Assistant Clinical Professor of Medicine
University of Texas Southwestern Medical Center at Dallas
Staff Physician
Presbyterian Hospital of Dallas
Assistant Clinical Professor of Medicine
University of Texas Southwestern Medical Center at Dallas
Chief of Gastroenterology
Presbyterian Hospital of Dallas
Cholelithiasis and biliary tract diseases constitute a common and costly health problem in the United States.1 The prevalence of gallstones increases with age in all racial groups. Increased body weight, rapid weight loss, pregnancy, alcoholic cirrhosis, and a family history of gallstone disease also appear to be risk factors.2–4
Incidence and Prevalence of Gallstones
In one epidemiologic study of persons 30 years of age and older, new gallstones were found to develop in 2.2% of men and 2.9% of women over a 5-year period.2 In the United States, gallstones occur in approximately 10% of persons older than 40 years, but the prevalence is significantly higher in women, increasing to 20% to 25% in women older than 50 years. Fortunately, only 20% to 30% of gallstones are symptomatic, with biliary colic being the most common symptom. A report from the Third National Health and Nutrition Examination Survey (NHANES III) stated that an estimated 6.3 million men and 14.2 million women 20 to 74 years of age had gallbladder disease.5
Two principal types of stone, the cholesterol stone and the pigment stone, form in the gallbladder and biliary tract. The cholesterol stone is composed mainly of cholesterol (> 50% of the stone) and comprises multiple layers of cholesterol crystals and mucin glycoproteins. Mixed gallstones contain 20% to 50% cholesterol. The pigment stone contains a wide variety of organic and inorganic components, including calcium bilirubinate (40% to 50% of dry weight). In Europe and the United States, 90% of gallstones are of the cholesterol or mixed type; the remainder are pigment gallstones. Multiple risk factors for cholesterol and pigment gallstone formation have been identified [see Table 1]. In cholesterol gallstone formation, a genetic predisposition has been proposed on the basis of murine models and epidemiologic studies in humans; these studies show familial clustering and ethnic and geographic differences in the prevalence of cholesterol gallstone disease.6
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The pathogenesis of pigment gallstones is not completely understood, but bacteria may play a central role.7 Black pigment stones are most often seen in patients with cirrhosis or hemolytic anemia and are found predominantly in the gallbladder. Brown pigment stones, which are common in Asians, are the most common stone to appear de novo in the bile duct and are associated with biliary tract infection. Pigment stones, in contrast to cholesterol stones, are often radiopaque and can be seen on plain abdominal x-rays [see Figure 1].
Cholesterol Gallstone Formation
Cholesterol is a minor but clinically significant component of bile. The other components of bile are bile salts, phospholipids, conjugated bilirubin, fatty acids, water, electrolytes, and other organic and inorganic substances. Cholesterol is a hydrophobic molecule that is relatively insoluble in water and precipitates unless it is maintained in solution by bile salts. Bile salt molecules possess hydrophilic (water-soluble) and hydrophobic (fat-soluble) regions that maintain cholesterol in a soluble state. When bile salt molecules in water reach concentrations of 2 to 4 mM, they form spherical complexes called micelles; the concentration at which micelles form is known as the critical micellar concentration (CMC). In micelles, the negatively charged hydrophilic ends of the molecules face outward, toward the water, and the uncharged hydrophobic regions face the center of the sphere, toward one another. Cholesterol molecules are enclosed in the hydrophobic interiors.
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A pure bile salt micelle must comprise at least 50 molecules to enclose a single molecule of cholesterol. The intercalation of phospholipids, principally lecithin, between bile salt molecules improves the efficiency with which micelles solubilize cholesterol. Such a mixed micelle [see Figure 2], which is the type that exists in bile, needs only seven bile salt molecules to solubilize one cholesterol molecule. Free bile salt molecules exist in equilibrium with mixed micelles in a water solution. The combined molar concentration of bile salt and phospholipid is about 11 times that of cholesterol.
Cholesterol gallstone formation is potentiated by hepatic secretion of bile containing excess cholesterol relative to the concentration of bile salt.3,8 This occurs most often because of an increase in the biliary concentration of cholesterol but may also result from decreased bile acid secretion in certain disease states. Excess cholesterol is solubilized in micelles and in vesicles composed of phospholipid bilayers. Cholesterol crystal formation seems to occur at the surface of these vesicles.
In addition to supersaturated bile, nucleation of crystals and gallbladder stasis are also important factors in gallstone formation. Microscopic crystals initially precipitate from a supersaturated bile in a process called nucleation, which is influenced by several pronucleating and antinucleating proteins.3,8 Protein mucins, which are secreted by the gallbladder, and calcium are crucial promoters of the nucleation process. Prostaglandins stimulate the synthesis and secretion of mucins. Antinucleating factors, such as certain apolipoproteins, have been less well studied. Gallbladder stasis, with concentration and acidification of bile, is also an important factor in gallstone formation, promoting the growth of cholesterol crystals into stones. Cholesterol stones rarely recur in patients after cholecystectomy.
Biliary sludge (or microlithiasis) is a term that is often applied to cholesterol crystals of sufficient number to be visualized on ultrasonography.9 Biliary sludge, the precursor of most gallstones, is a mix of mucus, cholesterol monohydrate microcrystals, and calcium bilirubinate granules.4 Gallbladder sludge and gallstones occur in 10% of women during pregnancy and in the early postpartum period with significant spontaneous regression.10 Gallbladder sludge is also associated with fasting, rapid weight loss, parenteral nutrition, cirrhosis, and medications (ceftriaxone, cyclosporine, and octreotide).9 Gallbladder sludge has been shown to precipitate biliary colic, acute cholecystitis, or pancreatitis and should be regarded as part of the spectrum of gallstone disease. Common bile duct stones (choledocholithiasis) may form de novo in bile ducts (so-called primary, constituting 5% of bile duct stones) or migrate from the gallbladder to the biliary tract (secondary choledocholithiasis, constituting 95% of bile duct stones). Stones in the biliary tract usually have the same composition as those in the gallbladder, although some are softer and are brownish in color. The brown color is a result of deposition of calcium bilirubinate and other calcium salts as a result of bacterial deconjugation of bilirubin and hydrolysis of phospholipids. Choledocholithiasis is more common in Asian populations, owing to the increased prevalence of parasitic infections of the biliary tree (e.g., clonorchiasis, fascioliasis, and ascariasis).
