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Cholelithiasis
Introduction
Background

Gallstones are concretions that form in the biliary tract, usually in the gallbladder. Their development is insidious, and they may remain asymptomatic for decades. Migration of gallstones may lead to occlusion of the biliary and pancreatic ducts, causing pain (biliary colic) and producing acute complications, such as acute cholecystitis, ascending cholangitis, or acute pancreatitis. Chronic gallstone disease may lead to fibrosis and loss of function of the gallbladder and predisposes to gallbladder cancer. Excision of the gallbladder (cholecystectomy) to cure gallstone disease is among the most frequently performed abdominal surgical procedures.
Pathophysiology

Gallstone formation occurs because certain substances in bile are present in concentrations that approach the limits of solubility. When bile is concentrated in the gallbladder, it can become supersaturated with these substances, which then precipitate from solution as microscopic crystals. The crystals are trapped in gallbladder mucus, producing gallbladder sludge. Over time, the crystals grow, aggregate, and fuse to form macroscopic stones. Occlusion of the ducts by sludge and stones produces the complications of gallstone disease.

The 2 main substances involved in gallstone formation are cholesterol and calcium bilirubinate.

Cholesterol gallstones

More than 80% of gallstones in the United States contain cholesterol as their major component. Liver cells secrete cholesterol into bile along with phospholipid (lecithin) in the form of small spherical membranous bubbles, termed unilamellar vesicles. Liver cells also secrete bile salts, which are powerful detergents required for digestion and absorption of dietary fats. Bile salts in bile dissolve the unilamellar vesicles to form soluble aggregates called mixed micelles. This happens mainly in the gallbladder, where bile is concentrated by reabsorption of electrolytes and water.

Compared to vesicles (which can hold up to 1 molecule of cholesterol for every molecule of lecithin), mixed micelles have a lower carrying capacity for cholesterol (about 1 molecule of cholesterol for every 3 molecules of lecithin). If bile contains a relatively high proportion of cholesterol to begin with, then the concentration of bile with progressive dissolution of vesicles may lead to a state in which the cholesterol carrying capacity of the micelles and residual vesicles is exceeded. At this point, bile is supersaturated with cholesterol and crystals may form. Thus, the main factors that determine whether cholesterol gallstones will form are as follows: (1) the amount of cholesterol secreted by liver cells, relative to lecithin and bile salts, and (2) the extent of concentration and stasis of bile in the gallbladder.

Calcium, bilirubin, and pigment gallstones

Bilirubin, a yellow pigment derived from the breakdown of heme, is actively secreted into bile by liver cells. Most of the bilirubin in bile is in the form of glucuronide conjugates, which are quite water soluble and stable, but a small proportion consists of unconjugated bilirubin. Unconjugated bilirubin, like fatty acids, phosphate, carbonate, and other anions, tends to form insoluble precipitates with calcium. Calcium enters bile passively along with other electrolytes.

In situations of high heme turnover, such as chronic hemolysis or cirrhosis, unconjugated bilirubin may be present in bile at higher than normal concentrations. Calcium bilirubinate may then crystallize from solution and eventually form stones. Over time, various oxidations cause the bilirubin precipitates to take on a jet black color, and stones formed in this manner are termed black pigment stones. Black pigment stones represent 10-20% of gallstones in the United States.

Bile normally is sterile, but, in some unusual circumstances (eg, above a biliary stricture), it may become colonized with bacteria. The bacteria hydrolyze conjugated bilirubin, and the resulting increase in unconjugated bilirubin may lead to precipitation of calcium bilirubinate crystals. Bacterial hydrolysis of lecithin leads to the release of fatty acids, which complex with calcium and precipitate from solution. The resulting concretions have a claylike consistency and are termed brown pigment stones. Unlike cholesterol or black pigment stones, which form almost exclusively in the gallbladder, brown pigment stones often form de novo in the bile ducts. Brown pigment stones are unusual in the United States but are fairly common in some parts of Southeast Asia, possibly related to liver flukes.

Mixed gallstones

Cholesterol gallstones may become colonized with bacteria and can elicit gallbladder mucosal inflammation. Lytic enzymes from bacteria and leukocytes hydrolyze bilirubin conjugates and fatty acids. As a result, over time, cholesterol stones may accumulate a substantial proportion of calcium bilirubinate and other calcium salts, producing mixed gallstones. Large stones may develop a surface rim of calcium resembling an eggshell that may be visible on plain x-ray films.
Frequency
United States

Gallstones are uncommon in children. Beginning at puberty, the concentration of cholesterol in bile increases. After age 15 years, the prevalence of gallstones in US women increases by about 1% per year; in men, the rate is less, about 0.5% per year. Incidence in women falls with menopause, but new stone formation in men and women continues at a rate of about 0.4% per year until late in life.

