Active sodium transport by the epithelium of the gallbladder causes concentration of the bile into a form that is up to 10 times more concentrated than when first excreted by the liver. This concentration process leads to changes in the solubility of the calcium and cholesterol components of the bile

  • Decreased gallbladder motility with bile stasis contributes to stone formation. Conditions associated with gallstones and decreased gallbladder contraction include obesity, rapid weight loss, pregnancy, diabetes mellitus, TPN, and octreotide use
  • Biliary tract infection may also contribute to stone formation
  • Pigment stones can be black or brown in color. Black pigment stones are primarily composed of bilirubin calcium, which is cross-linked and oxidized to produce a black polymer. These stones are sterile and are found in patients with hemolysis, sickle cell disease, chronic TPN, and cirrhosis. Brown pigment stones, containing bacteria, complicate bacterial and helminthic common bile duct infections. Brown pigment stones are more common in the Asian population

 

 

Cholelithiasis is the presence of gallstones in the gallbladder.

Cholesterol gallstones make up 75% of all gallstones; the remaining 25% are pigment stones.

Gallstones are classified according to their predominant chemical composition as cholesterol or calcium bilirubinate stones. The latter comprise less than 20% of the gallstones found in patients in the United States or Europe but 30–40% of gallstones found in patients in Japan.

A. Cholesterol Stones

Gallstones classified as cholesterol stones contain more than 50% cholesterol with variable admixtures of calcium salts, bile pigments, proteins, and fatty acids. Cholesterol stones account for more than 90% of all gallstones in Western industrialized countries. Pigment stones are composed primarily of calcium bilirubinate; they contain less than 20% cholesterol.

Because cholesterol is practically insoluble in water, solubilizing lipids (bile acids and phospholipids) are required for its incorporation into bile. Biliary lipid secretion is regulated by ATP-binding cassette (ABC) transporters in the hepatocyte canalicular membrane. The bile salt export pump (BSEP; ABCB11) transports bile acids into the bile, the multidrug resistance p-glycoprotein 3 (MDR3; ABCB4) translocates phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane, and the transporter ABCG5/G8 secretes cholesterol into the bile.

Cholesterol and phosphatidylcholine reach the bile as unilamellar vesicles and are subsequently converted into water-soluble mixed micelles by the bile acids (Figure 54–1).

Biliary secretion and solubilization of cholesterol. Cholesterol is secreted by the ABC-binding cassette (ABC) transporter ABCG5/G8, phosphatidylcholine by the multidrug-resistance p-glycoprotein 3 (MDR3; ABCB4), and bile acids by the bile salt export pump (BSEP; ABCB11). Cholesterol and phosphatidylcholine reach the bile as metastable unilamellar vesicles, which are converted into water-soluble stable mixed micelles by the bile acids. If the secretion of cholesterol into bile exceeds the solubilizing capacity of bile acids and phospholipids, cholesterol-rich vesicles remain, which aggregate into large unstable multilamellar vesicles from which cholesterol crystals precipitate. These crystals may aggregate and form cholesterol stones. Recent evidence indicates that a variant in the hepatocanalicular cholesterol transporter gene ABCG8 contributes to the risk of cholesterol gallstone formation (for details see text).

Supersaturation of bile with cholesterol is the thermodynamic requirement for the formation of cholesterol gallstones. It can result from secretion of cholesterol into bile that exceeds the solubilizing capacity of bile acids and phospholipids. If all cholesterol phosphatidyl vesicles cannot be converted into water-soluble mixed micelles, unstable cholesterol-rich vesicles remain. The unstable vesicles aggregate into large multilamellar vesicles from which cholesterol crystals precipitate. These crystals—if not expelled from the gallbladder—become entrapped in gallbladder mucin gel, where they grow and agglomerate to form stones.

The pathogenesis of cholesterol hypersecretion is multifactorial, with genetic and environmental components.

