Gallstone Disease: From Dyspepsia to Biliary...

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www.turner-white.com Vol. 16, No. 1 January 2009 JCOM 37 CASE-BASED REVIEW T en percent to 20% of Americans will develop gall- stones. Bile salts and bile acids may be interchange- ably used, although their strict physicochemical properties differ [1,2]. The basis for most biliary tract dis- ease, gallstones are a significant health care burden in the United States, where more than 700,000 cholecystectomies are performed annually. The resultant cost from symptoms and complications approach $10 billion [3]. Most (about 85%) gallstones consist of cholesterol. Cho- lesterol gallstones primarily form because of an imbal- ance in the composition of bile [4]. Bile is 95% water. Its 3 major organic solids are lipids: bile acids, phospholipids (lecithin), and cholesterol. Cholesterol and lecithin are water insoluble, being predominantly hydrophobic molecules. The remaining constituents are electrolytes plus a rather small amount of pigment (conjugated bilirubin). In the first stage of cholesterol gallstone formation, the liver secretes excess cholesterol relative to the solubilizing components, bile salts and lecithin. This results in supersaturated bile . The next stage is nucleation in which factors like certain proteins in bile has- ten the precipitation of the excess cholesterol out of solution, forming microcrystals. Mucin, a glycoprotein secreted in ex- cess by the gallbladder mucosa, then acts as a matrix scaffold to retain these cholesterol microcrystals. An early stage in gallstone formation is the appearance of biliary sludge (“mi- crolithiasis”). Sludge consists of cholesterol microcrystals, mucin, and pigment material (bilirubinate). In the last stage, retention and growth, impaired gallbladder contractility holds on to this precipitated material, allowing the microcrystals to agglomerate and grow into overt gallstones. The interaction of multiple genetic and environmental factors predisposes certain individuals to form gallstones [1,5]. Genes contribute 25% to the phenotype, most evident as the basis for ethnicity and a familial predisposition. A combination is necessary: genetic traits predisposing to stone formation triggered by exogenous and dietary factors, yield- ing the phenotypic expression. Gallstones reach epidemic proportions in the North and South American Indian popula- tions, in which 60% to 70% develop gallstones. The risk is also Gallstone Disease: From Dyspepsia to Biliary Complications Case Study and Commentary, Eldon Shaffer, MD, FRCPC From the Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada. This article has a companion CME exam that follows the article. To earn credit, read the article and complete the CME evaluation on pages 47 and 48. Estimated time to complete this activity is 1 hour. Faculty disclo- sure information appears on page 45. Release date: 15 January 2009; valid for credit through 30 January 2010. Program Audience Primary care physicians. Educational Needs Addressed Gallstones are common, affecting over 10% of adults in the Western world and representing a major health burden. Yet most people with gallstones are asymptom- atic. Only 10% of people harboring gallstones develop symptoms by 5 years, and only 20% by 20 years. The classic symptom of cholelithiasis is biliary colic: steady epigastric or right upper quadrant pain lasting more than 30 minutes and often radiating to the back or right scapula. Gallstones also can lead to major complica- tions: cholecystitis, pancreatitis, and cholangitis. Biliary sludge, a forerunner of cholelithiasis, develops rather commonly during pregnancy but usually resolves in the postpartum period without causing complications. Biliary-type pain in people without gallstones represents a clinical dilemma. Many have functional bowel problems that will not resolve following cholecystectomy. Primary care physicians represent the front lines to identify true biliary pain and manage biliary complications. Educational Objectives After participating in this CME activity, primary care physicians should be able to 1. Understand the risk factors for gallstone formation 2. Discern the clinical features of true biliary pain 3. Know the natural history of gallstone disease 4. Develop a management strategy for biliary pain in the absence of gallstones 5. Recognize and manage functional bowel disease, particularly acalculous gallbladder disease 6. Diagnose and treat postcholecystectomy diarrhea CME jointly sponsored by Wayne State University School of Medicine and JCOM

Transcript of Gallstone Disease: From Dyspepsia to Biliary...

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Ten percent to 20% of Americans will develop gall-stones. Bile salts and bile acids may be interchange-ably used, although their strict physicochemical

properties differ [1,2]. The basis for most biliary tract dis-ease, gallstones are a significant health care burden in the United States, where more than 700,000 cholecystectomies are performed annually. The resultant cost from symptoms and complications approach $10 billion [3].

Most (about 85%) gallstones consist of cholesterol. Cho-lesterol gallstones primarily form because of an imbal-ance in the composition of bile [4]. Bile is 95% water. Its 3 major organic solids are lipids: bile acids, phospholipids (lecithin), and cholesterol. Cholesterol and lecithin are water insoluble, being predominantly hydrophobic molecules. The remaining constituents are electrolytes plus a rather small amount of pigment (conjugated bilirubin). In the first stage of cholesterol gallstone formation, the liver secretes excess cholesterol relative to the solubilizing components, bile salts and lecithin. This results in supersaturatedbile. The next stage is nucleation in which factors like certain proteins in bile has-ten the precipitation of the excess cholesterol out of solution, forming microcrystals. Mucin, a glycoprotein secreted in ex-cess by the gallbladder mucosa, then acts as a matrix scaffold to retain these cholesterol microcrystals. An early stage in gallstone formation is the appearance of biliary sludge (“mi-crolithiasis”). Sludge consists of cholesterol microcrystals, mucin, and pigment material (bilirubinate). In the last stage, retentionandgrowth, impaired gallbladder contractility holds on to this precipitated material, allowing the microcrystals to agglomerate and grow into overt gallstones.

