1. Gallstone Disease 

Gallstones (cholelithiasis) are the most common cause of biliary tract disease in adults, afflicting 20-30 million persons in North America. Approximately one-fifth of men and one-third of women will eventually develop cholelithiasis. In Canada, calculous disease of the biliary tract is also a major health hazard, accounting for about 130,000 admissions to hospital and 80,000 cholecystectomies annually. Cholecystectomy is the second most common operation in Canada and the United States, where it is performed six to seven times as often as in the United Kingdom or France. Although the frequency of gallstone disease does vary between countries and regions, it is high in both Western Europe and North America (Table 1). The recent advent of laparoscopic cholecystectomy has further increased the use of surgery. Such variance suggests overuse of our health-care system, particularly as few (20%) ever become symptomatic.

Two major types of gallstones exist (Table 2).

1. Cholesterol stones are hard, crystalline stones that contain more than 50% cholesterol plus varying amounts of protein and calcium salts. They predominate (>85%) in the Western world.

2. Pigment stones consist of several insoluble calcium salts that are not normal constituents of bile.

1.2.1 CHOLESTEROL STONES

Cholesterol gallstones form in three stages (Figure 1).

Bile secreted by the liver becomes supersaturated with cholesterol. Such abnormal bile contains an excess of cholesterol relative to the solubilizing agents, bile salts and the phospholipid, lecithin. This stage may develop as early as puberty and is often associated with obesity. The liver, perhaps as a result of genetic programming, produces supersaturated bile by a decreased secretion of bile salts, an increased secretion of cholesterol, or both. Obesity is associated with excess cholesterol production. With ileal disease or loss, bile salt malabsorption breaks the enterohepatic circulation, decreasing its hepatic return and thus decreasing secretion. Reduced bile flux through the liver produces lithogenic bile with excess cholesterol.

The excess cholesterol precipitates out of solution as solid microcrystals. A nucleating factor (e.g., mucin) secreted in bile hastens this relatively rapid precipitation. Conversely, there may be a deficiency of antinucleating factors.

The cholesterol microcrystals precipitate from bile, are retained, aggregate and grow into macroscopic stones. Retention occurs in the gallbladder because the epithelium in stone-formers secretes excess mucus (consisting of mucin, a glycoprotein). This mucus gel forms a colloidal shell that entraps cholesterol microcrystals, preventing them from being ejected from the gallbladder. Mucin also creates a scaffold for the addition of more crystals. A defect in the contractile function of the gallbladder smooth muscle results in failure to properly evacuate the solid material.

"Biliary sludge" consists of calcium bilirubinate, cholesterol microcrystals and mucin. On ultrasound, biliary sludge is echogenic material that layers but does not cast an acoustic shadow (unlike gallstones). Sludge develops in association with conditions causing gallbladder stasis, such as pregnancy or total parenteral nutrition. Though frequently asymptomatic and prone to disappear, sludge in the gallbladder can produce biliary-type pain and progress to overt gallstones or precipitate pancreatitis.

In North America, black pigment stones constitute about 15% of gallstones found at surgery (cholecystectomy). They are frequently associated with hemolysis or alcoholic cirrhosis (Table 3). The basis for their formation is excessive bilirubin excretion in bile. Brown pigment stones are associated with stagnation and infection (often from a stricture) or infestation (e.g., liver flukes) of the biliary tract. Such conditions predispose to chronic cholangitis and eventually cholangiocarcinoma. Infection and inflammation increase b-glucuronidase, an enzyme that deconjugates bilirubin; the resultant free bilirubin then polymerizes and complexes with calcium, forming calcium bilirubinate in the bile duct system.

Gallstones grow at about 1-2 mm per year over a 5- to 20-year period before symptoms develop. They frequently are clinically "silent," being incidentally detected on routine ultrasound performed for another purpose. Most patients (80%) with gallstones never develop symptoms. Problems, if they do occur, usually arise in the form of biliary pain during the first 5 to 10 years. Complications are from stones obstructing

1. the cystic duct, leading to cholecystitis: this begins as a chemical inflammation and later may become complicated by bacterial invasion; or

2. the common duct, causing biliary obstruction (cholestasis), sometimes accompanied by bacterial infection in the ductal system (cholangitis) (Figure 2).

Biliary colic pain ensues when an obstructing stone causes sudden distention of the gallbladder and/or the biliary tract. "Colic" is a poor term, as biliary pain typically does not increase and decrease spasmodically. Rather, abdominal pain onsets suddenly, quickly becomes severe, remains steady for 1 to 3 hours and then gradually disappears over 30 to 90 minutes, leaving a vague ache. Its duration may be less than an hour, but is not as brief as 15 to 30 minutes. Although biliary-type pain can follow a fatty or spicy meal, such "fatty food intolerance" is not specific for biliary tract disease. Its location usually is the epigastrium or right upper quadrant. Mediated by splanchnic nerves, biliary pain may radiate like angina to the back, right scapula or shoulder tip, down the arm or into the neck. The pain may also be confined to the back. Analgesics are usually required for relief. Episodes of pain occur irregularly, being separated by pain-free periods lasting from days to years. The severity of pain also varies. Being a visceral pain, biliary colic is not aggravated by movement but is deep-seated. The patient is usually restless and may exhibit vasomotor features such as sweating and pallor. Nausea and vomiting often accompany a severe attack. Fever and rigors are absent unless infection supervenes.

Findings consist of right upper quadrant or epigastric tenderness, perhaps with some guarding. During an attack or often soon after one, the pain disappears. There are no peritoneal signs. Often the examination is completely normal.