There is no sure way of preventing gallstones, but one can reduce the risk of gallstone formation. Obesity is a known risk factor for gallstone formation; therefore, one should try to maintain a healthy weight. Eating regular balanced meals may prevent gallstones. The Nurses' Health Study suggested that increased consumption of vegetable protein in an energy-balanced diet can reduce the risk of cholecystectomy in women.11 Also, higher intake of trans-fatty acids increases the risk of gallstone disease in men.12 Estrogen therapy may also promote the formation of gallstones. Postmenopausal women using estrogen therapy appear to be at increased risk of cholelithiasis.13
Cholecystitis and Cholelithiasis
Patients who have stones in the gallbladder or the biliary tree display syndromes that range from acute disease to chronic symptomatic or silent disease. Most gallbladder stones remain silent throughout a person's lifetime. Diagnosis is further complicated by the fact that, with the exception of biliary colic, most symptoms of gallstones are not specific for gallstone disease.14 At any stage of disease, obstruction of the cystic duct or common bile duct by a gallstone that has passed from the gallbladder may cause pain, with or without acute inflammation.
The most common symptom of gallstones is biliary colic—a misnomer, because the pain is steady and not colicky. The pain of biliary colic is caused by functional spasm of the cystic duct obstructed by a stone, whereas the pain of acute cholecystitis is caused by inflammation of the gallbladder wall.8 Biliary colic often develops without any precipitating events. Typically, the pain is localized to the epigastrium, has a sudden onset, and increases rapidly in intensity to a plateau that can last as long as 3 hours before subsiding. Some patients describe the pain as excruciating or lancinating, whereas others describe it as a deep ache or cramp. The pain may radiate to the interscapular region or to the right shoulder, and it may be associated with nausea or vomiting. The pain is less frequently located in the left upper quadrant, precordium, or lower abdomen. Pain lasting longer than 6 hours or pain that is associated with fever suggests acute cholecystitis. Gastrointestinal symptoms, such as dyspepsia, heartburn, bloating, and fatty food intolerance, are common whether or not gallstones are present. Thus, the diagnosis of biliary colic is based on clinical judgment. Once an episode of biliary colic has occurred, repeated attacks of pain are common.
Obstruction of the cystic duct by an impacted gallstone produces acute inflammation of the gallbladder. Cholelithiasis is present in 90% to 95% of patients with acute cholecystitis with most patients having had previous attacks of biliary colic. Acute cholecystitis may present as an acalculous cholecystitis in 5% to 10% of patients, predominantly in older men who are critically ill following major surgery, severe trauma, or extensive burn injury.15 Rarely, acute cholecystitis can result from a specific infection, such as that caused by Salmonella species. Salmonella organisms can also colonize the gallbladder epithelium without inflammation (carrier state). Cytomegalovirus and cryptosporidia can infect the biliary system, resulting in cholecystitis or cholangitis in immunocompromised patients, such as those with AIDS or those who have undergone bone marrow transplantation. In men, repeated intentional weight loss and weight regain has been associated with an increased risk of symptomatic gallstone disease.16 Estrogen therapy in postmenopausal women and use of thiazide diuretics have been implicated as risk factors for cholecystitis.13,17
Clinical manifestations Clinical features of acute cholecystitis include anorexia, nausea, vomiting, fever, and abdominal pain that initially may localize to the epigastrium before shifting to the right upper quadrant. The pain typically lasts longer than 6 hours. Most patients with jaundice have stones in the common bile duct. Patients are ill for several days to a week before the acute attack completely subsides. In a meta-analysis, biliary colic was specific for gallstone disease, but 80% of patients with gallstones presented with other abdominal symptoms.14
Physical examination On physical examination, patients may present with epigastric pain or right upper quadrant subcostal tenderness and pain on inspiration, often with inspiratory arrest (the Murphy sign). Of all physical examination findings, the Murphy sign has the highest positive likelihood ratio (LR) for acute cholecystitis (2.8; 95% confidence interval, 0.8–8.6).18 The gallbladder may be palpable, especially at the time of the first attack, before fibrosis has reduced its distensibility. Tenderness, guarding, and rebound pain in the area of an inflamed gallbladder are important findings. Generalized rebound tenderness in a patient who has been ill for several days may reflect a perforation; however, localized tenderness may indicate secondary pancreatitis or an abscess in the area of the gallbladder.
Laboratory evaluation Laboratory tests frequently reveal leukocytosis and mild hyperbilirubinemia, which may occur in the absence of biliary obstruction secondary to reduced hepatic excretion of bile.19 In one prospective study, 25% of patients with acute cholecystitis had a serum bilirubin level between 2 and 5 mg/dl and had no common bile duct abnormality; 4% had an elevated amylase level and did not have pancreatitis.20 No single laboratory parameter has a sufficient positive or negative LR either to establish a diagnosis of acute cholecystitis or to rule it out.18
Imaging studies Transabdominal ultrasonography (TUS) is the diagnostic procedure of choice for a patient with suspected gallstones and acute cholecystitis. A meta-analysis revealed that ultrasonography had a sensitivity of 88% to 90% and a specificity of 97% to 98% for the diagnosis of gallstones greater than 2 mm in size.21 Gallbladder ultrasonography should ideally be preceded by an 8-hour fast, because gallstones are best visualized in a distended, bile-filled gallbladder. In addition to detecting gallstones, ultrasonography can be used to identify other causes of right upper quadrant pain, such as hepatic abscess or malignancy, and it may reveal biliary duct obstruction. However, specific evidence of acute cholecystitis (i.e., the presence of pericholecystic fluid, edema of the gallbladder wall, or both) is found infrequently. Occasionally, a so-called sonographic Murphy sign is elicited when the ultrasound probe is positioned below the right costal margin.