The lifetime risk of developing gallstones in Caucasians is 50% for women and 30% for men. Prevalence in Mexican Americans and Native Americans is similar, whereas African Americans have a somewhat lower risk.
International

The prevalence of cholesterol cholelithiasis in other Western cultures is similar to that in the United States, but it appears to be somewhat lower in Asia and Africa.
Mortality/Morbidity

Each year, in the United States, approximately 500,000 people develop symptoms or complications of gallstones requiring cholecystectomy. Gallstone disease is responsible for about 10,000 deaths per year in the United States. About 7000 deaths are attributable to acute gallstone complications, such as acute pancreatitis. About 2000-3000 deaths are caused by gallbladder cancers (80% of which occur in the setting of gallstone disease with chronic cholecystitis). Although gallstone surgery is relatively safe, cholecystectomy is a very common procedure, and its rare complications result in several hundred deaths each year.
Race

Caucasians, Mexican Americans, and Native Americans have a relatively high prevalence of gallstones. Gallstone disease is less common in Asians and Africans and their descendants.
Sex

Women are more likely to develop cholesterol gallstones than men, especially during their reproductive years, when the excess risk is 2-3:1. The difference appears to be attributable mainly to estrogen, which increases biliary cholesterol secretion. Pigment gallstones affect men and women equally.
Age

Gallstones continue to form throughout adult life, and the prevalence is greatest at advanced age.
Clinical
History

Gallbladder disease may be thought of as having 4 stages, as follows: (1) the lithogenic state, in which conditions favor gallstone formation; (2) asymptomatic gallstones; (3) episodes of biliary colic; and (4) complicated cholelithiasis. Symptoms and complications of gallstone disease result from effects occurring within the gallbladder or from stones that escape the gallbladder to lodge in the common bile duct.
Asymptomatic gallstones
Gallstones may be present in the gallbladder for decades without causing symptoms or complications. In patients with asymptomatic gallstones discovered incidentally, the likelihood of developing symptoms or complications is 1-2% per year. In most cases, asymptomatic gallstones do not require any treatment.
Because they are common, gallstones often coexist with other gastrointestinal conditions. Little evidence suggests that gallstones cause chronic abdominal pain, heartburn, postprandial distress, bloating, flatulence, constipation, or diarrhea. Dyspepsia that occurs reproducibly following ingestion of fatty foods is often wrongly attributed to gallstones, when irritable bowel syndrome or gastroesophageal reflux is the true culprit. Gallstones discovered during an evaluation for nonspecific symptoms usually are innocent bystanders, and treatment directed at the gallstones is unlikely to relieve these symptoms.
Biliary colic
Pain termed biliary colic occurs when gallstones fortuitously impact in the cystic duct during a gallbladder contraction, increasing gallbladder wall tension. In most cases, the stone dislodges, the obstruction is relieved after 30-90 minutes following relaxation of the gallbladder, and the pain resolves.
Episodes of biliary colic are sporadic and unpredictable. The patient localizes the pain to the epigastrium or right upper quadrant and may describe radiation to the right scapular tip. From onset, the pain increases steadily over about 10 minutes and then persists for up to several hours before waning. The pain is constant and is not relieved by emesis, antacids, defecation, or positional changes. It may be accompanied by nausea and vomiting.
Complications of gallbladder stones
Acute cholecystitis occurs when persistent stone impaction in the cystic duct causes the gallbladder to become distended and progressively inflamed. Patients experience pain of biliary colic, but, instead of resolving spontaneously, the pain persists and worsens. Overgrowth of colonizing bacteria in the gallbladder often occurs, and, in severe cases, accumulation of pus in the gallbladder, termed gallbladder empyema, occurs. The gallbladder wall may become necrotic, resulting in perforation and pericholecystic abscess. Acute cholecystitis is considered a surgical emergency, although pain and inflammation may subside with conservative measures, such as hydration and antibiotics.
Chronic gallstones may cause progressive fibrosis of the gallbladder wall and loss of gallbladder function, termed chronic cholecystitis. The pathogenesis of this complication is not completely understood. Repeated attacks of acute cholecystitis may play a role, as may localized ischemia produced by pressure of stones against the gallbladder wall. The chronically fibrotic gallbladder may become shrunken and adherent to adjacent viscera.
Gallbladder adenocarcinoma is an uncommon cancer that usually develops in the setting of gallstones and chronic cholecystitis. Gallbladder cancers commonly invade the adjacent liver and common bile duct, producing jaundice. Prognosis is poor unless the cancer is localized to the gallbladder, in which case cholecystectomy may be curative.
Occasionally, a large stone may erode through the wall of the gallbladder into an adjacent viscus, producing a cholecystoenteric fistula. The stone, if sufficiently large, may obstruct the small intestine, usually at the level of the ileum, a phenomenon termed gallstone ileus.
Complications of stones in the common bile duct
Gallstones initially are retained in the gallbladder by the spiral valves of the cystic duct. Following episodes of gallstone impaction in the cystic duct, these valves may become obliterated and stones may pass into the common bile duct. Patients who have passed one stone tend to pass other stones over the subsequent months.
Stones in the common bile duct may be asymptomatic, but, more commonly, they impact distally in the ampulla of Vater. This may produce biliary colic indistinguishable from that caused by cystic duct stones. Because impaction of common bile duct stones occludes the flow of bile from the liver to the intestine, pressure rises in the intrahepatic bile ducts, leading to increased liver enzymes and jaundice.
Bacterial overgrowth in stagnant bile above an obstructing common duct stone produces purulent inflammation of the liver and biliary tree, termed ascending cholangitis. Characteristic features include the Charcot triad of fever, jaundice, and right upper quadrant pain. Patients may rapidly develop septic shock unless ductal obstruction is relieved.
A stone impacted in the ampulla of Vater may transiently obstruct the pancreatic duct, leading to in situ activation of pancreatic proteases and triggering an attack of acute pancreatitis.
Stone impaction in the distal common bile duct is often relieved spontaneously within hours to days by passage of the stone into the intestine.
Physical

