understanding of gallstone formation.

Bile Composition and Function

Healthy livers produce between 600 and 750 mL of bile per day. Normal bile is composed of bile acids

(or salts, 61%), fatty acids (12%), cholesterol (9%), proteins (7%), phospholipids (3%), bilirubin (3%),

and other substances (5%).3 Bilirubin is the breakdown product of spent red blood cells and is

conjugated with glucuronic acid prior to being excreted. Bile acid components can be further

subclassified as primary bile acids and secondary bile acids. Primary bile acids (cholic and

chenodeoxycholic acids) are synthesized in the liver and secondary bile acids (deoxycholic and

lithocholic acids) represent primary bile acids that undergo deconjugation in the gut by bacteria.

Cholesterol is produced primarily by the liver with little contribution from dietary sources, and is highly

nonpolar and insoluble in water and thus in bile, as well. Phospholipids (95% phosphatidylcholine in

healthy individuals) are synthesized in the liver in conjunction with bile salt synthesis. Percentages of

biliary phospholipid and cholesterol vary with underlying liver disease.

Bile facilitates the intestinal absorption of lipids, fat-soluble vitamins and various drugs, and promotes

excretion of certain organic solids, such as bilirubin and cholesterol. Bile acids solubilize lipids and

facilitate their absorption and excretion through emulsification of dietary fats. More recent evidence

shows that bile acids regulate their own synthesis, perform various endocrine and autocrine functions,

and serve as ligands for various nuclear receptors involved in carbohydrate, triglyceride, and sterol

metabolism.4 Bile acids also interact with cell surface receptors involved in glucose and lipid

metabolism, energy consumption, and immune response.5

The potency of bile is increased through the process of concentration (5 to 10×) within the

gallbladder, as electrolytes, water, and calcium are reabsorbed (Table 61-1). Sodium chloride channels

actively transport salt across the epithelium efficiently6 and water follows passively in response to the

resultant osmotic force. Calcium absorption is less efficient, resulting in a net increase in calcium

percentage in stored bile. As gallbladder bile becomes concentrated, the capacity of bile to solubilize

cholesterol lessens. Solubility of the micellar fraction is increased; however, solubility of phospholipid–

cholesterol vesicles is reduced. It is the vesicular fraction of vesicular cholesterol combined with the

increased concentration of calcium in the gallbladder lumen that promotes development of cholesterol

crystals and subsequent gallstones.

Table 61-1 Composition of Hepatic and Gallbladder Bile

Enterohepatic Circulation

Bile acids travel in the bile through the liver, biliary tree, intestines, and the portal venous circulation to

return to the liver, thereby recovering 95% of bile acids, with the other 5% passing in stool.

Hepatocytes secrete bile acids through a rate-limiting, ATP-dependent process via a bile salt export

pump. Approximately 600 to 750 mL of bile is produced daily. Hormones, such as secretin,

cholecystokinin (CCK), and gastrin increase bile flow primarily by promoting active secretion of

chloride-rich fluid in the bile ducts.

Gallbladder Function

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The main functions of the gallbladder are to concentrate and store bile during the fasting state and

deliver bile into the duodenum when needed. Bile reenters the distal bile duct and is secreted into the

duodenum in response to a meal. The gallbladder mucosa is unique in that it has the greatest absorptive

capacity per unit of any structure in the body, but the gallbladder itself has a limited storage capacity of

approximately 50 mL; thus the bile it can store is made more effective through the process of

concentration.

The gallbladder’s mucosa secretes mucous glycoproteins and hydrogen ions. Mucous glycoproteins are

actively secreted from the mucosal glands in the gallbladder neck and cystic duct. The resultant mucous

barrier protects the gallbladder epithelium from the detergent effect of concentrated bile salts. The

transport of hydrogen ions by the gallbladder epithelium leads to a decrease in bile pH through an

active sodium-exchange mechanism. Acidification of bile in the gallbladder promotes calcium solubility,

thereby preventing its precipitation as calcium salts and subsequent gallstone formation. The

gallbladder’s normal acidification process lowers the pH of hepatic bile from 7.5 to 7.8 down to 7.1 to

7.3.7

Biliary Motility

Gallbladder filling is facilitated through tonic contraction of the ampullary sphincter, which maintains a

constant pressure in the common bile duct (CBD) (10 to 15 mm Hg). There are periods of gallbladder

filling flanked by brief periods of partial emptying (10% to 15% of its volume) of concentrated bile.

These emptying periods are coordinated with each passage of chyme through the duodenum via the

migrating myoelectric complex (MMC) and the hormone motilin. Following a meal, the release of

stored bile from the gallbladder requires coordination of both gallbladder contraction and sphincter of

Oddi relaxation. CCK is released from the duodenal mucosa in response to a meal, and this hormone

serves as a major stimulus for gallbladder contraction. Following a meal, the gallbladder releases 50%

to 70% of its contents within 30 to 40 minutes. Gallbladder refilling then occurs gradually over the next

60 to 90 minutes. Many other hormonal and neural pathways are also necessary for the coordinated

action of the gallbladder and sphincter of Oddi. Dysmotility of the gallbladder increases the time bile

dwells in the gallbladder, and along with calcium precipitation, plays a central role in the pathogenesis

of gallstones.8

Sphincter of Oddi

The human sphincter of Oddi is a complex structure that is functionally independent from the duodenal

musculature. Endoscopic manometric studies demonstrate that the sphincter of Oddi creates a highpressure zone between the bile duct and the duodenum, which regulates the flow of bile and pancreatic

juice into the duodenum while preventing regurgitation of duodenal contents into the biliary tract.