Cholescintigraphy is the best method of confirming the clinical diagnosis of acute cholecystitis.21 This procedure, which takes only 60 to 90 minutes, involves the intravenous injection of technetium-99m-labeled hepatoiminodiacetic acid (HIDA, or lidofenin), which is selectively excreted into the biliary tree and enters the gallbladder. In the presence of acute cholecystitis, radiolabeled material enters the common bile duct and duodenum but not the gallbladder. A meta-analysis suggests that radionuclide scanning is the most accurate method of diagnosing acute cholecystitis.21 Occasionally, the scan gives false positive results in patients who have alcoholic liver disease, in those who are fasting, or in those receiving total parenteral nutrition; however, false negative results are rare. Radionuclide scanning may not be useful for patients with deep jaundice, because the labeled agent fails to enter the biliary tree.
Direct examination of bile is more sensitive than ultrasonography in the diagnosis of biliary sludge. Ideally, cholecystokinin-induced gallbladder bile, rather than hepatic and ductal bile, should be obtained to maximize sensitivity for detecting sludge or microlithiasis. Bile must undergo centrifugation and be examined under polarizing or light microscopy for detection of crystals. Bile collected at endoscopic retrograde cholangiopancreatography (ERCP) after the injection of contrast may lead to false positive findings of crystals.22
Plain abdominal x-rays are much less useful than cholescintigraphy or ultrasonography, because only 15% to 20% of stones are radiopaque; oral cholecystography is also less useful and is now rarely performed because it requires 24 to 48 hours to perform and is less accurate than ultrasonography.
Because no single clinical or laboratory parameter carries sufficient weight in establishing or excluding acute cholecystitis,18 the differential diagnosis of acute cholecystitis is broad; it includes a number of diseases that are characterized by severe epigastric symptoms and transient abnormal results on liver function testing.
Severe acute viral hepatitis or alcoholic hepatitis may be associated with moderately severe right upper quadrant pain, fever, and leukocytosis. A history of acute alcoholism, the finding of an enlarged liver, or markedly elevated aminotransferase levels should help distinguish one of these diagnoses from acute cholecystitis.
A patient with a penetrating or perforating ulcer may have severe epigastric pain and usually has a history of ulcer; free air may be evident on a plain abdominal x-ray if the ulcer has perforated. Early in its course, acute appendicitis may produce symptoms similar to those of acute cholecystitis, particularly if the appendix is retrocecal or the cecum is malpositioned in the subhepatic area. Acute pyelonephritis of the right kidney may produce anterior pain similar to the pain that occurs with acute cholecystitis. Pneumonia or infarction of the right lung may also cause abdominal symptoms.
Acute pancreatitis may be nearly impossible to distinguish from acute cholecystitis. Patients with either disorder may exhibit moderate signs on physical examination, with tenderness or localized rebound pain in the epigastrium; serum amylase and lipase levels can be elevated in patients with either condition, but the higher these enzyme levels are, the more likely it is that pancreatitis is present. Cholelithiasis occasionally causes pancreatitis, which further complicates the diagnosis. At times, only the clinical course distinguishes pancreatitis from cholecystitis.
Ultimately, the combination of certain symptoms, signs, and laboratory results (e.g., a positive LR of 25 to 30) lead experienced clinicians to consider acute cholecystitis as the possible cause; once cholecystitis is suspected, further diagnostic imaging is required to confirm the clinical impression.18
Medical therapy Patients with a clinical diagnosis of acute cholecystitis should not be fed and should be given intravenous fluids and electrolytes. It is usually necessary to give a narcotic analgesic, such as morphine or meperidine, to alleviate severe pain. Febrile patients who have leukocytosis or bandemia (i.e., elevated circulating band forms) should be given a broad-spectrum antibiotic, such as a third-generation cephalosporin or, for broader coverage against Enterococcus, ampicillin-sulbactam or piperacillin-tazobactam. Nasogastric tube decompression may be required in patients with vomiting or evidence of an ileus. The usual course is one of gradual improvement over several days. Persistence of severe symptoms may indicate pericholecystic abscess or perforation.
Surgery Early laparoscopic cholecystectomy is recommended for acute cholecystitis, because delaying surgery does not reduce morbidity, mortality, the rate of conversion to open surgery, or mean hospital stay.23,24 In skilled hands, the laparoscopic procedure carries approximately the same risk as open cholecystectomy, but it is associated with much less postoperative pain, and the convalescence period is much shorter.25 In patients with cirrhosis, cholecystectomy is performed for emergent reasons; in these patients, cholecystectomy carries an increased risk of morbidity. In patients with compensated cirrhosis, the laparoscopic approach offers the advantages of less blood loss, shorter operative time, and shorter length of hospitalization.26 In addition, laparoscopic cholecystectomy can be safely performed during pregnancy.27 Laparoscopic cholecystectomy is less expensive than minilaparotomy or open cholecystectomy in high-volume surgery.28
In the United States, approximately 75% of all cholecystectomies are being performed laparoscopically; in 5% to 10% of these patients, the procedure has to be converted to open cholecystectomy.29 The complication rate of laparoscopic cholecystectomy is less than 5%, which is comparable to the rate reported for conventional cholecystectomy. Complications of laparoscopic cholecystectomy (e.g., bleeding and injury to the common bile duct, vasculature, and bowel) are more common when the surgeon is inexperienced.30 Although mortality appears to be lower for laparoscopic cholecystectomy than for open cholecystectomy, the total number of cholecystectomy-related deaths has not decreased over the years, because more procedures are being performed.31–33 This suggests that the benefits of laparoscopic cholecystectomy have expanded the indications for cholecystectomy.
