versus pancreatic sphincters or both (e.g.; occurring simultaneously).

**a.** Functional Biliary Sphincter of Oddi Disorder

Type I manifest biliary pain; abnormal liver biochemistries (elevated aminotransferases, alkaline phosphatase and/or bilirubin) >2 times normal on two or more occasions; plus a dilated common bile duct > 8mm on abdominal ultrasound. Most will exhibit biliary SO dysfunction on formal manometry. They are considered to have stenosis of the sphincter causing structural outflow obstruction.

Type II patients with biliary sphincter dysfunction experience the biliary-type pain plus exhibit one of either the laboratory or the imaging abnormalities.

Type III patients only complain of the pain. There are no laboratory or imaging abnormalities

**b.** Functional Pancreatic Sphincter of Oddi Disorder [65, 66]

Pancreatic-type SOD encompasses patients with pancreatic-type pain, elevated serum amylase or lipase plus pancreatic duct dilation.

Type I has pain, lipase elevation and pancreatic duct dilation

Type II has pain plus either lipase elevation or pancreatic duct dilation.

Type III has only pancreatic-type pain.

Investigations

**1.** ERCP Manometry.

The "gold" standard to diagnose SOD is sphincter of Oddi manometry. This entails endoscopic retrograde cholangiopancreatography (ERCP) allowing passage of a manometric catheter through the duct and measurement of basal sphincter pressures on slow withdrawal of the catheter. A basal sphincter pressure of greater than or equal to 40 mmHg is used to diagnose SOD [67]. Manometry is abnormal in 65-100% with type I, 50-65% with type II, and falls to 12-60% of biliary type III SOD patients [65, 67, 68]. Positive manometric findings, based on type, are similar in both types of sphincter dysfunction. The distinction between types I, II, and III SOD, however, is important as it may predict a favorable response to endoscopic sphincterotomy and thus, guide further management. The algorithm for diagnosing and treating functional biliary sphincter of Oddi dysfunction is outlined in Figure 4.

**2.** Non-invasive Methods

Additional non-invasive methods for diagnosing SOD have been studied, given the inherent risk of complications in sphincter of Oddi manometry, particularly precipitating pancreatitis, and the generally poor outcomes especially in patients with biliary type III SOD [69].

**a.** Ultrasonographic measurement of duct diameter

The common bile duct normally has a diameter of 6mm or less in healthy individuals whose gallbladders are intact. Above 8mm indicates biliary obstruction. This value becomes some‐ what obscure following cholecystectomy, a situation in which dilation occurs to 10mm even in those without symptoms [70]. Adding a fatty meal to release CCK seeks to show duct dilation to indicate SO dysfunction but its diagnostic usefulness is limited.

**c.** Endosonography

imaging studies) have any pathology at EUS [74].

**d.** Hepatobiliary scintigraphy [10]

native medical therapies can be attempted.

Endoscopic ultrasound (EUS) generally has a low yield in diagnosing abnormalities in the context of a normal upper endoscopy and imaging studies in patients with SOD Type III [72, 74]. Only 8% of patients with suspected SOD Type III (normal endoscopy and standard

**Figure 4.** Algorithm for the diagnostic workup and management of sphincter of Oddi disorder (SOD) [8] Patients with biliary type pain should initially undergo non-invasive investigations including relevant laboratory work and an ab‐ dominal ultrasound. An endogastroduodenoscopy (EGD), endoscopic ultrasound (EUS) and a magnetic resonance cholangiopancreatography (MRCP) should then be performed. Any structural abnormalities detected should be treat‐ ed by medical, endoscopic or surgical management. SOD should be classified as Type I, Type II and Type III according to the Milwaukee classification described in the text,. Patients with Type I disease will benefit from an endoscopic sphincterotomy (ES). Otherwise first line management should be medical. If there is no response, an ERCP with sphinc‐ ter of Oddi manometry (SO manometry) can be performed. If manometry is abnormal, ES is indicated. If normal, alter‐