The interaction of multiple genetic and environmental factors predisposes certain individuals to form gallstones [1,5]. Genes contribute 25% to the phenotype, most evident as the basis for ethnicity and a familial predisposition. A combination is necessary: genetic traits predisposing to stone formation triggered by exogenous and dietary factors, yield-ing the phenotypic expression. Gallstones reach epidemic proportions in the North and South American Indian popula-tions, in which 60% to 70% develop gallstones. The risk is also

Gallstone Disease: From Dyspepsia to Biliary ComplicationsCase Study and Commentary, EldonShaffer,MD,FRCPC

From the Division of Gastroenterology, Department of Medicine, University ofCalgary,Calgary,Alberta,Canada.

This article has a companion CME exam that follows the article. To earn credit, read the article and complete the CME evaluation on pages 47 and 48. Estimated time to complete this activity is 1 hour. Faculty disclo-sure information appears on page 45. Release date: 15 January 2009; valid for credit through 30 January 2010.

Program audiencePrimary care physicians.

educational Needs addressedGallstones are common, affecting over 10% of adults in the Western world and representing a major health burden. Yet most people with gallstones are asymptom-atic. Only 10% of people harboring gallstones develop symptoms by 5 years, and only 20% by 20 years. The classic symptom of cholelithiasis is biliary colic: steady epigastric or right upper quadrant pain lasting more than 30 minutes and often radiating to the back or right scapula. Gallstones also can lead to major complica-tions: cholecystitis, pancreatitis, and cholangitis. Biliary sludge, a forerunner of cholelithiasis, develops rather commonly during pregnancy but usually resolves in the postpartum period without causing complications. Biliary-type pain in people without gallstones represents a clinical dilemma. Many have functional bowel problems that will not resolve following cholecystectomy. Primary care physicians represent the front lines to identify true biliary pain and manage biliary complications.

educational ObjectivesAfter participating in this CME activity, primary care physicians should be able to1. Understand the risk factors for gallstone formation2. Discern the clinical features of true biliary pain3. Know the natural history of gallstone disease4. Develop a management strategy for biliary pain in

the absence of gallstones5. Recognize and manage functional bowel disease,

particularly acalculous gallbladder disease6. Diagnose and treat postcholecystectomy diarrhea

CMe jointly sponsored by wayne state University school of Medicine and JCOM

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• Which laboratory tests would be helpful?

gallstONe disease

increased in Hispanics. In contrast, the rate in sub-Saharan Africa and Asia is quite low. Obesity, a major risk factor, likely relates to insulin resistance (the metabolic syndrome) and leads to excessive cholesterol secretion by the liver. Evolution and circumstance in Native American Indians may have ironically selected those with “thrifty” genes that conserve energy; these genes likely had a survival advantage in the distant past. Abundant access to food now has placed such individuals at an increased risk for obesity and cholelithiasis. Hence, a genetic trait complicated by obesity (and the meta-bolic syndrome) elicits excessive cholesterol secretion into bile and results in a cascade that yields a gallstone.

In addition to cholesterol gallstones, there are pigmented stones. Black pigment stones, which make up a minority of gallstones (< 15%), consist of a polymer of calcium bilirubi-nate. They develop in cirrhosis (likely from altered bilirubin metabolism), hemolytic states (from excess bilirubin produc-tion), and ileal Crohn’s disease (enhanced bilirubin absorp-tion in the intestine and return to the liver for re-secretion). Altered bilirubin metabolism may, in part, account for age increasing the prevalence in both sexes. Brown pigment stones, in contrast, develop in the bile ducts as a result of bacteria and inflammation that degrade (deconjugate) bili-rubin and other bile constituents. They are associated with infection/inflammation from biliary strictures in developed countries and with parasitic infestations in Asia.

Case stUdYinitial Presentation

A 27-year-old pregnant Hispanic women is found to have gallbladder sludge at routine ultrasono-

graphic evaluation done as part of her prenatal assessment.

HistoryThe pregnancy, her first, has been uneventful. In the first trimester, she experienced morning nausea and vomiting that disappeared after 6 weeks. She also developed heart-burn, manifest by retrosternal burning and occasional acid regurgitation, occurring 2 to 3 times a week and responding to periodic use of ranitidine 300 mg. The ultrasound was per-formed at 12 weeks as part of a routine prenatal screen. The fetus was normal, but the ultrasound incidentally revealed the presence of biliary sludge in the gallbladder (Figure 1).