Cholangiography can be performed during laparoscopic biliary surgery. However, because 10% to 15% of patients with acute cholecystitis may have common duct stones, the physician should consider preoperative ERCP in patients with suspected choledocholithiasis (e.g., those patients with jaundice, cholangitis or a dilated common bile duct, as seen on ultrasound).34 Common duct stones can be removed endoscopically. If endoscopic common duct stone removal is not possible, the operative procedure of choice is cholecystectomy, either open or laparoscopic in centers with expertise, for common bile duct exploration and stone removal.
In patients with acute cholecystitis, laparoscopic cholecystectomy should be performed within 96 hours of the onset of symptoms, because the increasing inflammatory changes that occur over time have been implicated in bile duct injury; these changes may necessitate converting the procedure to an open cholecystectomy.25,35
Some patients (e.g., those with septic shock, peritonitis, severe pancreatitis, portal hypertension, or marked clotting disorders) are not candidates for laparoscopic cholecystectomy. These patients should generally undergo either open cholecystectomy, if their condition permits, or simple cholecystostomy. Cholecystostomy, either operative or percutaneous and performed under ultrasound guidance, involves extracting the stones and draining the biliary tree through a catheter left in the gallbladder. Percutaneous cholecystostomy is superior to gallbladder aspiration in severe acute cholecystitis.36 Cholangiography can be carried out later through this drainage catheter. For patients who respond to cholecystostomy and who improve enough to become candidates for elective surgery, interval cholecystectomy is recommended, because the risk of recurrent symptoms is significant.35
Surgery is contraindicated for some patients because of the presence of other serious medical problems. In these cases, conservative medical therapy, including the use of antibiotics, may be the only possible approach to treatment of the acute attack.
Cholecystectomy has been associated with an increased risk of intestinal cancer. Large epidemiologic studies have suggested that cholecystectomy is associated with a modest increased risk of colon cancer but not of colon polyps.37–39 An increased risk of small bowel adenocarcinoma and carcinoids has also been demonstrated.40 The putative biologic mechanism for the increased risk of intestinal cancer after cholecystectomy has been attributed to the exposure of intestinal mucosa to altered bile acids, some of which may be carcinogenic.
The major complications of acute cholecystitis are related to severe inflammation and necrosis of gallbladder tissue.41 Jaundice in the absence of choledocholithiasis can be noted in 15% of patients with acute cholecystitis; the stone impacted in the cystic duct results in edema and swelling, leading to extrinsic compression of the common hepatic duct, the common bile duct, or both (Mirizzi syndrome).42
Localized perforation and abscess Localized perforation and abscess formation are commonly found in patients who have severe symptoms that persist for many days. Such patients usually show localized right upper quadrant tenderness and rebound pain. In patients who present acutely, the clinical differentiation of uncomplicated cholecystitis from gallbladder perforation is difficult; in this setting, sonography is the initial diagnostic modality.43 These patients often have diabetes or other immuncompromising conditions. Free perforation occurs in 2% to 10% of patients with acute cholecystitis; it is associated with a mortality of 10% to 30%.44 A delay in the diagnosis of acute cholecystitis can result in a gallbladder distended by clear mucoid fluid (hydrops of the gallbladder).
Empyema Empyema of the gallbladder occurs in 2% to 3% of patients with acute cholecystitis.45 Typically, abdominal pain is severe and lasts for more than 7 days. The physical examination is not distinctive. Mortality approaches 25%; death often occurs as a result of septicemia.
Emphysematous cholecystitis
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Emphysematous cholecystitis, which has a higher morbidity than uncomplicated acute cholecystitis, is usually caused by gas-forming bacteria, such as Clostridium perfringens and other clostridia, Escherichia coli, or anaerobic streptococci. Patients who have such infections are often very ill, and 20% also have diabetes or are compromised by coexisting conditions. Emphysematous cholecystitis occurs three times more often in men than in women.46 Many cases of this type of cholecystitis are not associated with cholelithiasis. A plain abdominal x-ray, ultrasound, or computed tomography scan frequently reveals gas within the gallbladder [see Figure 3].
Cholecystenteric fistula Another possible complication of acute cholecystitis is a cholecystenteric fistula, in which the gallbladder is connected either to the duodenum or the hepatic flexure of the colon. In rare cases, the gallbladder communicates directly with the stomach or jejunum. A large gallstone (> 2.5 cm in diameter) will erode through the gallbladder wall into the duodenum. Subsequently, the stone may become impacted at the terminal ileum, causing small bowel obstruction, or in the duodenal bulb, resulting in gastric outlet obstruction (Bouveret syndrome). Treatment of cholecystenteric fistula usually consists of one-stage cholecystectomy, exploration of the common bile duct, closure of the fistula, and extraction of the impacted stone.
Gallstones and malignancy Gallstones are present in 65% to 90% of patients with gallbladder cancer, although it is not clear whether gallstones themselves are the causal factor.47 A palpable gallbladder is usually found in malignant obstruction of the common bile duct (Courvoisier's law) and is uncommon in cases in which obstruction is caused by gallstones.
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Chronic cholelithiasis is usually accompanied by evidence of chronic cholecystitis. The wall of the gallbladder is often thickened, fibrotic, and rigid, and the gallbladder is thus prevented from contracting and expanding normally. This condition may arise from a series of attacks of acute cholecystitis, from chronic mechanical irritation by calculi, or from both. The gallbladder wall may calcify and appear as the so-called porcelain gallbladder on plain abdominal x-ray [see Figure 4].