1. Cholesterol supersaturation of bile

An excess of biliary cholesterol in relation to its carriers (phospholipids and bile acids) is asine qua non condition for the formation of cholesterol gallstones. It may result from hypersecretion of cholesterol, hyposecretion of bile acids or phospholipids, or a combination of the two. Relative cholesterol hypersecretion is by far the most common cause of supersaturation of bile. It may result from increased synthesis of cholesterol, increased uptake by the liver of endogenous (via low-density lipoproteins) or exogenous (via chylomicrons) cholesterol, and increased hepatocanalicular transport of cholesterol. An inappropriately low rate of cholesterol 7α-hydroxylation, the rate-limiting step in the conversion of cholesterol to bile acids, can also increase cholesterol secretion into bile. This may occur in a rare genetic defect, but also with age. A defect in the ileum characterized by impaired absorption and increased fecal loss of bile acids, thus lowering the amount of bile acids in the enterohepatic circulation, may also play a role. Obese individuals secrete more cholesterol into bile because they ingest and synthesize more cholesterol. During weight loss, there is an increased excretion of cholesterol into bile, often combined with decreased gallbladder emptying.

2. Destabilization of bile

Supersaturation of bile is a prerequisite for stone formation, but alone it is not sufficient for lithogenesis. About 50% of adults have supersaturated bile at least at some times during the day, but only about 10–15% form stones. The majority of people with supersaturated bile do not have stones because the time required for cholesterol crystals to nucleate and to grow is longer than the time the bile spends in the gallbladder. The stability of phospholipid cholesterol vesicles depends on their cholesterol content and on the balance between inhibitors and promoters of cholesterol crystal formation. Normally, inhibitors of cholesterol crystal formation and growth appear to outweigh the promoters. The influence of promoting and inhibiting factors on the appearance of crystals in bile has been assessed by the “nucleation time” or crystal “observation time.” It is much shorter in gallbladder bile from patients with cholesterol gallstones than in equally supersaturated gallbladder bile from normal subjects. A protein that promotes crystal nucleation or growth, or both, is gallbladder mucin. Gallbladder mucin, a mixture of high molecular weight mucus glycoproteins, is layered at the mucosal surface of the gallbladder wall, where it forms a viscous bed facilitating nucleation and aggregation of cholesterol crystals (Figure 54–2). Release of mucin and perhaps other glycoproteins from the gallbladder is stimulated by deoxycholic acid.

Formation, growth, and aggregation of cholesterol crystals in the mucin gel layered at the mucosal surface of the gallbladder wall (for details see text).

3. Stasis of bile in the gallbladder

If the gallbladder emptied all supersaturated bile completely before crystals had formed, stones would not be able to grow. Thus, prolonged retention of all or parts of the gallbladder contents seems to be another important prerequisite for lithogenesis. A high percentage of patients with gallstones exhibit abnormalities of gallbladder emptying. Studies of gallbladder motility using ultrasonography have shown that patients with gallstones have increased fasting and residual gallbladder volume and that fractional emptying of the gallbladder is decreased (Figure 54–3). The incidence of gallstones is increased in conditions associated with infrequent or impaired gallbladder emptying, such as fasting, parenteral nutrition, or pregnancy, and in patients using drugs that inhibit gallbladder motility. Gallbladder hypomotility during fasting results from lack of gallbladder stimulation. Consequently, the risk of stone formation during parenteral nutrition can be decreased by administration of cholecystokinin. During pregnancy, both the fasting volume and the residual volume of the gallbladder rise with serum progesterone, which inhibits smooth muscle contractility and impairs emptying.


Impaired gallbladder emptying after a test meal in patients with gallstones measured by ultrasonography. (Data from Paumgartner G, Pauletzki J, Sackmann M. Ursodeoxycholic acid treatment of cholesterol gallstone disease. Scand J Gastroenterol Suppl. 1994;204:27–31.)

B. Pigment Stones

Pigment stones can be black pigment stones, which are composed of either pure calcium bilirubinate or polymer-like complexes containing mainly calcium and mucin glycoproteins. They are more common in patients who have chronic hemolytic states (with increased conjugated bilirubin in bile), liver cirrhosis, Gilbert syndrome, or cystic fibrosis (Table 54–2). Gallbladder stones in patients with ileal disease, ileal resection, or ileal bypass generally are also black pigment stones. Enterohepatic cycling of bilirubin contributes to their pathogenesis.


Major risk factors for pigment stones.