The patient has had gut problems dating back to child-hood. She had had chronic constipation that recently wors-ened with the pregnancy. She also experiences bloating and lower abdominal crampy pains, usually relieved by defecation. She has had indigestion for the past few years. Fatty foods are a particular problem, aggravating the ab-dominal discomfort and occasionally precipitating diarrhea in the form of 2 to 4 loose bowel movements. Investigations several years ago for these digestive complaints led to her being told that she had irritable bowel syndrome (IBS). Celiac serology was negative. Family history is pertinent. Her mother and 2 of 3 sisters have had gallbladder surgeries as did the maternal grandmother. None have known liver disease. The patient uses no drugs other than supplemental vitamins and folic acid. She has always been overweight: her body mass index prior to the pregnancy had been 32 kg/m2. Her weight gain in the first trimester was some-what higher than that recommended by her physician.

Physical examinationThe patient appears healthy and has normal vital signs. She is afebrile. Abdominal examination reveals a gravid uterus at the expected gestational age. There is no tenderness or other abnormal findings. The fetal heart sounds are normal at 130 bpm.

investigationsLaboratory tests show a normal complete blood count (white blood cell count, 7500/mm3), elevated alkaline phosphatase of 367 U/L (normal, < 150 U/L), and normal total bilirubin 9.6 μmol/L (normal, < 20 μmol/L). Other biochemistries (aminotransferase, δGT, and lipase) are normal. On the abdominal ultrasound done at 12 weeks, no gallstones are evident. The gallbladder wall is not thickened. There is no sonographic Murphy’s sign.

• How common is gallbladder disease during pregnancy?

Biliary sludge develops in one third of women during preg-nancy but commonly resolves in the postpartum period

Figure 1. Gallbladder abdominal ultrasound showing biliary sludge as identified by echogenic material layering on the dependent wall of the gallbladder (arrow). Gallbladder sludge differs from cholelithiasis in that it does not cast an acoustic shadow. Sludge will also shift in the gallbladder with a change of position (not shown).

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[6]. After delivery, 5% of women continue to have sludge. Gallstones appear in 3% of pregnant women and may not disappear in the puerperium.

Biliary sludge is a precursor to gallstones. When aggre-gates of sludge grow above 2 to 3 mm in size, they produce higher amplitude echoes with acoustic shadowing, evolv-ing into gallstones that possess different characteristics on ultrasonography (Figure 2). Sludge and gallstone formation during pregnancy relate to the accompanying changes that predispose to each stage: the excessive secretion of cholester-ol (from estrogens) and gallbladder stasis (from progestins). Additional factors in this particular patient are her obesity and genetic background. Hispanics with some admixture of Native American have a predilection to cholesterol gallstone formation [1].

• How are complications of biliary stone disease managed in pregnancy?

Sludge and/or gallstones can lead to a range of complica-tions, from episodes of self-limiting biliary colic to acute cholecystitis to either biliary tract obstruction and cholangi-tis or pancreatic duct obstruction and acute pancreatitis [6].

Such biliary tract complications of gallstones represent the second most common nongynecologic condition requiring surgery in pregnancy, with cholecystectomy performed in 1 to 8 of every 10,000 pregnancies. The presence of biliary sludge or gallstones, however, does not necessarily mean that a complication will ensue.

The appropriate management of biliary tract complica-tions during pregnancy has been controversial. Some advo-cate avoiding surgery, whereas more recent evidence favors an aggressive surgical management. Despite the attendant grave implications for maternal and fetal morbidity, surgery in appropriate cases can be safe. It reduces the need for labor induction, preterm deliveries, and fetal morbidity [7,8]. Thus, should acute cholecystitis, cholangitis, or pancreatitis develop during a pregnancy, early cholecystectomy and, when ap-propriate, endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP), become quite reasonable. In the past, ERCP and MRCP have been contraindicated in pregnancy because of the perceived concerns that exposure of the fetus to ionizing radiation and magnetic fields posed a risk. The quantity of radiation during ERCP is estimated at 18 to 310 mrad, much lower than the harmful dose (5–20 mrad) at which fetal damage occurs [8]. Radiation risk is highst during the first trimester. Another precaution is to limit the fluoroscopy time. Case reports on the use of MRCP indicate that this too does not yield any increased risk to the fetus or the mother [8].

• What is the significance of the patient’s abdominal complaints?

This patient does not exhibit features of typical biliary colic. True biliary pain (biliary colic) consists of episodes of steady right upper abdominal or epigastric pain that persists for 30 minutes to less than 6 hours. It may be accompanied by nausea and vomiting but not fever. Laboratory features of inflammation or cholestasis are absent. In this patient, only the alkaline phosphatase is elevated, a common finding dur-ing pregnancy; the source of the alkaline phosphatase is not the liver but instead arises from the placenta.

The patient does not have symptoms of gallstone disease. True biliary pain (biliary colic) from gallstone disease is characteristically pain in the right hypochondrium and/or epigastrium [3,9]. This patient’s symptoms are more reflec-tive of functional dyspepsia and IBS. Dyspepsia as defined in an American Gastroenterological Association position statement is “a chronic or recurrent pain or discomfort cen-tered in the upper abdomen [10].” The Rome III diagnostic criteria for functional dyspepsia includes a negative gastros-copy to rule out organic disease (Table 1) [11], something that is not warranted in this case. There is nothing to suggest a peptic ulcer. The symptoms are not recent, and there are no “alarm” features. Further, her crampy abdominal pain relieved by defecation, bloating, and altered bowel habits are more in line with the IBS. IBS is characterized by chronic ab-dominal pain and altered bowel habits in the absence of any organic cause [12] and includes a wide array of symptoms

Figure 2. Ultrasound of gallbladder containing a gallstone. Gallbladder abdominal ultrasound showing a single gallstone as identified by echogenic material in the neck of the gall-bladder (arrow) that casts an acoustic shadow below it (un-like gallbladder sludge). The gallbladder wall is not thickened, a finding that would indicate acute cholecystitis.