Clinical manifestations It is difficult to attribute any symptom to chronic cholecystitis per se. Complaints of flatulence, heartburn, and nonspecific postprandial distress are common in patients with chronic cholecystitis, but such symptoms are also common in patients with no evidence of gallbladder disease. It is possible, however, to elicit a history of discrete attacks of abdominal pain resembling those of acute cholecystitis.
Physical examination Findings on physical examination are usually normal unless the patient is experiencing an acute attack of cholecystitis. The gallbladder is rarely palpable because scarring associated with chronic cholecystitis prevents expansion.
Laboratory evaluation Results of routine laboratory tests are usually normal; occasionally, the serum alkaline phosphatase level is modestly elevated.
Imaging studies
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TUS is the procedure of choice for the diagnosis of chronic gallbladder disease. In 90% to 95% of cases of cholelithiasis, ultrasonography demonstrates the echo of the calculus and the acoustic shadow behind the calculus [see Figure 5]. When the ultrasound is nondiagnostic, oral cholecystography may still be used to evaluate a patient with suspected gallbladder disease. If a double dose of the oral contrast agent fails to cause gallbladder opacification, cholelithiasis and chronic cholecystitis are almost certainly present. Cholescintigraphy [see Acute Cholecystitis, above] is not helpful in diagnosing chronic cholelithiasis or chronic cholecystitis.
ERCP may reveal gallstones in the gallbladder of patients who have biliary tract pain and whose oral cholecystograms and gallbladder sonograms are normal. In one study, small gallstones were identified on ERCP in 29 of 206 such patients (14%); the presence of these stones was confirmed during surgery.48 CT or magnetic resonance imaging may also detect gallstones, but these techniques are unlikely to demonstrate stones not detected by ultrasonography. Endoscopic ultrasound (EUS), with or without duodenal bile aspiration, may be a promising diagnostic approach in patients with typical biliary symptoms but normal TUS.49–51
Additional tests Gallbladder bile can be obtained by nasogastric tube or endoscopic aspiration in the duodenum after infusing cholecystokinin intravenously to promote gallbladder emptying. In patients with biliary sludge or microlithiasis, examination of bile under light and polarizing microscopy can show cholesterol crystals, which appear as rhomboid plates with a notch in one corner. Bile collected from the common bile duct at ERCP rarely contains precipitate because of rapid transit of hepatic bile through the biliary system.9 Additionally, bile collected from the common bile duct at ERCP after the injection of contrast can lead to false-positive results.22 In one small study, EUS-guided aspiration of gallbladder bile was complicated by bile peritonitis in two of three patients.52 Although some consider bile microscopy to be the gold standard in diagnosing sludge, crystal analysis is limited by the need for invasive evaluation, meticulous sample processing, and institutional expertise.
Surgery Elective cholecystectomy is indicated for patients who have symptomatic gallstones and chronic cholecystitis. Recurrent pain is to be expected in these patients if cholecystectomy is not performed. As many as 50% of patients with symptomatic gallstones who do not undergo cholecystectomy experience serious complications within 20 years of the initial onset of symptoms.53
It is occasionally difficult to determine whether abdominal symptoms are secondary to documented gallbladder disease. A history of typical recurrent pain makes this determination easier. In certain cases, elective cholecystectomy is performed as a last diagnostic procedure when a thorough search for other causes of abdominal symptoms has proved negative. All too often, the symptoms recur postoperatively.
Dissolution therapy Oral bile acids such as ursodeoxycholic acid (8 to 12 mg/kg/day) and chenodeoxycholic acid (13 to 15 mg/kg/day) can decrease biliary cholesterol levels with complete gallstone dissolution; when administered for months to years, ursodeoxycholic acid and chenodeoxycholic acid can result in complete gallstone dissolution in 30% and 14% of patients, respectively.54 In one study, combination therapy with these two agents was not found to be superior to monotherapy with ursodeoxycholic acid.55 Chenodeoxycholic acid has largely been replaced by the safer ursodeoxycholic acid. However, these drugs are effective only in patients who have small cholesterol stones and a functioning gallbladder. A high rate of gallstone recurrence is noted after cessation of therapy. The infusion of methyl tert-butyl, ether through a transhepatic catheter directly into the gallbladder, can rapidly dissolve cholesterol stones.56 The rapid infusion and removal of this ether, which remains liquid at body temperature, results in the dissolution of most cholesterol gallstones within 4 to 31 hours. Dissolution therapy has limited value except in patients who are poor candidates for surgery.
Extracorporeal biliary lithotripsy Stones in the gallbladder or common bile duct have been successfully fragmented using extracorporeal shock wave lithotripsy (ESWL), a technique widely employed for the nonsurgical fragmentation of kidney stones. Patients undergoing biliary ESWL are carefully positioned and monitored so that the shock waves are targeted at the gallstones. The highest success rates of biliary ESWL are seen in patients who have a solitary radiolucent solitary gallstone less than 2 cm in diameter; 60% to 84% of these patients are free of stones 6 to 12 months after therapy.57 ESWL has been associated with low rates of adverse events, such as pancreatitis, biliary pain, hepatic hematoma, and hematuria. The administration of oral ursodeoxycholic acid after fragmentation of stones has been associated with an increase in the percentage of patients who are free of gallbladder stones 6 months after ESWL.58,59 In one study, 21% of patients who received 10 to 12 mg/kg/day of ursodeoxycholic acid daily for 6 months after ESWL were free of gallbladder stones; in contrast, of patients who received placebo for 6 months, only 9% were free of stones.59 Stone fragments in the common bile duct may pass spontaneously after endoscopic sphincterotomy or can be extracted with a basket. The usefulness of biliary ESWL is limited by its high rate of gallstone recurrence and the widespread availability of laparoscopic cholecystectomy.