Through this action, a higher luminal pressure is maintained in the biliary tract than in the duodenal

lumen.

Both neural and hormonal factors influence the sphincter of Oddi. In humans, sphincter of Oddi

pressure and phasic wave activity diminish in response to CCK. Thus, sphincter pressure relaxes after a

meal, allowing the passive flow of bile into the duodenum. During fasting, high-pressure phasic

contractions of the sphincter of Oddi persist through all phases of the MMC. Results of animal studies

demonstrate that sphincter of Oddi phasic waves do vary with the MMC, permitting partial gallbladder

emptying and increasing bile flow during phase III of the MMC; a mechanism which may serve to limit

accumulation of biliary crystals during fasting.9 Neurally mediated reflexes link the sphincter of Oddi

with the gallbladder and stomach to coordinate the flow of bile and pancreatic juice into the duodenum.

The cholecystosphincter of Oddi reflex allows the sphincter to relax as the gallbladder contracts.

Similarly, antral distention causes both gallbladder contraction and sphincter relaxation.

GALLSTONES

Ten to 20% of adults in the United States will be affected by gallstones during their lifetime.10 The vast

majority of people with gallstone will have asymptomatic disease diagnosed incidentally via imaging

(ultrasound [US], computed tomography [CT], or magnetic resonance imaging [MRI]) for other health

problems. It is estimated that 2% to 3% per year of those with known gallstones will develop

symptoms

11 and 1% to 2% will develop more complex problems such as cholecystitis, pancreatitis, or

cholangitis annually.12 Gallstones represent a failure to maintain certain biliary solutes, primarily

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cholesterol and calcium salts, in a solubilized state, and can form in the gallbladder and less commonly

in the bile ducts.

Gallstone Formation

1, 2 The gallbladder fills with hepatic bile during tonic contraction of the ampullary sphincter.

Following a meal, the duodenum releases the gut peptide CCK, which stimulates gallbladder emptying.

Fifty to 70% of the gallbladder contents are forced into the duodenum and then refilling gradually

happens within the next 60 to 90 minutes.13 The combination of hepatic bile acidification and

concentration in the gallbladder, by 5 to 10-fold, enhance calcium solubility; however, the secretion of

mucous glycoproteins to protect the mucosa from bile salts serves as a nidus for cholesterol stone

formation. An important biliary precipitate in gallstone pathogenesis is biliary “sludge,” which refers to

a mixture of cholesterol crystals, calcium bilirubinate granules, and a mucin gel matrix. Biliary sludge

has been observed clinically in prolonged fasting states or with the use of long-term total parenteral

nutrition (TPN). Both of these conditions are also associated with gallstone formation. The finding of

macromolecular complexes of mucin and bilirubin, similar to biliary sludge in the central core of most

cholesterol gallstones, suggests that sludge may serve as the nidus for gallstone formation.

Figure 61-1. A: Cholesterol gallstones. B: Black pigment gallstones. C: Brown pigment gallstones.

Gallstone Types

3 Gallstones are classified by their cholesterol content as either cholesterol or pigment stones. Pigment

stones are further classified as either black or brown (Fig. 61-1). In most American populations, 70% to

80% of gallstones are cholesterol stones and the others are black pigment stones.

Cholesterol Gallstones

Pure cholesterol gallstones are uncommon, as most have a core of calcium salts (90%). The

pathogenesis of cholesterol gallstones involves four key factors: (a) cholesterol supersaturation in bile,

(b) crystal nucleation, (c) gallbladder dysmotility, and (d) gallbladder absorption/secretion.

Cholesterol Supersaturation. The key to maintaining cholesterol in solution is the formation of

micelles, a bile salt–phospholipid–cholesterol complex, and cholesterol–phospholipid vesicles (Fig. 61-

2). Present theory suggests that in states of excess cholesterol production, these large vesicles may

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exceed their capability to transport cholesterol and crystal precipitation may occur. Cholesterol

solubility depends on the relative concentration of cholesterol, bile salts, and phospholipid. By plotting

the percentages of each component on triangular coordinates, the micellar zone in which cholesterol is

completely soluble can be demonstrated (Fig. 61-3). In the area above the curve, bile is supersaturated

with cholesterol and precipitation of cholesterol crystals can occur.

Figure 61-2. Phases of cholesterol in bile.

Figure 61-3. Equilibrium phase diagram for bile salt–lecithin–cholesterol–water at a concentration of 10% solids, 90% water. The

monomeric phase is not depicted as a phase because it exists at the same concentration throughout. The one-phase zone contains

only micelles. Several other zones exist, but only the two on the left above the one-phase zone apply to human gallbladder bile,

and both contain cholesterol monohydrate crystals at equilibrium.