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• Which laboratory tests would be helpful?

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with both gastrointestinal and extraintestinal complaints (Table 2). Clinical overlap between these functional gut disorders is common.

In the past, the abdominal discomfort and bloating that follow a heavy, particularly fatty meal has been termed “fatty food” intolerance. In fact, dyspepsia is not a particular manifestation of gallstone disease, while fatty foods do not necessarily precipitate attacks of biliary colic [9,13].

• What is the association between gallstones and biliary pain?

Biliary-type pain is common. In a U.S. household survey of presumed “healthy” individuals, 0.6% of men and 2.3% of women had biliary pain [7]. In an Italian ultrasound study, biliary pain occurred in as many as 7.6% of men and 20.7% of women, none of whom had gallstones [14,15]. From a different perspective, up to 82% of patients with gallstones incidentally detected on ultrasonography do not have any biliary symptoms [14,16]. These “silent” gallstones remain clinically innocuous in most individuals. Only 13% of people with gallstones develop biliary pain when followed for 15 to 20 years [17].

If symptoms develop in a person with documented cholelithiasis, the likelihood of recurrent symptoms is high (30%–50% per year) [9,15]. Pain severity appears to progres-sively increase from clinically silent to overt symptoms (sufficient to stop activity or the development of gallstone complications) parallel to the natural history of gallstone disease: from silent gallstones to symptomatic gallstones to cholecystectomy [9]. Although stone characteristics do not predict pain, sex differences exist in terms of pain frequency

in those with gallstones. In men, the prevalence of biliary-type pain is no different in those with stones (7.6%) than those without gallstones (7.8%). In women, pain is more common, approaching 34.8% in those with gallstones versus 20.7% in those without gallstones. Such frequency differ-ences may be iatrogenic because women have more regular visits to their physicians or perhaps reflect their natural his-tory: women develop stones earlier in life. Thus, gallstones and abdominal pain are not synonymous, and biliary-type pain can occur in the absence of gallstones. It is therefore not surprising that biliary pain occurs without gallstones, and chronic abdominal pain can persist in 20% to 50% of patients following cholecystectomy [18,19]. Many of these postcholecystectomy complaints are rather nonspecific. In the “postcholecystectomy syndrome,” only 14% of patients experience true biliary pain. Hence, routine cholecystectomy is not warranted for gallstones that are clinically silent [17].

• What causes biliary pain?

The basis for biliary pain when the gallbladder is intact has been attributed to obstruction: the gallbladder contracting against a fixed (eg, gallstone) or functional obstacle either at the cystic duct or at the sphincter of Oddi (eg, sphincter of Oddi spasm). Such obstruction might then stimulate the gallbladder mucosa to produce a phospholipase, which hydrolyses one fatty acid from the phospholipid (lecithin) in bile, producing lysolecithin. This biological detergent will initiate an inflammatory reaction (cholecystitis); the attendant inflammatory mediators then contribute to the pain. Prostaglandin, for example, might mediate the inflammatory response. The pathogenesis of biliary pain is less clear in cholesterol gallstone disease without cholecystitis, where the excessive cholesterol in bile actually

Table 1. Rome III Diagnostic Criteria for Functional Dyspepsia

One or more of:

Bothersome postprandial fullness

Early satiety

Epigastric pain

Epigastric burning

AND

No evidence of structural disease (including a negative upper endoscopy) that is likely to explain the symptoms

These criteria should be present for the last 3 months with symp-tom onset at least 6 months before diagnosis

Adapted with permission from Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders [published erratum appears in Gastroenterology 2006;131:136]. Gastroenterology 2006;130: 1466–79.

Table 2. Rome III Diagnostic Criteria for Irritable Bowel Syndrome

Recurrent abdominal pain or discomfort at least 3 days per month in the last 3 months

Associated with 2 or more of the following:

Improvement with defecation

Onset associated with a change in frequency of stool

Onset associated with a change in form (appearance) of stool

These criteria should be present for the last 3 months with symp-tom onset at least 6 months before diagnosis

Adapted with permission from Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders [published erratum appears in Gastroenterology 2006;131:688]. Gastroenterology 2006;130: 1480–91.

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leads to defective signal transduction (at the level of the sarcolemma) and depressed smooth muscle contractility, begging the question as to how reduced gallbladder contraction can result in pain [20]. In fact, the normal biliary tract is a low-pressure conduit for bile secreted from the liver. During the interdigestive period, the gallbladder should function as a reservoir to decompress and modu-late any marked increases of intrabiliary pressure. With meals, the gallbladder contracts and the sphincter of Oddi customarily relaxes to expedite bile entering the duodenum. Other than the gallbladder and sphincter of Oddi, the biliary tract is devoid of smooth muscle. In acute cholecystitis, the basis for biliary pain resides in the inflammatory process. In a setting of biliary colic without overt inflammation or clear cut mechanical obstruction, the origin remains obscure at this time.