Most gallstones are asymptomatic (silent gallstones). In one prospective study, gallstones or evidence of previous cholecystectomy was present in 291 of 1,701 persons (17%) at the time of postmortem examination.60 Of these 291 persons, only 31 had undergone cholecystectomy, presumably because of symptomatic disease. Ten deaths were directly attributable to the gallstones; four of these deaths occurred after cholecystectomy.
Silent gallstones seldom lead to problems. In a long-term follow-up study of asymptomatic patients, the cumulative risk of the development of symptoms was 10% at 5 years, 15% at 10 years, and 18% at 15 years or later.61 Nineteen percent of patients who experienced symptoms (2.5% of the entire group) subsequently developed acute cholecystitis or pancreatitis. No patients died of gallbladder disease during a mean follow-up period of more than 10 years.
Asymptomatic gallstones are usually identified incidentally with TUS or pelvic ultrasonography performed for other diagnostic purposes, such as the evaluation of gynecologic symptoms or findings on physical examination.
Patients who have asymptomatic gallstones should generally be managed conservatively without surgery. Exceptions may be made for patients at increased risk for gallbladder cancer, such as Pima Indians, persons with calcified gallbladders (porcelain gallbladder), patients with very large gallstones (> 3 cm), and patients with an associated gallbladder polyp greater than 10 mm in diameter.62
In the past, prophylactic cholecystectomy was recommended for diabetic patients who had asymptomatic gallstones; anecdotal reports suggested that such patients did poorly when cholecystectomy was performed as an emergency procedure. However, two well-controlled retrospective studies of patients undergoing surgery for acute cholecystitis, as well as a decision analysis, showed that diabetes was not an independent risk factor of operative mortality or serious postoperative complications, and prophylactic cholecystectomy resulted in a shortened life span.63,64 Thus, prophylactic cholecystectomy cannot be recommended for patients with diabetes.
Choledocholithiasis, a condition in which a stone lodges in the common bile duct after passage from the gallbladder through the cystic duct, develops secondary to chronic cholelithiasis in 15% to 20% of patients.8,65 Primary common bile duct stones are more commonly seen in Asian populations than in the Western world. This increased incidence of primary common bile duct stones is attributed to the increased prevalence of flukes and parasitic infections (e.g., clonorchiasis, fascioliasis, ascariasis) in Asia. Other risk factors for choledocholithiasis include the presence of periampullary diverticula and advancing age.66
Clinical manifestations The signs and symptoms associated with choledocholithiasis vary. Some patients have no symptoms, whereas others may present with an acute serious illness. Pain, which is a common feature, is often located in the right upper quadrant or midepigastrium, with radiation to the interscapular region. Pain may be associated with nausea or vomiting, or both; it can be indistinguishable from biliary colic. Cholangitis may present with Charcot triad (fever, pain and jaundice) or Reynold pentad (Charcot triad of symptoms, hypotension, and mental status change). Patients may also present with pancreatitis.
Physical examination Vital signs may reveal an elevated temperature. In more acutely ill patients, hypotension and tachycardia may occur. Findings on physical examination may include tenderness and guarding in the right upper quadrant and midepigastrium. Hepatomegaly may be found when common bile duct obstruction has been present for some time. Scleral icterus may be also be seen.
Laboratory evaluation Both serum bilirubin and alkaline phosphatase levels can rise markedly. However, when the stones do not obstruct the duct, the serum bilirubin level may rise only slightly or not at all, whereas the alkaline phosphatase level is substantially elevated. Typically, serum aminotransferase levels rise only modestly. It would be unusual to see aminotransferase levels greater than 1,000 IU/L. In some instances, aminotransferase levels rise and fall rapidly early in the course of bile duct obstruction.
Imaging studies
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TUS may detect only 50% of common bile duct stones.67 TUS can often detect a dilated common bile duct and intrahepatic ducts. The sensitivity of TUS for detecting common duct stones increases to 76% when ductal dilation greater than 6 mm is used as the primary endpoint for choledocholithiasis. CT is no more sensitive or specific than TUS. Cholescintigraphy may show common bile duct obstruction, particularly when symptoms are of recent onset, but not all common bile duct stones will cause complete bile duct obstruction. Magnetic resonance cholangiopancreatography (MRCP) and EUS are similar with regard to accuracy in detecting common bile duct stones. MRCP [see Figure 6] is noninvasive and may be preferred in cases where the suspicion of choledocholithiasis is mild to moderate.68,69
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ERCP allows radiographic visualization of the biliary tree [see Figure 7] and the option of therapeutic intervention.70,71 EUS has greater sensitivity and specificity than ERCP in the detection of common bile duct stones but lacks the therapeutic option available with ERCP.72 Therefore, ERCP is the test of choice if common bile stones are highly suspected on the basis of history, physical examination, and laboratory and imaging studies. Percutaneous transhepatic cholangiography (PTC) involves accessing the bile ducts via a small needle.73 The success rate of PTC in patients with dilated ducts is close to 100%; nondilated ducts are entered successfully about 70% of the time. Complication rates for both ERCP and PTC approach 5%. ERCP has replaced PTC as the technique of choice.
Endoscopic sphincterotomy is the initial treatment for the patient with choledocholithiasis. In one large study, sphincterotomy was successful in 97.5% of patients with common bile duct stones, although more than one attempt was necessary in some patients. The overall rate of clearance of bile duct stones was 84.5%. The remaining patients required either surgery or the permanent placement of a biliary endoprosthesis. The overall complication rate was 6.9%; the complications included bleeding, cholangitis, pancreatitis, and perforation. The 30-day procedure-related mortality was 0.6%.74 Follow-up studies have shown a low rate of recurrence of biliary duct problems and a low incidence of papillary stenosis.75 Operative exploration of the common duct should be reserved for the few patients in whom endoscopic sphincterotomy is unsuccessful. Laparoscopic removal of biliary stones may be an alternative to preoperative ERCP.76,77
Endoscopic sphincterotomy is also the treatment of choice for patients with retained bile duct stones after gallbladder or biliary tract surgery. If sphincterotomy fails and if the patient has a T tube in place, instrumental extraction through the mature T-tube tract may be successful. Surgical exploration of the biliary tree is indicated if nonsurgical treatments fail.