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Nuclear medicine scanning of the biliary tract (choledochoscintigraphy) uses 99mTc HIDA as the radiopharmaceutical to measure biliary emptying: the transit time from the liver to the duodenum. Prolonged duodenal arrival reflects SO dysfunction [75]. Specificity approaches 90% but reported sensitivities are variable [76]. Although lacking controlled studies, choledo‐

**b.** Magnetic resonance pancreatography (MRCP)

Administration of the hormone secretin increases pancreatic exocrine secretion [71]. In suspected SOD involving the pancreas, secretin improves MRCP visualization of the pancre‐ atic ducts to eliminate structural disease and elicits duct dilation [72]. Overall, secretinstimulated magnetic resonance cholangiopancreatography (ss-MRCP) is not sensitive in predicting abnormal manometry results in patients with suspected SOD type III, though somewhat accurate in predicting results in patients with SOD type II (73%) [73].

**Figure 4.** Algorithm for the diagnostic workup and management of sphincter of Oddi disorder (SOD) [8] Patients with biliary type pain should initially undergo non-invasive investigations including relevant laboratory work and an ab‐ dominal ultrasound. An endogastroduodenoscopy (EGD), endoscopic ultrasound (EUS) and a magnetic resonance cholangiopancreatography (MRCP) should then be performed. Any structural abnormalities detected should be treat‐ ed by medical, endoscopic or surgical management. SOD should be classified as Type I, Type II and Type III according to the Milwaukee classification described in the text,. Patients with Type I disease will benefit from an endoscopic sphincterotomy (ES). Otherwise first line management should be medical. If there is no response, an ERCP with sphinc‐ ter of Oddi manometry (SO manometry) can be performed. If manometry is abnormal, ES is indicated. If normal, alter‐ native medical therapies can be attempted.

#### **c.** Endosonography

Type III patients only complain of the pain. There are no laboratory or imaging abnormalities

Pancreatic-type SOD encompasses patients with pancreatic-type pain, elevated serum amylase

The "gold" standard to diagnose SOD is sphincter of Oddi manometry. This entails endoscopic retrograde cholangiopancreatography (ERCP) allowing passage of a manometric catheter through the duct and measurement of basal sphincter pressures on slow withdrawal of the catheter. A basal sphincter pressure of greater than or equal to 40 mmHg is used to diagnose SOD [67]. Manometry is abnormal in 65-100% with type I, 50-65% with type II, and falls to 12-60% of biliary type III SOD patients [65, 67, 68]. Positive manometric findings, based on type, are similar in both types of sphincter dysfunction. The distinction between types I, II, and III SOD, however, is important as it may predict a favorable response to endoscopic sphincterotomy and thus, guide further management. The algorithm for diagnosing and

Additional non-invasive methods for diagnosing SOD have been studied, given the inherent risk of complications in sphincter of Oddi manometry, particularly precipitating pancreatitis,

The common bile duct normally has a diameter of 6mm or less in healthy individuals whose gallbladders are intact. Above 8mm indicates biliary obstruction. This value becomes some‐ what obscure following cholecystectomy, a situation in which dilation occurs to 10mm even in those without symptoms [70]. Adding a fatty meal to release CCK seeks to show duct dilation

Administration of the hormone secretin increases pancreatic exocrine secretion [71]. In suspected SOD involving the pancreas, secretin improves MRCP visualization of the pancre‐ atic ducts to eliminate structural disease and elicits duct dilation [72]. Overall, secretinstimulated magnetic resonance cholangiopancreatography (ss-MRCP) is not sensitive in predicting abnormal manometry results in patients with suspected SOD type III, though

somewhat accurate in predicting results in patients with SOD type II (73%) [73].

and the generally poor outcomes especially in patients with biliary type III SOD [69].

treating functional biliary sphincter of Oddi dysfunction is outlined in Figure 4.

**b.** Functional Pancreatic Sphincter of Oddi Disorder [65, 66]

Type I has pain, lipase elevation and pancreatic duct dilation

Type II has pain plus either lipase elevation or pancreatic duct dilation.

or lipase plus pancreatic duct dilation.

122 Dyspepsia - Advances in Understanding and Management

Type III has only pancreatic-type pain.