Patient Follow-upThe patient is not having any biliary symptoms, but her 18-week (routine follow-up screen) ultra-

sound examination still shows evidence of sludge in the gallbladder. She subsequently has a rather normal delivery. Because of the potential confusion with her functional gut symptoms, another ultrasound is performed at 6 weeks postpartum. This time, the gallbladder is free of sludge (Fig-ure 3). However, the mid-abdominal, crampy pain relieved by defecation, chronic constipation, bloating, and flatulence continue.

Four years later she returns with slightly different symp-toms. She has been having rather severe, steady right upper quadrant pain that is sufficient in severity to bring her to her physician. Attacks are quite discrete, lasting 1 to several hours. Between episodes, she is otherwise well, although the IBS features have not resolved.

Her physical examination is unremarkable except that she continues to be obese with a body mass index of 34 kg/m2. Laboratory testing shows normal complete blood count, liver biochemistries, and lipase. An abdominal ultra-sound is normal. There is no sludge or stones; the wall is not thickened.

The primary care physician arranges a cholecystokinin (CCK)-cholescintigraphic scan. The CCK-8 (octapeptide of cholecystokinin) infusion causes some abdominal discomfort but does not reproduce her pain. Gallbladder emptying is impaired with an ejection fraction less than 30% (Figure 4).

• What is the patient’s diagnosis?

The gallbladder and the sphincter of Oddi normally func-tion as an integrated unit, regulating the delivery of bile

from the liver through the biliary tract and into the duo-denum. The sphincter of Oddi also controls pancreatic secretions. The gallbladder collects and stores hepatic bile during fasting, concentrating it to reduce the volume. The gallbladder accommodates this volume through receptive relaxation, limiting any rise in pressure [20]. Eating causes the gallbladder to evacuate 75% of its contents through neural (cholinergic and local gastroduodenal reflexes) and hormonal (CCK acting via cholinergic nerves) mechanisms. Emptying occurs through smooth muscle contraction of the gallbladder, coordinated with a reduction in sphincter of Oddi tone. CCK also relaxes the sphincter of Oddi through neural (nitric oxide–mediated) pathways. Biliary tract pres-sures therefore should normally remain rather low, well below the maximal secretory pressure generated by the liver that can be as high as 40 mm Hg.

Gallbladder dyskinesia represents true biliary-type pain occurring in the absence of gallstones: the gallbladder ap-pears normal on abdominal ultrasound. Functional disorders of the gallbladder and the sphincter of Oddi must be distin-guished from such common conditions as gastroesophageal reflux disease, functional dyspepsia, IBS, and more sinister entities like cholecystitis and pancreatitis [21] (Table 3). The basis has been attributed to impaired gallbladder emptying, hence the term dyskinesia [20]. This may occur from reduced gallbladder contraction [22] due to inflammation (hence the synonym, chronic acalculous cholecystitis) or an intrinsic contractile problem (perhaps related to excess cholesterol in the membrane as occurs in cholesterolosis). Changes of chronic cholecystitis are variable and not predictive of a thera-peutic success [23,24].

Perhaps there is a spectrum of gallbladder disease com-mencing with cholesterol saturation of bile, followed by gallbladder dysmotility leading to microcrystal growth and culminating in gallstone formation and gallbladder

Figure 3. Abdominal ultrasound showing a normal gallblad-der. It contains no echogenic material.

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Figure 4. Cholecystokinin (CCK)-cholescintigraphy showing normal gallbladder filling and emptying in response to cholecys-tokinin (CCK). Continuous imaging of the gallbladder is acquired for 60 minutes, following the intravenous IV administration of 2 mCi technetium (99mTc)-labeled hepatoiminodiacetic acid (HIDA). Gallbladder emptying is then assessed in response to CCK-8 infused intravenously at 0.02 µg/kg over 30 minutes. Representative scans are shown for 5, 30, and 60 minutes af-ter the 99mTc-HIDA injection and then at 60 minutes following the CCK infusion. (A) The radiolabel has been taken up by the liver. (B) At 30 minutes, activity has declined over the liver as it fills the gallbladder and enters the duodenum. (C) By 60 min-utes, little remains in the liver while the gallbladder is well-delineated with the reminder of activity seen in the small intestine. (D) 60 minutes after initiating the CCK infusion, the gallbladder has become quite empty. Most radioactivity is now in the small intestine. CCK-cholescintigraphy showing impaired emptying in response to CCK. (E) Shows normal gallbladder filling. At 30 minutes after 99mTc-HIDA injection, radioactivity is clearing the liver and filling the gallbladder. Following CCK administration, the gallbladder retains most of its contents at 60 (F) and at 90 minutes (G), indicating that emptying is impaired, as it is in this case.