Patients with the lithogenic state or asymptomatic gallstones have no abnormal findings on physical examination.
During attacks of biliary colic, and especially in acute cholecystitis, patients may experience tenderness to palpation over the gallbladder. This can be elicited by having the patient inhale while the examiner maintains steady pressure below the right costal margin (Murphy sign). Localized rebound tenderness, guarding, or rigidity may occur with pericholecystic inflammation.
Patients with acute cholecystitis, ascending cholangitis, or acute pancreatitis, in addition to abdominal pain, may exhibit fever and may be tachycardic and hypotensive. In severe cases, bowel sounds are often absent or hypoactive.
Choledocholithiasis with obstruction of the common bile duct produces cutaneous and scleral icterus that may evolves over hours to days as bilirubin accumulates.
The Charcot triad of severe right upper quadrant tenderness with jaundice and fever is characteristic of ascending cholangitis.
Acute gallstone pancreatitis is often characterized by epigastric tenderness. In severe cases, retroperitoneal hemorrhage may produce ecchymoses of the flanks and periumbilical ecchymoses (Cullen sign and Grey-Turner sign).
Causes

Cholesterol gallstones, black pigment gallstones, and brown pigment gallstones have different pathogenesis and different risk factors, which will be discussed separately.
Cholesterol gallstones are associated with female gender, European or Native American ancestry, and increasing age, as discussed above. Other risk factors include the following:
Obesity: The metabolic syndrome of truncal obesity, insulin resistance, type II diabetes mellitus, hypertension, and hyperlipidemia is associated with increased hepatic cholesterol secretion and is a major risk factor for the development of cholesterol gallstones.
Pregnancy: Cholesterol gallstones are more common in women who have experienced multiple pregnancies. A major contributing factor is thought to be the high progesterone levels of pregnancy. Progesterone reduces gallbladder contractility, leading to prolonged retention and greater concentration of bile in the gallbladder.
Gallbladder stasis: Other causes of gallbladder stasis associated with increased risk of gallstones include high spinal cord injuries, prolonged fasting with total parenteral nutrition, and rapid weight loss associated with severe caloric and fat restriction (eg, diet, gastric bypass surgery).
Drugs: Estrogens administered for contraception or for treatment of prostate cancer increase the risk of cholesterol gallstones. Clofibrate and other fibrate hypolipidemic drugs increase hepatic elimination of cholesterol via biliary secretion and appear to increase the risk of cholesterol gallstones. Somatostatin analogs appear to predispose to gallstones by decreasing gallbladder emptying.
Heredity: About 25% of the predisposition to cholesterol gallstones appears to be hereditary, as judged from studies of identical and fraternal twins. At least a dozen genes may contribute to the risk. A rare syndrome of low phospholipid–associated cholelithiasis occurs in individuals with a hereditary deficiency of the biliary transport protein required for lecithin secretion.
Black pigment gallstones occur disproportionately in individuals with high heme turnover. In most cases, however, no risk factor can be identified.
Disorders of hemolysis associated with pigment gallstones include sickle cell anemia, hereditary spherocytosis, and beta thalassemia.
In cirrhosis, portal hypertension leads to splenomegaly. This, in turn, causes red cell sequestration, leading to a modest increase in hemoglobin turnover. About half of all cirrhotic patients have pigment gallstones.
Prerequisites for formation of brown pigment gallstones include colonization of bile with bacteria and intraductal stasis. In the United States, this combination is most often encountered in patients with postsurgical biliary strictures or choledochal cysts. In hepatolithiasis, a condition encountered mainly in rice-growing regions of East Asia, intraductal formation of brown pigment stones accompanies multiple strictures throughout intrahepatic and extrahepatic bile ducts. This condition causes recurrent cholangitis and predisposes to biliary cirrhosis and cholangiocarcinoma. The etiology is unknown, but liver flukes have been implicated.

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