Investigations

**1.** ERCP Manometry.

**2.** Non-invasive Methods

**a.** Ultrasonographic measurement of duct diameter

**b.** Magnetic resonance pancreatography (MRCP)

to indicate SO dysfunction but its diagnostic usefulness is limited.

Endoscopic ultrasound (EUS) generally has a low yield in diagnosing abnormalities in the context of a normal upper endoscopy and imaging studies in patients with SOD Type III [72, 74]. Only 8% of patients with suspected SOD Type III (normal endoscopy and standard imaging studies) have any pathology at EUS [74].

**d.** Hepatobiliary scintigraphy [10]

Nuclear medicine scanning of the biliary tract (choledochoscintigraphy) uses 99mTc HIDA as the radiopharmaceutical to measure biliary emptying: the transit time from the liver to the duodenum. Prolonged duodenal arrival reflects SO dysfunction [75]. Specificity approaches 90% but reported sensitivities are variable [76]. Although lacking controlled studies, choledo‐ choscintigraphy is a reasonable non-invasive test before embarking on an intrusive approach with ERCP-manometry.

**b.** Functional Sphincter of Oddi Disorder

surgical methods.

following a single infusion [87].

limited by small patient numbers.

Endoscopic Therapy

in quality; well-done clinical trials are warranted.

Medical

The aim in patients with SOD is to reduce the resistance caused by the sphincter of Oddi to the flow of bile and/or pancreatic juice [3]. This can be achieved by medical, endoscopic or

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Medical management of sphincter of Oddi dysfunction is also unclear. Therapy has been primarily focused on the use of smooth muscle relaxants. Nifedipine, a calcium channel antagonist, has previously been studied with conflicting results in the treatment of sphincter of Oddi dysfunction. Nifedipine 20mg can significantly decrease the basal pressure in the sphincter of Oddi and also reduce the amplitude, duration and frequency of phasic contrac‐ tions [85]. This effect is not seen at lower doses of nifedipine; unfortunately, hypotension is a common side effect at the higher dose. Nevertheless, nifedipine use over 3 months decreases pain, especially in patients with predominant antegrade propagation of phasic contractions [86]. Once treatment ceases, the effect becomes lost in a week [86]. Nicardipine also appears to have a similar effect on the sphincter of Oddi with a decrease in basal and phasic pressures

Trimebutine (a spasmolytic), sublingual nitrates or a combination of both agents provides complete or partial relief of pain in most cases (64-71%) [88, 89]. All such studies however are

Several other medications such as anticholinergics (e.g.; hyoscine butylbromide), antispas‐ modics (e.g.; tiropramide), opioid antagonists (e.g.; naloxone), alpha-2 adrenergic agonists (e.g.; clonidine), and even corticosteroids may have a potential benefit in managing sphincter of Oddi dysfunction or functional gallbladder disorder [90]. Nevertheless, reports are limited

The goal of endoscopic therapy is to disable the dysfunctional sphincter through various methods. Botulinum toxin, a neurotoxin, when injected directly into the ampulla of Vater at endoscopy, improves symptoms in 44% of SOD patients for 6 to 12 weeks after the treatment [91]. Unfortunately, repeated injections of botulinum toxin may be associated with antibody formation and a subsequent reduced efficacy [90]. Hence, rather than being used to treat sphincter of Oddi dysfunction, botulinum toxin injections appear more helpful in directing further therapy, predicting the success of endoscopic sphincterotomy for pain relief [90, 91]. Endoscopic sphincterotomy (ES) is the current treatment for SOD Type I. At ERCP, deep cannulation of the bile (or pancreatic) duct allows electrocautery to sever the biliary or the pancreatic segment of the sphincter of Oddi. Pain relief after an ES is 90-95% in Type I patients, 85% in Type II patients with an abnormal sphincter of Oddi manometry and 55-60% in Type III patients with an abnormal manometry [92, 93]. Conversely, in patients with a normal manometry, the relief rates are much reduced: 35% for Type II and <20% in Type III patients, respectively [92, 93]. Complications from this procedure are mostly due to pancreatitis, which can be seen in up to 20% of patients [94]. ES as an indication of SOD results in a 2-5 fold increase

**e.** Morphine-prostigmine provocation (Nardi) test

The Nardi test assesses the response to an injection of morphine and prostigmine to provoke biliary sphincter spasm and stimulate pancreatic enzyme secretion. A positive test should elicit typical symptoms and/or increase in serum activities of pancreatic and/or liver enzymes. This provocative test is not specific or sensitive: 60% of normal individuals and others with IBS have a positive test [77]. Sphincterotomy decreases the pain and enzymatic response (amylase and lipase) to such provocation in only about 50% of individuals [78].