Cholesterol Crystallization. Cholesterol supersaturation does not always result in stone formation. As

bile is concentrated in the gallbladder, a net transfer of phospholipids and cholesterol from vesicles to

micelles occurs. The phospholipids are transferred more efficiently than cholesterol, leading to

cholesterol enrichment in the vesicles. These cholesterol-rich vesicles aggregate to form large

multilamellar liquid vesicles that then precipitate cholesterol monohydrate crystals. Several

pronucleating factors including mucin glycoproteins, immunoglobulins, and transferrin accelerate the

precipitation of cholesterol in bile.

Gallbladder Motility. For gallstones to cause clinical symptoms, they must obtain a size sufficient to

produce mechanical injury to the gallbladder or obstruction of the biliary tree. Growth of stones may

occur in two ways: (a) progressive enlargement of individual crystals or stones by deposition of

additional insoluble precipitate at the bile–stone interface, or (b) fusion of individual crystals or stones

to form a larger conglomerate. Poor gallbladder motility increases the dwell time of bile in the

gallbladder, further promoting stone formation. Clinical conditions associated with reduced gallbladder

motility include prolonged fasting, long-term TPN administration, surgical vagotomy, diabetes mellitus,

and supratherapeutic levels of somatostatin resulting from either somatostatin-producing tumors or in

patients receiving long-term somatostatin therapy.

Gallbladder Absorption/Secretion. Alterations in sodium, chloride, bicarbonate, and water

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absorption may alter the milieu for cholesterol saturation and crystal formation as well as for calcium

precipitation.14

Pigment Gallstones

Pigment gallstones are classified as either brown or black pigment stones.

Brown Pigment Stones. These stones are composed of calcium bilirubinate, fatty acid soaps (calcium

palmitate and calcium stearate), cholesterol, and mucinous glycoproteins (products of bacterial

biofilms). They are earthy in texture and are typically found in the intrahepatic and extrahepatic bile

ducts (as opposed to the gallbladder) in states of increased bile duct stasis, such as sclerosing

cholangitis, congenital biliary cystic disease, chronic biliary strictures, chronic pancreatitis, duodenal

diverticula, and infections with bacteria or biliary parasites. East Asian populations are particularly at

risk of brown stone formation due to susceptibility to oriental cholangiohepatitis (recurrent pyogenic

cholangitis). In this condition, bacteria produce a biofilm rich in glucuronidase, which hydrolyses

conjugated bilirubin to free bilirubin. Free bilirubin precipitates when mixed with calcium.

In these settings, bacteria-producing slime and bacteria containing the enzyme glucuronidase cause

enzymatic hydrolysis of soluble conjugated bilirubin glucuronide to form free bilirubin, which then

precipitates with calcium leading to stone formation.

Black Pigment Stones. These stones form primarily in the gallbladder in sterile bile and are associated

with advanced age, chronic hemolysis, alcoholism, cirrhosis, pancreatitis, and total parenteral nutrition,

and are typically tarry. These stones are usually not associated with infected bile and are located almost

exclusively in the gallbladder.

INDICATIONS FOR CHOLECYSTECTOMY

Asymptomatic Patients

4 Given that the large majority of individuals with gallstones are asymptomatic and have no associated

complications, most patients can be managed expectantly without surgical intervention. Prophylactic

cholecystectomy may, however, be indicated in certain circumstances (Table 61-2). Patients who have a

higher risk of cancer in the setting of gallbladder disease, such as Native Americans, presence of large

gallstones (>2.5 cm), or calcification of gallbladder wall (“porcelain gallbladder”) are commonly

offered prophylactic cholecystectomy. Patients who are more likely to have recurrent symptoms or

complications secondary to gallstone disease may also undergo prophylactic cholecystectomy; examples

of these conditions include hereditary spherocytosis, sickle cell disease, other hemoglobinopathies, the

bariatric patients, and pediatric patients. Finally, some clinicians argue that organ transplant patients

with gallstones should undergo pretransplant prophylactic cholecystectomy given the possible higher

risk of developing complicated gallstone disease due to chronic immunosuppression.

Patients with asymptomatic gallstones who are not offered a cholecystectomy, or choose not to

undergo an operation, can be managed with other therapies. In patients with small gallstones (<5 mm)

oral dissolution therapy with bile salts may be utilized.22 Ursodeoxycholic acid (ursodiol) appears to

work by dissolving cholesterol crystals and decreasing hepatic secretion of biliary cholesterol thereby

decreasing the number of stones. It is also thought that this would decrease the number of colic attacks.

Unfortunately, the majority of stones recur (>50% at 5 years) and in a prospective randomized study of

177 patients from the Netherlands, a country that has a long waiting list for elective biliary procedures,

ursodiol did not decrease the number of attacks nor gallstone-related complications during the waiting

period for cholecystectomy.23

Table 61-2 Indications for Prophylactic Cholecystectomy

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