Laboratory tests are usually normal. In 10-20% of cases, there may be a slight elevation of serum bilirubin, alkaline phosphatase, aminotransferases (AST and ALT) or g-glutamyl transpeptidase (GGT).

Between attacks the patient feels well. Liver biochemistry is normal. Over long periods the activity of the disease remains fairly constant. If having frequent episodes of biliary pain, the patient will probably continue to experience this pattern.

Pain lasting more than 6 to 12 hours, especially if accompanied by persistent vomiting or fever, suggests another process such as cholecystitis or pancreatitis (Table 4). Conversely, abdominal pain and bloating relieved by defecation suggests the irritable bowel syndrome.

Diagnosis of the gallstones (but not symptomatic disease) is radiological. Plain abdominal x-ray will identify the 10-15% with a high calcium content as radiopaque densities in the right upper quadrant. Ultrasonography is the most sensitive and specific method for detecting gallstones (appearing as echogenic objects that cast an acoustic shadow) or a thickened gallbladder wall (indicating inflammation). In suspected cases of acute cholecystitis, cholescintigraphy will assist the diagnosis by failing to visualize the gallbladder because of a stone obstructing the cystic duct.

1.6.1 MEDICAL THERAPY

1.6.1.1 Expectant

Management should be expectant in asymptomatic adults with gallstones, as most will never develop problems. In minimally symptomatic patients without major complications or those unfit for or unwilling to undergo surgery, medical therapy offers techniques for dissolving, fragmenting or extracting stones.

1.6.1.2.1 Bile acids

Administered orally, bile acids can dissolve cholesterol gallstones. Two bile acids, chenodeoxycholic acid and ursodeoxycholic acid, work to reduce cholesterol saturation of bile. The stones must be radiolucent and hence presumably composed of cholesterol, and the gallbladder must function (i.e., fill and empty through a patent cystic duct) for the unsaturated bile to bathe the stones. Gallbladder function can be assessed by visualization on either oral cholecystography or cholescintigraphy, or by change in gallbladder size on fatty meal ultrasonography. The reported success rate varies from 13-80% over one to two years. Gallstone size largely determines the success rate. Stones must be less than 1.5 cm in diameter. Small stones with a relatively great surface area have the best result. Ideal cases have tiny (< 0.5 cm) gallstones that float on oral cholecystography (floating indicates a low calcium content); here, dissolution has a success rate greater than 80%. Large stones in obese individuals have less favorable results. Chenodeoxycholic acid (15 mg/kg/day), though cheaper, has significant side effects in terms of dose-related diarrhea and liver damage. Ursodeoxycholic acid (8-10 mg/kg/day) is therefore the drug of choice. It also reduces the frequency of episodes of biliary colic. Combination therapy with both agents at lower doses appears to be equally effective and safe. Ursodeoxycholic acid therapy can result in calcification of gallstones, negating dissolution; combination therapy avoids this. About 15-20% of patients are candidates for ursodeoxycholic acid therapy. Even after successful dissolution, 50% will experience gallstone recurrence, although most are asymptomatic. Prevention of gallstone formation is possible in those at high risk, such as obese people undergoing rapid weight loss either after gastric bypass surgery or while on a very restrictive caloric diet.

The surface area of gallstones is so critical to successful dissolution that stone fragmentation has been undertaken with shock-wave lithotripsy. This is then followed by bile acid therapy to dissolve the residual fragments. Ultrasonic fragmentation has a low complication rate: 1% develop pancreatitis, 40% experience biliary pain. The cystic duct must be patent (i.e., the gallbladder must function as demonstrated by oral cholecystography or cholescintigraphy). Within a year, 60-80% will go on to successful clearance of debris from the gallbladder using oral bile acids to dissolve the remnants. Best results (up to 95% success) occur with a single gallstone 2 cm in diameter. Again, only about 20% of patients overall are eligible. Gallstones can recur, although the rate is low at 15%.

1.6.2.1 Open cholecystectomy

The term "open" connotes the need for an incision to open the abdominal cavity for direct visualization and operation. In contrast, the laparoscopic technique uses endoscopy and tiny incisions. Cholecystectomy is the "gold standard" for treating gallstone disease. The operation is relatively safe, with mortality less than 0.5% when electively performed for biliary colic. Mortality reaches 3% for emergency surgery in acute cholecystitis or for common duct procedures, and is higher in the elderly.

This technique views the abdominal contents through a laparoscope (with the peritoneal cavity insufflated with gas) and uses instruments inserted through three trocars in the abdominal wall to perform surgical manipulation. In 5% of cases the procedure must be converted to an open cholecystectomy because of technical problems. There is overwhelming enthusiasm for this procedure because it leaves the patient with less postoperative pain and with tiny scars, and it allows for an early discharge from hospital (about two days) and return to work. Selected cases can even be done on an outpatient basis. The disadvantage is a somewhat higher complication rate, particularly from common duct injury and retained common duct stones, plus the potential for overuse. Laparoscopic cholecystectomy is now the standard for elective surgery and for most cases of acute cholecystitis.

Surgery is indicated in those with significant symptoms (e.g., repeated visits to the emergency room for narcotic relief) or with complications. Prophylactic cholecystectomy is not warranted except for rare cases suspected of developing/harboring carcinoma of the gallbladder (e.g., very large stones >3 cm or a calcified gallbladder wall). It generally should not be done on asymptomatic people with gallstones.