#### **6. Management**

**a.** Functional Gallbladder Disorder

#### Medical

The medical options for management of functional biliary disorders are quite limited. The spice turmeric (Curcuma longa) modulates multiple cell signalling pathways and is a putative therapy for inflammatory bowel disease [79]. In patients with biliary dyspepsia, the extracts of Curcuma seem to reduce abdominal pain at least during the first week of treatment [80]. Oddly, curcumin increases gallbladder contraction. Tenoten, an anxiolytic, appeared to decrease the pain syndrome, burning and belching, and increase gallbladder contraction in a small Russian study assessing patients with biliary dyskinesia and personality disorders [81]. Such reports have marked limitations including small patient numbers and unclear diagnostic criteria for biliary dyspepsia. As such, further studies are needed to clarify any role for medical therapy in biliary dyskinesia, including use of agents like tricyclic antidepressants that help visceral hypersensitivity.

#### Surgical

Although there may be a rising tide of cholecystectomies being performed for biliary dyski‐ nesia, most reports touting efficacy are retrospective reviews with small sample sizes and lack appropriate non-operative controls. One meta-analysis supported the notion of surgery in adults that provided 98% symptomatic relief compared to 32% with non-operative manage‐ ment [59]. Although the success rate in pediatric patients may reach 80% in some reports, a retrospective assessment of outcomes indicated no difference over a 2 year follow up: threequarters of both the surgical and non-surgical groups improved [82]. Further, gallbladder emptying assessed by CCK-cholescintigraphy may not be a sensitive test that predicts a benefit from cholecystectomy [83]. Certainly cholecystectomy for dyspeptic complaints of gassiness, bloating, indigestion and fatty food intolerance is disappointing [84]. Despite the Rome III consensus [8], the literature does not yet support cholecystectomy being done routinely for biliary dyspepsia.

#### **b.** Functional Sphincter of Oddi Disorder

The aim in patients with SOD is to reduce the resistance caused by the sphincter of Oddi to the flow of bile and/or pancreatic juice [3]. This can be achieved by medical, endoscopic or surgical methods.

#### Medical

choscintigraphy is a reasonable non-invasive test before embarking on an intrusive approach

The Nardi test assesses the response to an injection of morphine and prostigmine to provoke biliary sphincter spasm and stimulate pancreatic enzyme secretion. A positive test should elicit typical symptoms and/or increase in serum activities of pancreatic and/or liver enzymes. This provocative test is not specific or sensitive: 60% of normal individuals and others with IBS have a positive test [77]. Sphincterotomy decreases the pain and enzymatic response (amylase

The medical options for management of functional biliary disorders are quite limited. The spice turmeric (Curcuma longa) modulates multiple cell signalling pathways and is a putative therapy for inflammatory bowel disease [79]. In patients with biliary dyspepsia, the extracts of Curcuma seem to reduce abdominal pain at least during the first week of treatment [80]. Oddly, curcumin increases gallbladder contraction. Tenoten, an anxiolytic, appeared to decrease the pain syndrome, burning and belching, and increase gallbladder contraction in a small Russian study assessing patients with biliary dyskinesia and personality disorders [81]. Such reports have marked limitations including small patient numbers and unclear diagnostic criteria for biliary dyspepsia. As such, further studies are needed to clarify any role for medical therapy in biliary dyskinesia, including use of agents like tricyclic antidepressants that help

Although there may be a rising tide of cholecystectomies being performed for biliary dyski‐ nesia, most reports touting efficacy are retrospective reviews with small sample sizes and lack appropriate non-operative controls. One meta-analysis supported the notion of surgery in adults that provided 98% symptomatic relief compared to 32% with non-operative manage‐ ment [59]. Although the success rate in pediatric patients may reach 80% in some reports, a retrospective assessment of outcomes indicated no difference over a 2 year follow up: threequarters of both the surgical and non-surgical groups improved [82]. Further, gallbladder emptying assessed by CCK-cholescintigraphy may not be a sensitive test that predicts a benefit from cholecystectomy [83]. Certainly cholecystectomy for dyspeptic complaints of gassiness, bloating, indigestion and fatty food intolerance is disappointing [84]. Despite the Rome III consensus [8], the literature does not yet support cholecystectomy being done routinely for

with ERCP-manometry.