Mirizzi syndrome refers to an obstruction of the common hepatic duct caused by a stone impacted at the neck of the gallbladder or the cystic duct. Mirizzi syndrome can be classified into two basic types.78 In Mirizzi type I syndrome, there is only an extrinsic compression of the common hepatic duct by the gallstone and the accompanying inflammatory process. In Mirizzi type II syndrome, a cholecystocholedochal fistula is established by the mechanism of pressure-induced necrosis from the gallstone.
The clinical presentation of individuals with Mirizzi syndrome varies greatly.79 Obstructive jaundice is commonly seen. However, 20% to 40% of patients may present without jaundice or have normal serum aminotransferase levels.80 Biliary imaging tests many times fail to demonstrate the features of Mirizzi syndrome; therefore, successful management of patients with Mirizzi syndrome is a challenge and relies heavily upon clinical suspicion and early recognition by the treating physician.
Nonsurgical treatment of Mirizzi syndrome is limited and suboptimal. Long-term biliary stenting has a relatively high incidence of complications, including cholangitis and secondary biliary cirrhosis.79 Nonsurgical lithotripsy and stone removal is restricted to patients with Mirizzi type II syndrome.81 In Mirizzi type I syndrome, the offending stones are not accessible for clearance via bile ducts. Cholecystectomy is the treatment of choice. If the gallbladder is not removed, patients with Mirizzi syndrome are left at significant risk for complications from continued gallstones disease, including acute cholangitis, cholecystitis, liver abscess, secondary biliary cirrhosis, and perhaps gallbladder carcinoma.79,81,82 Nonsurgical treatment of patients with Mirizzi syndrome should be limited to those that have an increased or unreasonable risk for abdominal surgery or a shortened life expectancy.
Chronic inflammation of biliary ducts is usually caused by partial or complete obstruction of the biliary tree. Some patients with chronic cholelithiasis or other chronic disease of the biliary ducts will experience associated chronic inflammation or stricturing of the biliary tree.
Clinical manifestations Patients with chronic inflammation of the biliary tree may complain of fatigue, intermittent fever and chills, anorexia, pruritus, and weight loss. The physical examination may be fairly unremarkable. One should look for jaundice, excoriations of the skin related to marked pruritus, and stigmata of chronic liver disease.
Laboratory evaluation Laboratory testing will often reveal chronically elevated serum alkaline phosphatase levels and increased levels of serum 5'-nucleotidase, leucine aminopeptidase, and g-glutamyl transpeptidase (GGT). Transient elevations of the total bilirubin can also been seen.
Imaging studies Direct visualization of the biliary tree is important in determining whether the symptoms and signs result from an anatomic defect that can be corrected by endoscopic therapy or surgery. Use of MRCP or ERCP usually leads to identification of the obstructive site.
Common bile duct strictures may be benign or malignant, and the appearance of both forms of strictures, as imaged by ERCP or MRCP, can be quite similar. Evaluation of biliary strictures with brush cytology, fine-needle aspiration, endoscopic pinch forceps biopsy, or aspiration brush biopsy allows for epithelial sampling. The sensitivity of brush cytology is as high as 70% for the diagnosis of a malignant stricture of the bile duct; specificity is as high as 100%. Simple bile aspiration alone is not as reliable. Common bile duct stricture, which may result from biliary tract surgery, can be treated endoscopically with balloon dilation or with the placement of an endoprosthesis. If either of these treatments is unsuccessful, surgical intervention may prove beneficial for selected patients.
Primary Sclerosing Cholangitis
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Primary sclerosing cholangitis (PSC) is a disease of unknown etiology that is characterized by an irregular inflammatory fibrosis of both the intrahepatic and extrahepatic bile ducts [see Figure 8].83 It usually occurs in men between the ages of 20 and 50 years. Patients may present with jaundice, pruritus, nonspecific pain, fever, and weight loss. Approximately 75% of patients will have chronic ulcerative colitis. Liver function tests show cholestatic abnormalities.83 Ursodeoxycholic acid therapy will usually result in an improvement in the biochemical markers of cholestasis, but it has not shown a survival benefit.84 Endoscopic treatment of significant ductal strictures may also improve biochemical markers of cholestasis and reduce the number of episodes of cholangitis.85 A combined approach using therapeutic stricture dilation and ursodeoxycholic acid therapy may benefit a select group of patients. Patients with PSC are at increased risk for cholangiocarcinoma. The incidence of cholangiocarcinoma in patients with PSC is as high as 30%, and there is an increased risk of gallbladder and pancreatic cancer.86 A substantial number of patients with PSC may have undetected cholangiocarcinoma at the time of liver transplantation.
Recurrent Pyogenic Cholangitis
Recurrent pyogenic cholangitis (RPC), as its name suggests, is characterized by recurrent bouts of cholangitis. It most commonly affects patients of Asian descent. Patients typically present with repeated attacks of fever, chills, abdominal pain, and jaundice. Laboratory tests usually demonstrate an elevation in serum bilirubin and alkaline phosphatase. Elevations in serum aminotransferases and prothrombin time signify hepatocyte injury, although the prothrombin time may also be prolonged because of vitamin K malabsorption.87 The exact etiology of RPC is unclear. Some propose a dietary or infectious etiology for the condition. The parasites Opisthorchis sinensis and Ascaris lumbricoides are commonly found in the stools of affected patients.88 Imaging studies, such as sonography, may be somewhat confusing in patients with RPC, because there may be areas of intrahepatic biliary dilation without common bile duct dilation. Evaluation using CT or MRCP usually defines the areas of intrahepatic and extrahepatic biliary dilation more clearly the sonography and provides three-dimensional information.89 ERCP is often required to confirm areas of stricturing and dilation. ERCP also allows for possible therapeutic intervention. PTC provides access to peripheral ducts that may be inaccessible by ERCP.90 Treatment usually consists of antibiotics and improvement of biliary drainage (endoscopically or surgically).