A B

C

D

E F GG

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inflammation [25]. The common occurrence of dysmotility- like symptoms (eg, constipation, gastroparesis) in those with gallbladder dyskinesia has lead to the suggestion that the basis may reflect a generalized motility disorder of the gut [26,27]. Another cause of impaired gallbladder empty-ing might result from partial obstruction of outflow from the gallbladder. Such obstruction might reside at the level of the gallbladder neck or cystic duct (termed the cystic duct syn-drome, the “fighting gallbladder”), or the sphincter of Oddi (sphincter of Oddi dysfunction). Alternatively, the source of pain might be a feature of visceral hypersensitivity involv-ing the gallbladder, biliary tree, or an adjacent structure, just as it occurs with other functional gut problems [20,28]. In fact, there might be more than one origin of the symptoms, explaining some of the difficulty in identifying adequate diagnostic tests and the reported differences in outcome following cholecystectomy. In some individuals, the under-lying problem may relate to dysfunction of the sphincter of Oddi rather than the gallbladder [29]. Others may have stone disease that was missed by standard diagnostic imag-ing. Transabdominal ultrasound, although over 95% sensi-tive, has its limitations, particularly for small stones. Some reports have found gallstones at cholecystectomy performed for presumed gallbladder dyskinesia [27,30,31]. Endoscopic ultrasound and the microscopic analysis have been used to better exclude gallstone disease [32,33], but validated stan-dards do not exist at this time.

• How is functional gallbladder disorder diagnosed?

The diagnosis of functional disorder of the gallbladder cur-rently rests on demonstrating impaired gallbladder empty-ing, using cholescintigraphy to quantitate a decrease in the gallbladder ejection fraction induced by CCK (Figure 5) [21].

This nuclear scanning technique generates time-activity curves for the gallbladder after intravenous CCK-8 ad-ministration [34]. The radionucleotide originally used was technetium 99m-labeled hydroxy iminodiacetic acid, hence the term HIDA scan. Gallbladder emptying is expressed as an ejection fraction, which is the percentage change of gall-bladder counts after the CCK stimulus. The dose of CCK-8 used and the duration of administration have not been uniformly established. Most reasonable is to infuse CCK at a low dose and slowly over 30 minutes rather than 3 to 5 minutes. The long, slower infusion simulates CCK release after a meal rather than the acute pharmacologic bolus that likely has poorer reproducibility. The “normal” response to the 30-minute CCK infusion is commonly set at an ejection fraction greater than 30% to 35% although one (Rome III) consensus placed the normal gallbladder ejection fraction

at greater than 40% [21]. Further confounding the value of CCK-cholescintigraphy are the multiple causes of impaired gallbladder emptying (Table 4). All these factors limit the value of gallbladder emptying to predict those who might benefit from cholecystectomy [20,23]. Critical analysis of reports suggests that CCK-cholescintigraphy is not reliable in predicting a positive outcome following cholecystectomy [35,36]. The various methods used to perform cholescintig-raphy (particularly the rapid CCK bolus dosing) undoubt-edly detract from the ability of this test to accurately predict those who would benefit from cholecystectomy [37]. Fur-ther, the entity may well represent more than just impaired gallbladder emptying [20]. Laparoscopic cholecystectomy, intuitively the definitive therapy for a disorder affecting the gallbladder, is therefore not warranted except in exceptional cases or in a research protocol.

additional Follow-upThe patient has additional episodes that lead to a surgical opinion and an uneventful laparoscopic

cholecystectomy. The gallbladder shows an increase infil-tration of chronic inflammatory cells, sufficient for the pa-thologist to label it as chronic mild cholecystitis. Within a few weeks of the surgery, the patient begins noticing a change

Table 3. Rome III Diagnostic Criteria for Functional Gallbladder Disorder

Episodes of pain located in the epigastrium and/or right upper quadrant

The gallbladder is normal—no stones or sludge. Tests of the liver (enzymes, conjugated bilirubin) and pancreatic (lipase/amylase) are normal

Plus all of the following:

Episodes lasting ≥ 30 minutes

Recurrent symptoms occurring at different intervals (not daily)

The pain builds up to a steady level

The pain is moderate to severe, enough to interrupt daily ac-tivities or lead to an emergency department visit

The pain is not relieved by:

Bowel movements

Postural change or

Antacids

Exclusion of other structural diseases that would explain the symptoms, including a normal upper gastrointestinal endoscopy

Supportive criteria:

Pain associated with nausea and vomiting

Pain radiates to the back and/or right infrasubscapular region

Pain awakens from sleep in the middle of the night

Adapted with permission from Behar J, Corazziari E, Guelrud M, et al. Functional gallbladder and sphincter of Oddi disorders. Gas-troenterology 2006;130:1498–509.

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in her bowel motions. She has 4 to 5 loose stools during the day in association with crampy abdominal pain, which is relieved by defecation. Soon thereafter, the troublesome bloating recurs. The diarrhea becomes a significant problem in her daily existence.

• What is the cause of this patient’s diarrhea?

The “postcholecystectomy syndrome” is an ill-defined en-tity, ranging from mild digestive symptoms to severe at-tacks of abdominal pain and jaundice. Following removal of the gallbladder for symptomatic cholelithiasis, most patients experience a satisfactory outcome with relief of symptoms. Depending upon the original indications for the cholecystectomy, however, 20% to 50% of patients will con-tinue to have a variety of abdominal symptoms, including dyspepsia, flatulence, eructation, and food intolerances [38].