**6. Management**

visceral hypersensitivity.

biliary dyspepsia.

Medical

Surgical

**a.** Functional Gallbladder Disorder

**e.** Morphine-prostigmine provocation (Nardi) test

124 Dyspepsia - Advances in Understanding and Management

and lipase) to such provocation in only about 50% of individuals [78].

Medical management of sphincter of Oddi dysfunction is also unclear. Therapy has been primarily focused on the use of smooth muscle relaxants. Nifedipine, a calcium channel antagonist, has previously been studied with conflicting results in the treatment of sphincter of Oddi dysfunction. Nifedipine 20mg can significantly decrease the basal pressure in the sphincter of Oddi and also reduce the amplitude, duration and frequency of phasic contrac‐ tions [85]. This effect is not seen at lower doses of nifedipine; unfortunately, hypotension is a common side effect at the higher dose. Nevertheless, nifedipine use over 3 months decreases pain, especially in patients with predominant antegrade propagation of phasic contractions [86]. Once treatment ceases, the effect becomes lost in a week [86]. Nicardipine also appears to have a similar effect on the sphincter of Oddi with a decrease in basal and phasic pressures following a single infusion [87].

Trimebutine (a spasmolytic), sublingual nitrates or a combination of both agents provides complete or partial relief of pain in most cases (64-71%) [88, 89]. All such studies however are limited by small patient numbers.

Several other medications such as anticholinergics (e.g.; hyoscine butylbromide), antispas‐ modics (e.g.; tiropramide), opioid antagonists (e.g.; naloxone), alpha-2 adrenergic agonists (e.g.; clonidine), and even corticosteroids may have a potential benefit in managing sphincter of Oddi dysfunction or functional gallbladder disorder [90]. Nevertheless, reports are limited in quality; well-done clinical trials are warranted.

#### Endoscopic Therapy

The goal of endoscopic therapy is to disable the dysfunctional sphincter through various methods. Botulinum toxin, a neurotoxin, when injected directly into the ampulla of Vater at endoscopy, improves symptoms in 44% of SOD patients for 6 to 12 weeks after the treatment [91]. Unfortunately, repeated injections of botulinum toxin may be associated with antibody formation and a subsequent reduced efficacy [90]. Hence, rather than being used to treat sphincter of Oddi dysfunction, botulinum toxin injections appear more helpful in directing further therapy, predicting the success of endoscopic sphincterotomy for pain relief [90, 91].

Endoscopic sphincterotomy (ES) is the current treatment for SOD Type I. At ERCP, deep cannulation of the bile (or pancreatic) duct allows electrocautery to sever the biliary or the pancreatic segment of the sphincter of Oddi. Pain relief after an ES is 90-95% in Type I patients, 85% in Type II patients with an abnormal sphincter of Oddi manometry and 55-60% in Type III patients with an abnormal manometry [92, 93]. Conversely, in patients with a normal manometry, the relief rates are much reduced: 35% for Type II and <20% in Type III patients, respectively [92, 93]. Complications from this procedure are mostly due to pancreatitis, which can be seen in up to 20% of patients [94]. ES as an indication of SOD results in a 2-5 fold increase in complications compared to the risk when performing this procedure for ductal stones [95, 96]. Placing a temporary stent in the pancreatic duct helps lessen such complications.

[3] Kraag N, Thijs C, Knipschild P. Dyspepsia—how noisy are gallstones? A meta-analy‐ sis of biliary pain, dyspepsia symptoms, and food. Scand J Gastroenterol.

