Gallstones

I. ANATOMY AND PHYSIOLOGY

The biliary tract starts at the hepatocyte canaliculi, which empty into biliary ductules. Larger ducts join the right and left hepatic ducts, which drain into the common hepatic duct (CHD) at the porta hepatis. When the cystic duct from the gallbladder joins the CHD, the common bile duct (CBD) is formed. The CBD is usually 8 cm long and 0.5 to 0.9 cm in diameter. It passes behind the first portion of the duodenum, through a groove in the head of the pancreas, and empties into the second portion of the duodenum at the ampulla of Vater. Distally the pancreatic duct may join the CBD before it also empties into the ampulla.

The gallbladder, a pear-shaped distensible organ, 4 × 8 cm in size with a normal capacity of 30 to 50 mL, lies in a fossa on the visceral surface of the liver on a line separating the right and left hepatic lobes. When distended with acute inflammation, the fundus comes in close contact with the anterior abdominal wall in the right upper quadrant near the ninth and tenth costal cartilages, giving rise to the Murphy’s sign. Posteriorly, it abuts the first and second portion of the duodenum and the hepatic flexure of the colon. Thus, extension of the inflammation of the gallbladder may lead to spontaneous fistulas into these hollow organs.

C. Bile flow.

Bile, formed by the hepatocytes (600 mL per day), consists of water, electrolytes, bile salts, cholesterol, phospholipids, bilirubin, and other organic solutes. The gallbladder stores and concentrates bile during fasting. Approximately 90% of the water and the electrolytes are resorbed by the gallbladder epithelium, resulting in bile rich in organic constituents. The stratification of this bile into a density gradient is thought to play a role in gallstone formation.

II. Gallstone disease

is a major health problem in the United States. It affects approximately 20% of adult Americans. Gallstones are formed by the precipitation of insoluble bile constituents: cholesterol, polymerized bilirubin, bile pigments, calcium salts, and proteins. Gallstones are classified into cholesterol, black pigment, and brown pigment stones. Cholesterol stones are most frequent in industrialized societies. Black pigment stones occur in patients with chronic hemolytic disorders, and brown pigment stones are associated with impaction in the biliary tract. These stones are more prevalent than cholesterol stones in the Far East. Cholesterol stones may be pure, large (>2.5 cm), solitary or mixed (>70% cholesterol), multiple, smooth, and faceted. Black and brown stones contain less than 25% cholesterol and are multiple and irregular. They contain polymerized bilirubin and calcium salts (bilirubinate, phosphate, and fatty acids). All types of gallstones may become calcified. The calcification is usually central in pigment stones and peripheral in cholesterol stones.

A. Pigment stones (black and brown)

1. Epidemiology.

Clinically, black pigment stones are more prevalent in three major settings: hemolytic states, cirrhosis, and the elderly. In the United States, approximately 30% of gallstones are pigment (mostly black) stones. The incidence is age-dependent: Pigment stones are more common in the sixth and seventh decades. In Asia, biliary tract parasitism with Clonorchis sinensis and Ascaris lumbricoides, biliary ductal stasis, and chronic or repeated spasm at the sphincter of Oddi as a result of widespread use of opium may contribute to the increased prevalence (approximately 70%) of brown pigment cholelithiasis.

The pathogenesis of black pigment stone formation is not clear; however, there seems to be an increased concentration of the insoluble, unconjugated bilirubin and poorly soluble bilirubin monoglucuronide in the bile of these patients. Abnormal motor function of the gallbladder and reduced bile salt concentration may also contribute to the pathogenesis. Infections with organisms such as Escherichia coli reduce biliary pH and deconjugate bilirubin glucuronide, which may create a nidus for gallstone formation.

B. Cholesterol gallstones

1. Risk factors

a. Heredity. The prevalence of cholesterol gallstones varies in different populations. There is a strong correlation between the percentage of cholesterol saturation of gallbladder bile and gallstone formation, as in Pima Indian women in whom the prevalence reaches 80%. Thus hereditary mechanisms are important.

b. Age. Gallstones may be found at all ages, but the incidence increases with age.

c. Gender. Women, starting at puberty, have a two to three times greater risk of developing gallstones compared to men.

d. Pregnancy. Supersaturation of bile with impaired gallbladder emptying during pregnancy due to an increase of estriol, progesterone, and other sex hormone levels increases the incidence of cholelithiasis.

e. Use of exogenous estrogens. There is increased cholelithiasis among users of exogenous estrogens and progesterone, as in birth control pills and in postmenopausal estrogen replacement. The condition could be secondary to gallbladder stasis induced by these hormones and to reduced bile flow and altered lipid composition of bile.

f. Diabetes. The increased prevalence of cholelithiasis in diabetes is largely due to obesity and increased biliary cholesterol secretion.

g. Obesity. The bile of obese people is more lithogenic due to excessive cholesterol secretion caused by increased cholesterol synthesis.

h. Rapid weight loss. Regardless of the method of weight loss, up to 25% of patients who lose weight rapidly will develop symptomatic gallstones. With weight loss, cholesterol is mobilized from peripheral adipose tissue and secretes into bile leading to cholesterol supersaturation. Also, the stimulus for gallbladder contraction from dietary fat is diminished leading to gallbladder stasis. Weight fluctuation is also a risk factor for gallstones.

i. Hyperlipidemia. Patients with type I and IV hyperlipidemia have a high risk of cholesterol gallstone formation.

j. Cystic fibrosis and pancreatic insufficiency. Malabsorption of bile salts decreases the bile salt pool and increases the lithogenicity of bile, leading to cholelithiasis.