As there are over 700,000 cholecystectomies performed an-nually in the United States, a frequency that has been rising with the advent of laparoscopic cholecystectomy [39], this syndrome could represent an ever-increasing health prob-lem. An overt, structural problem, such as retained common duct stones, biliary stricture, pancreatitis, or a neoplasm, is an obvious cause of continued symptoms in some individu-als following cholecystectomy. They will experience rather classical biliary-type pain, cholestasis, or cholangitis. Oth-ers with less specific complaints have no obvious disease. Whether or not a cystic duct remnant might give rise to

symptoms in some patients is unclear. In this case, the in-dications for performing the cholecystectomy were flawed, and the patient developed a postcholecystectomy complica-tion, diarrhea.

A continuation of symptoms following cholecystectomy is usually construed as “functional” when no organically defined basis exists for the discomfort or complaint. Sphinc-ter of Oddi dysfunction is an uncommon entity [21]. It char-acteristically is accompanied by features of transient biliary obstruction with elevated liver enzymes. If the pancreatic component of the sphincter is involved, pain, elevated pan-creatic enzymes, and even pancreatitis can result. Measur-ing pressure in the sphincter of Oddi requires ERCP, which is invasive and carries a high risk of complications. Sus-pected patients should be referred to an expert unit for such assessment, but only in the presence of compelling clinical evidence and after noninvasive tests are negative.

In the present case, the patient’s symptoms of abdominal pain, altered bowel movements, and bloating remain in keeping with the diagnosis of IBS. The development of diar-rhea might be a feature of this entity. Alternatively, it could be an unmasking of a congenital defect in bile salt absorp-tion in the terminal ileum [40]. Removal of the gallbladder and its reservoir function provides a rather continuous delivery of bile to the small intestine. Failure to actively absorb bile salts/bile acids in the ileum allows their spill

Table 4. Causes of Impaired Gallbladder Emptying

Primary gallbladder disease

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 hemoglobinopa-thy

Neuromuscular defects

Myotonia dystrophic

Denervation (spinal cord injury, vagotomy)

Functional abdominal pain

Irritable bowel syndrome including functional dyspepsia

Deficiency of cholecystokinin

Celiac disease, fasting/TPN

Drugs

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

Figure 5. Algorithm for the management of acalculous biliary pain (gallbladder dyskinesia) as suggested by the Rome III consensus [21]. Cholescintigraphy (hepatoiminodiacetic acid scan) assesses gallbladder emptying in response to a slow infusion of cholecystokinin (CCK) infusion over 30 minutes.

Abdominal ultrasoundLiver-pancreatic enzymes

Upper endoscopy

Dx and Rx of structural alteration

Cholecystectomy

CCK-cholescintigraphy

Reduced emptying Normal emptying

Abnormal Normal

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Case-based review

into the colon, leading to net water and electrolyte secretion, termed cholerrheic diarrhea. Bile salts and bile acids may be interchangeably used although their strict physicochemical properties differ. Bile salt malabsorption also may be a com-ponent of the diarrhea associated with microscopic colitis. Malabsorption of bile salts arises in Crohn’s disease or from ileal loss. It can also be idiopathic (presumably the result of a congenital absence of the bile salt transporter in the ileum) and therefore cause diarrhea after cholecystectomy [41].

Diagnosis may come from a therapeutic trial of a bile salt sequestering agent such as cholestyramine but more reliably warrants measuring the turnover of a synthetic radiolabeled bile acid. The 75SeHCAT scan involves the ingestion of the radiolabeled bile salt selenium-75 homocholic acid taurine. Retention of the radiopharmaceutical is assessed by whole body counts at 7 days. Less than 15% retention indicates marked loss from the intestines and bile salt malabsorption. Therapy employs an anionic, bile salt-binding resin, either cholestyramine or colestipol. The 75SeHCAT test is not avail-able in the United States. The diagnosis of bile acid–related diarrhea often depends on the clinical response to treatment with a bile acid–binding agent.

treatment and Case ConclusionThe patient is placed on 5-g packets of colesti-pol daily in a therapeutic trial. She experiences a

marked improvement in her bowel function, having formed bowel movements once a day. Nevertheless, the bloating and abdominal pains continue. Management focuses on IBS. A trial of low-dose, tricyclic antidepressant agent in the form of nortriptyline 10 to 20 mg at night improves the abdominal pain. Its presumed mechanism is to reduce the visceral hy-persensitivity component of functional gut pain. Supportive care and stress management alleviate the other symptoms.

sUMMarYBiliary sludge is a common feature that may develop during pregnancy. In a few women, sludge can progress to gall-stones or cause obstruction leading to biliary or pancreatic complications. Most have no true biliary symptoms and the sludge disappears in the postpartum period.

The management of gallstones is clear. Gallstones with-out symptoms (“silent” stones) need no treatment with few exceptions [3]. Abdominal pain is the most common symptom. The term “colic” is a misnomer, as this pain is not colicky in nature but instead is rather steady. A typical episode persists for several hours. Once symptoms develop in a person with documented cholelithiasis, the likelihood of recurrence is high. Laparoscopic cholecystectomy repre-sents definitive treatment for such symptomatic gallstones and is usually successful.