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127

[4] Mertens MC, Roukema JA, Scholtes VPW, De Vries J. Risk assessment in cholelithia‐ sis: Is cholecystectomy always to be preferred? Gastrointest Surg. 2010;14:1271–1279.

[5] Festi D, Reggiani ML, Attili AF, Loria P, Pazzi P, Scaioli E, Capodiscasa S, Romano F, Roda E, Colecchia A. Natural history of gallstone disease: Expectant management or active treatment? Results from a population-based cohort study. J Gastroenterol Hep‐

[6] Thistle JL, Longstreth GF, Romero Y, Arora AS, Simonson JA, Diehl NN, Harmsen WS, Zinsmeister AR. Factors That Predict Relief From Upper Abdominal Pain After

[7] Kirk G, Kennedy R, McKie L, Diamond T, Clements B. Preoperative symptoms of ir‐ ritable bowel syndrome predict poor outcome after laparoscopic cholecystectomy.

[8] Behar J, Corazziari E, Guelrud M, Hogan W, Sherman S, Toouli J. Functional gall‐ bladder and sphincter of oddi disorders. Gastroenterology. 2006;130:1498-1509.

[9] Hansel SL, DiBaise JK. Functional gallbladder disorder: Gallbladder dyskinesia. Gas‐

[10] Shaffer, E. Acalculous biliary pain: new concepts for an old entity. Dig Liver Dis.

[11] Varadarajulu S, Hawes R. Key issues in sphincter of Oddi dysfunction. Gastrointest

[12] Oustamaanolakis P, Tack J. Dyspepsia: Organic versus functional. J Clin Gastroenter‐

[14] Peery AF, Dellon ES, Lund J, Crockett SD, McGowan CE, Bulsiewicz WJ, Gangarosa LM, Thiny MT, Stizenberg K, Morgan DR, Ringel Y, Kim HP, Dibonaventura MD, Carroll CF, Allen JK, Cook SF, Sandler RS, Kappelman MD, Shaheen NJ. Burden of Gastrointestinal Disease in the United States: 2012 Update. Gastroenterology.

[15] GREPCO (The Rome group for epidemiology and prevention of cholelithiasis). The epidemiology of gallstone disease in Rome, Italy. I. Prevalence data in men. Hepatol‐

[16] GREPCO (Rome group for epidemiology and prevention of cholelithiasis). Preva‐ lence of gallstone disease in an Italian adult female population. Am J Epidemiol.

Cholecystectomy. Clin Gastroenterol Hepatol. 2011;9: 891-6.

1995;30:411–21.

atol. 2010;25:719-724.

Surg Endosc. 2011, 25: 3379-3384.

troenterol Clin N Am. 2010;39:369-379.

Endosc Clin N Am. 2003;13:671-94.

[13] Agreus L. Natural history of dyspepsia. Gut. 2002; 50:2-9.

2003;35 (Suppl 3):S20-5.

ol. 2012;46:175-190.

2012;143: 1179-1187.

ogy 1988;8:904–6.

1984:119:796–805.

#### Surgical

Surgical options include transduodenal biliary sphincteroplasty with a transampullary septoplasty [97]. Due to the advances in endoscopic techniques, surgery is generally reserved for patients who experience restenosis or when endoscopy is not available [97]. Endoscopy is preferred with lower cost, morbidity and mortality compared to surgical procedures.

#### **7. Summary**

Functional gallbladder disease and sphincter of Oddi disorders can be quite frustrating for the patient as well as the physician, in terms of arriving at a diagnosis and effective therapeutic options. Initially, non-invasive investigations should be performed. Further, sphincter of Oddi manometry requires specialized endoscopic equipment as well as physician expertise. Unfortunately, this is not readily available in many centers. Perhaps with the procurement of these resources in the future, physicians may be able to predict which patients with SOD will benefit from endoscopic or surgical therapy. In terms of management, medical therapies should be tried as first line. Further, surgical and endoscopic management in type II and type III SOD should be initiated with caution. The suggested algorithm should assist the investi‐ gation and management of these patients (Figure 3 and 4).