k. Ileal disease, bypass, or resection. Extensive disease of the distal small intestine as in Crohn’s disease, or surgical resection of the distal ileum impairs bile salt resorption and predisposes to gallstone formation due to decreased bile acid pool.

l. Drugs. Clofibrate used in the treatment of hyperlipidemia decreases serum cholesterol by inhibiting cholesterol synthesis. This stimulates tissue mobilization and increases cholesterol secretion into bile. Bile becomes more lithogenic, leading to cholelithiasis. The somatostatin analog octreotide predisposes to gallstone formation by inducing gallbladder stasis.

m. Diet. A high-calorie diet, refined carbohydrates, and diets high in polyunsaturated fatty acids predispose to cholelithiasis. Increased dietary fiber seems to decrease the risk of cholelithiasis. Weight-reduction diets with severe caloric restriction leading to rapid weight loss also may result in cholelithiasis.

n. Genetic factors. The prevalence of gallstones is highest in the American Indian tribes, especially the Pima Indians of Arizona. By the age of 30, 80% of Pima women have gallstones. There is also a high prevalence of gallstones
in Chile. In addition to genetic factors, it is thought that this high prevalence in Chile is due partly to the high intake of beans, which adversely affects biliary cholesterol saturation. Gallstones are more common in first-degree relatives of patients with gallstones than in the general population.

o. Spinal injury, especially high spinal section, is associated with a high incidence of gallstones, probably secondary to gallbladder stasis.

p. Total parenteral nutrition promotes gallbladder stasis and the formation of sludge and gallstones with prolonged use.

q. Truncal vagotomy may be a risk factor for cholelithiasis secondary to decreased gallbladder motility.

2. Cholesterol gallstone formation.

The first step in the formation of gallstones is the secretion by the liver of bile supersaturated with cholesterol. Cholesterol in dilute hepatic bile is transported in spherical vesicles of phospholipid and cholesterol into the biliary tract and the gallbladder. Hepatic bile is concentrated in the gallbladder.

The second step in gallstone formation is crystallization. The precipitation of cholesterol crystals initiates the formation of gallstones. When the gallbladder bile becomes abnormally supersaturated with cholesterol, nucleation, flocculation, and precipitation of cholesterol crystals occur, leading to the initiation of gallstone formation. The excessive presence of promoters of crystallization and relative deficiency of inhibitors of crystallization are also thought to be important in the initiation of nucleation and crystal formation. The promoters and inhibitors are most likely proteins such as mucous glycoprotein. The growth of the crystals to macroscopic stones is further facilitated by the gallbladder mucus.

Patients who have cholesterol gallstones may have defects leading to the production of abnormally supersaturated bile due to an absolute increase in the secretory rate of biliary cholesterol or an absolute decrease in the secretory rate of biliary bile salts, lecithin, and phospholipids. Changes in the concentration of one of the key promoters of crystallization, mucous glycoprotein, are mediated by mucosal prostaglandins (PGs). Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs), by decreasing PG synthesis, also prevent microcrystal and gallstone formation, especially in obese people undergoing weight reduction through dieting.

Gallbladder motor dysfunction and stasis also contribute to gallstone formation and may be a primary phenomenon.

3. Clinical presentation.

Long-term studies have shown that at least one half of the individuals with gallstones remain asymptomatic, one third experience severe symptoms, and one fifth experience serious complications.

a. The complications of cholelithiasis include the following:

i. Cystic duct obstruction, leading to

a) Colic.

b) Acute cholecystitis.

c) Cholangitis, sepsis.

d) Perforation, peritonitis.

e) Fistulization, gallstone ileus.

ii. Choledocholithiasis, which may cause

a) Obstructive jaundice.

b) Cholangitis, sepsis.

c) Acute pancreatitis.

d) Stricture formation.

iii. There is some evidence to suggest that gallstones and chronic cholecystitis also may predispose to carcinoma of the gallbladder.

b. Biliary colic. Dyspeptic symptoms such as heartburn, fat intolerance, and increased “gas” (bloating, flatulence, and belching) are not symptoms specific to gallbladder disease. Biliary colic is pain arising from a distended gallbladder due to obstruction of the cystic duct with a gallstone. Commonly, the “attacks” follow heavy meals. The pain is felt mostly in the right upper quadrant and may radiate to the epigastrium, back, or shoulder. It may be
mild or severe, lasts 1 to 6 hours, and usually is accompanied by nausea and vomiting. At times, when the cystic duct obstruction is transient, biliary colic is relieved spontaneously. However, prolonged cystic duct obstruction with a gallstone usually results in acute cholecystitis, cholangitis, and their complications.

c. Prognosis. Both complications and mortality from gallstones increase with age and with passage of time. The first attack may be severe, especially in the elderly and patients with other serious illness. Because the mortality for these patients from complications of gallstones may be as high as 15% to 20%, elective surgery should be considered when asymptomatic gallstones are found. Surgery is also recommended for patients with symptoms or complications of cholelithiasis.

4. Differential diagnosis.

Other causes of severe upper abdominal pain need to be considered in the differential diagnosis of biliary colic. These causes include acute myocardial infarction, ruptured aortic aneurysm, perforated peptic ulcer, pneumonia, pneumothorax, pleurisy, intestinal obstruction, intestinal ischemia, pancreatitis, and renal colic.

5. Diagnostic studies.

The demonstration of gallstones by ultrasound is currently the best diagnostic test, having the highest sensitivity (90%-95%) and specificity (98%). An oral cholecystogram may also demonstrate gallstones as well as gallbladder contractile function after ingestion of fat; however, this test is not as sensitive as ultrasound. Computed tomography (CT) scan of the gallbladder is much more sensitive than conventional radiography in detecting gallstone calcium. However, ultrasound is more sensitive than CT in detecting gallbladder sludge and stones.

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