Biliary cystic disease includes choledochal cyst disease and the less common gallbladder cysts and cystic duct cysts.91 Choledochal cyst is an ectasia of the common bile duct that may present in late childhood or in adult life as obstructive jaundice. The cause of the disorder is not fully defined, and both congenital and acquired etiologies are postulated.92
Choledochal cysts may involve any segment of the bile duct and are categorized according to the classification proposed by Todani and colleagues [see Table 2]. An abnormal pancreatobiliary duct junction is more common in patients with choledochal cysts and could expose the bile ducts to pancreatic juices and abnormally high pressures. Type I cysts are the most common, accounting for 40% to 60% of all cases, followed by type IV. Types II, III and V are rare.
Diagnosis Clinical manifestations of choledochal cysts in children include abdominal pain, cholangitis, and an abdominal mass. A palpable mass is unusual in adults, because adults tend to present with recurrent cholangitis, pancreatitis, or, rarely, portal hypertension.
Diagnosis may be achieved by several different types of imaging studies. Sonography may delineate the cyst and intrahepatic portions of the disease. CT and MRCP may provide useful information in regard to the extent of disease and potential malignancy. ERCP, PTC, and intraoperative cholangiography are important for the evaluation and planning of surgical treatment of bile duct cysts.
Treatment The initial management of patients with choledochal cysts depends on the age of the patient, the presentation, and the type of the cyst. In terms of definitive treatment, pharmacologic or endoscopic management offers little benefit in that they do not address the well described malignant potential of bile duct cysts.93 Therefore, the primary role of endoscopic procedures is in the initial evaluation and diagnosis of bile ducts cysts. Endoscopic interventions such as lithotripsy, stone extraction, and laser ablation have been successful in the treatment of intrahepatic and extrahepatic biliary stones in patients with Caroli disease, a congenital disorder associated with renal cystic disease of varying severity.94 The current standard for surgical treatment in the patient who is a reasonable surgical risk is excision of the cyst with free biliary drainage into the gastrointestinal tract. The classical surgical reconstruction is a hepaticojejunostomy with a Roux-en-Y [see Table 2] reconstruction.95
Sphincter of Oddi dysfunction (SOD) is a benign condition of intermittent or permanent obstruction of biliary drainage, pancreatic drainage, or both that is caused by either a stenosis or by smooth muscle dysfunction of the sphincter muscle.96 Biliary SOD is classified by using the modified Milwaukee criteria [see Table 3].
Diagnosis Biliary SOD is usually seen in women in their fourth to sixth decades of life. The symptoms arise typically after cholecystectomy, although SOD may occur in patients with an intact gallbladder.97,98 The clinical presentation of biliary SOD is episodic abdominal pain in the epigastric or right upper quadrant region that may radiate to the back or shoulders. It may be associated with nausea or vomiting that worsens with eating. Laboratory tests may reveal abnormalities in liver function. Right upper quadrant sonography and CT may reveal a dilated common bile duct.
ERCP with sphincter of Oddi manometry is the gold standard for the diagnosis of SOD. A basal sphincter pressure of greater than 40 mm Hg is abnormal and indicative of SOD.99 Other tests that are noninvasive and less reliable may also indicate the presence of SOD; such tests include a provocation test using morphine (or neostigmine), which produces biliary pain and serum aminotransferase elevation; ultrasound evaluation of dilation and emptying of the common bile duct after secretin stimulation; and the scintigraphic evaluation of the kinetics of ductal emptying.100
Sphincter of Oddi manometry is not required to confirm the diagnosis in biliary type I SOD. However, patients with biliary type II SOD should undergo sphincter of Oddi manometry because only 50% of these patients have SOD. In biliary type II SOD, only patients whose SOD is confirmed by sphincter of Oddi manometry should undergo endoscopic sphincterotomy. Sphincter of Oddi manometry, endoscopic sphincterotomy, or both have low efficacy in patients with biliary type III SOD.
Treatment A low-fat diet may decrease biliary or pancreatic stimulation, although the efficacy of this approach is unknown. Endoscopic sphincterotomy is the primary treatment for patients with type I SOD and for patients with types II and III disease in whom the presence of SOD has been confirmed by manometry. Over 90% of patients with type I SOD will have a favorable response to endoscopic sphincterotomy; therefore, manometry should not be performed. Pharmacologic therapies (i.e., calcium channel blockers and nitrates) are primarily used in patients with type III disease, because in these patients, sphincter of Oddi manometry has the greatest risk of complication and the smallest diagnostic yield. Treatment with calcium channel blockers and nitrates decreases pain by relaxing the sphincter smooth muscle.101 Other endoscopic therapies such as balloon dilation, injection of botulinum toxin, temporary stent placement, and surgical sphincteroplasty are not widely used.102–104
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Acknowledgments
Figure 1 Courtesy of William E. Stevens, M.D.
Figure 2 Alan Iselin.
Figure 3 Courtesy of Laura Thomas, M.D., and Mark Feldman, M.D.
Figures 4 and 5 Courtesy of Mark Feldman, M.D.
Figure 6 Courtesy of David Riepe, M.D.
Figures 7 and 8 Courtesy of Malcolm F. Anderson, M.D.
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