#### **Author details**

Meena Mathivanan, Liisa Meddings and Eldon A. Shaffer\*

\*Address all correspondence to: shaffer@ucalgary.ca

Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada

#### **References**


[3] Kraag N, Thijs C, Knipschild P. Dyspepsia—how noisy are gallstones? A meta-analy‐ sis of biliary pain, dyspepsia symptoms, and food. Scand J Gastroenterol. 1995;30:411–21.

in complications compared to the risk when performing this procedure for ductal stones [95,

Surgical options include transduodenal biliary sphincteroplasty with a transampullary septoplasty [97]. Due to the advances in endoscopic techniques, surgery is generally reserved for patients who experience restenosis or when endoscopy is not available [97]. Endoscopy is

Functional gallbladder disease and sphincter of Oddi disorders can be quite frustrating for the patient as well as the physician, in terms of arriving at a diagnosis and effective therapeutic options. Initially, non-invasive investigations should be performed. Further, sphincter of Oddi manometry requires specialized endoscopic equipment as well as physician expertise. Unfortunately, this is not readily available in many centers. Perhaps with the procurement of these resources in the future, physicians may be able to predict which patients with SOD will benefit from endoscopic or surgical therapy. In terms of management, medical therapies should be tried as first line. Further, surgical and endoscopic management in type II and type III SOD should be initiated with caution. The suggested algorithm should assist the investi‐

gation and management of these patients (Figure 3 and 4).

Meena Mathivanan, Liisa Meddings and Eldon A. Shaffer\*

Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada

[1] DiBaise JK. Evaluation and management of functional biliary pain in patients with an

[2] Gracie WA, Ransohoff DF. The natural history of silent gallstones. The innocent gall‐

intact gallbladder. Expert Rev Gastroenterol Hepatol. 2009;3:305-313.

stones are not a myth. New Engl J Med. 1982;307:798–800.

\*Address all correspondence to: shaffer@ucalgary.ca

96]. Placing a temporary stent in the pancreatic duct helps lessen such complications.

preferred with lower cost, morbidity and mortality compared to surgical procedures.

Surgical

126 Dyspepsia - Advances in Understanding and Management

**7. Summary**

**Author details**

**References**


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**Chapter 8**

**Upper Gastrointestinal Symptoms and Cardiovascular**

Cardiovascular disease, primarily encompassing coronary heart disease, hypertensive heart disease, heart failure, and stroke, is the number one cause of death globally, with 17.3 million dying from such causes in 2008 and a projected 23.6 million dying from cardiovascular disease in 2030 [1]. Cardiovascular disease affects 1 in every 3 Americans, or an estimated 83.6 million people (myocardial infraction, 7.6 million; angina pectoris, 7.8 million; heart failure, 5.1 million; and stroke of any kind, 6.8 million; high blood pressure, 77.9 million) [2]. Heart disease and stroke results in over 500,000 and 160,000 deaths, respectively, each year in the United States; giving rise to an enormous annual economic burden exceeding \$312 billion in both direct and

Upper gastrointestinal (or dyspeptic) symptoms, often sub-classified as ulcer-like (localized epigastric pain or nocturnal/fasting pain), gastroesophageal-like (heartburn or regurgitation) or dysmotility-like dyspepsia (postprandial fullness, early satiety, diffuse epigastric pain, belching or abdominal distention) are also highly prevalent worldwide with an average 3 month prevalence rate across an international sample of survey respondents of about 28%, but with higher rates in some countries such as the United States (41.8%) [3] and lower rates in others (Japan's rate=9.4%). Clinically-relevant upper gastrointestinal symptoms have been found to result in high healthcare utilization [4,5]; as noted in one study [4] which found 20% of affected patients visited a physician's office during the 3-months prior to being surveyed, 2% were hospitalized, nearly half used an over-the-counter medication and 27% were prescri‐ bed at least one medication to address their symptoms. Upper gastrointestinal symptoms have

> © 2013 Coleman et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Craig I. Coleman, Brendan L. Limone, Jeff R. Schein,

Additional information is available at the end of the chapter

Winnie W. Nelson, Joyce C. LaMori, Jeffrey Kluger and C. Michael White

http://dx.doi.org/10.5772/56564

**1. Introduction**

indirect costs [1,2].

**Disease**