Not all right upper quadrant abdominal pain is biliary

colic. Dyspeptic symptoms are not valid features of biliary tract disease. In the absence of cholelithiasis, functional ab-dominal pain (eg, IBS) can account for pain simulating biliary colic. Biliary dyskinesia represents a functional gallbladder problem that has been characterized by absence of an overt, identifiable (organic) cause. Rather, the current hallmark is im-paired gallbladder emptying as detected by nuclear medicine scan (CCK-cholescintigraphy). This test, although valuable, has not been uniformly standardized. Further, its sensitivity and specificity is in question, a factor leading to mixed results in identifying those with acalculous biliary pain who might benefit from cholecystectomy. People with IBS who undergo cholecystectomy will likely continue to have symptoms after the surgery. Removal of the gallbladder has its own inherent risks and can also unmask bile acid diarrhea.

Acknowledgment:TheauthorappreciatestheconstructivecommentsondiagnosticimagingthatDr.SamSharekindlyprovided.

Correspondingauthor:Dr.EAShaffer,UniversityofCalgary,Div.ofGas-troenterology,TeachingResearch&WellnessBldg.,Rm.6D48,3280Hos-pitalDrNW,Calgary,Alberta,CanadaT2N4N1,[email protected].

Financialdisclosures:None.

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disorders [published erratum appears in Gastroenterology 2006;131:136]. Gastroenterology 2006;130:1466–79.

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15. Sakorafas GH, Milingos D, Peros G. Asymptomatic choleli-thiasis: is cholecystectomy really needed? A critical reappraisal 15 years after the introduction of laparoscopic cholecystec-tomy. Dig Dis Sci 2007;52:1313–25.

16. GREPCO (Rome group for epidemiology and prevention of cholelithiasis). Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984;119:796–805.

17. Gracie WA, Ransohoff DF. The natural history of silent gall-stones. The innocent gallstones are not a myth. N Engl J Med 1982;307:798–800.

18. Fenster LF, Lonborg R, Thirlby RC, Traverso LW. What symp-toms does cholecystectomy cure? Insights from an outcomes measurement project and review of the literature. Am J Surg 1995;169:533–8.

19. Ros RE, Zambon D. Post-cholecystectomy symptoms. A pro-spective study of gallstone patients before and two years after surgery. Gut 1987;28:1500–4.

20. Shaffer E. Acalculous biliary pain: new concepts for an old entity. Dig Liver Dis 2003;35 Suppl 3:S20–5.

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22. Amaral J, Xiao ZL, Chen Q, et al. Gallbladder muscle dysfunc-tion in patients with chronic acalculous disease. Gastroenterol-ogy 2001;120:506–11.

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29. Rastogi A, Slivka A, Moser AJ, et al. Controversies concerning pathophysiology and management of acalculous biliary-type abdominal pain. Dig Dis Sci 2005;50:1391–401.

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31. Frassinelli P, Werner M, Reed JF, et al. Laparoscopic chole-cystectomy alleviates pain in patients with acalculous biliary disease. Surg Laparosc Endosc 1998;8:30–4.

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Copyright 2009 by Turner White Communications Inc., Wayne, PA. All rights reserved.

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CMe evalUatiON: gallstone disease: From dyspepsia to biliary Complications

1. What percentage of Americans will develop gallstones in their lifetime?A. 1% to 5%B. 5% to 10%C. 10% to 20%D. 20% to 30%E. 30% to 40%

2. All of the following are risk factors for developing choles-terol gallstones EXCEPTA. Insulin resistanceB. Male sexC. Native American ethnicityD. ObesityE. Pregnancy

3. All of the following are included in the Rome III diagnos-tic criteria for a functional gallbladder disorder EXCEPTA. Episodes lasting less than 30 minutesB. Normal gallbladder with no sludge or stonesC. Pain in the epigastrium and/or right upper quad-

rantD. Pain not relieved by bowel movementsE. Recurrent symptoms occurring at different intervals

4. All of the following can cause impaired gallbladder emp-tying EXCEPTA. CholecystitisB. Cholesterol and pigment gallstonesC. Inflammatory bowel diseaseD. Irritable bowel syndromeE. Pregnancy

5. Which of the following is commonly considered a normal gallbladder ejection fraction in response to the 30-minute cholecystokinin infusion initiated during cholescintigra-phy?A. ≥ 10% to 15%B. ≥ 15% to 20% C. ≥ 20% to 25%D. ≥ 30% to 35%

DIRECTIONS: Each of the questions below is followed by several possible answers. Select the ONE lettered answer that is BEST in each case and circle the corresponding letter on the answer sheet.

JCOMCME

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JCOMCME

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evalUatiON FOrM: gallstone disease: From dyspepsia to biliary Complications

This activity has been planned and implemented in ac-cordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Wayne State University School of Medicine and the Journal of ClinicalOutcomes Management. Wayne State University School of Medicine is accredited by the ACCME to provide continu-ing medical education for physicians.

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