Associated conditions

  • Chronic hemolysis

  • Pernicious anemia

  • Liver cirrhosis

  • Cystic fibrosis

  • Chronic biliary tract infections

  • Biliary parasites

  • Ileal disease

  • Ileal resection or bypass

Demographic factors

  • Asia, rural setting

Brown pigment stones consist of calcium salts and unconjugated bilirubin with varying amounts of cholesterol and protein. They are caused by the presence of increased amounts of unconjugated, insoluble bilirubin in bile. Deconjugation of soluble conjugated bilirubin glucuronide may be caused by bacterial enzymes when bile is infected, but may also occur by spontaneous alkaline hydrolysis. Brown pigment stones are frequent in Asia, where there is a high prevalence of infection of the biliary tree. They often form in the bile ducts, whereas cholesterol gallstones usually originate in the gallbladder.

  • They are associated with obesity, diabetes, female gender, and childbearing.

    Pigment stones are associated with hemolysis and cirrhosis of the liver

    Major risk factors for cholesterol gallstones include age >50, female sex, Native American or Mexican ethnicity, genetic predisposition, family history, pregnancy and parity, estrogens, obesity, and the metabolic syndrome.

  • It is about twice as high in women as in men. The gender difference at least partly results from endogenous estrogens, which increase biliary cholesterol secretion and cholesterol saturation of bile. Pregnancy increases the risk of gallstones because impaired gallbladder emptying, caused by progesterone, combines with the influence of estrogen, which increases cholesterol hypersecretion. In obese persons an overproduction of cholesterol causes cholesterol hypersecretion into bile and thus predisposes to gallstone formation. In many obese patients, cholesterol gallstones may be regarded as a component of the metabolic syndrome (Table 54–1).


    Major risk factors for cholesterol gallstones.

    General

    • Increasing age
    • The prevalence of gallstones increases with age.

    • Female gender
    • Ethnicity
    • Family history

    Diet

    • Overnutrition

    • High calorie

    • Low fiber

    • High refined carbohydrates

    Lifestyle

    • Low-grade physical activity

    • Prolonged fasting

    • Rapid weight loss

    • Weight cycling

    • Pregnancy and parity

    • Oral contraceptives

    Associated conditions

    • Obesity

    • Metabolic syndrome

    • Estrogen replacement therapy

 

  • Major complications of gallstone disease requiring treatment are acute cholecystitis, choledocholithiasis, obstructive jaundice, cholangitis, and pancreatitis.

  • Acute cholangitis caused by an obstructing gallstone should be treated by endoscopic removal of the stone under antibiotic coverage as soon as possible.

 

 

Age:

  • The highest incidence occurs in the fifth and sixth decades of life.
  • Gallstones in incidence in both sexes and all races with age. After age 40 years the incidence of cholesterol gallstones increases with age

 

In the United States, the prevalence of gallstones is 8.6% in women and 5.5% in men, with the highest rates in persons over age 60 and higher rates in Mexican Americans than in non-Hispanic whites and African Americans, and gallstone disease is associated with increased overall, cardiovascular, and cancer mortality. Although cholesterol gallstones are less common in black people, cholelithiasis attributable to hemolysis occurs in over a third of individuals with sickle cell disease. Native Americans of both the Northern and Southern Hemispheres have a high rate of cholesterol cholelithiasis, probably because of a predisposition resulting from “thrifty” (LITH) genes that promote efficient calorie utilization and fat storage. As many as 75% of Pima and other American Indian women over the age of 25 years have cholelithiasis. Other genetic mutations that predispose persons to gallstones have been identified. Obesity is a risk factor for gallstones, especially in women. Rapid weight loss, as occurs after bariatric surgery, also increases the risk of symptomatic gallstone formation. Diabetes mellitus, glucose intolerance, and insulin resistance are risk factors for gallstones, and a high intake of carbohydrate and high dietary glycemic load increase the risk of cholecystectomy in women. Hypertriglyceridemia may promote gallstone formation by impairing gallbladder motility. The prevalence of gallbladder disease is increased in men (but not women) with cirrhosis and hepatitis C virus infection. Moreover, cholecystectomy has been reported to be associated with an increased risk of NAFLD and cirrhosis, possibly because gallstones and liver disease share risk factors. A low-carbohydrate diet, physical activity, and cardiorespiratory fitness may help prevent gallstones. Consumption of caffeinated coffee appears to protect against gallstones in women, and a high intake of magnesium and of polyunsaturated and monounsaturated fats reduces the risk of gallstones in men. A diet high in fiber, a diet rich in fruits and vegetables, and statin use reduce the risk of cholecystectomy, particularly in women. The incidence of gallstones is high in individuals with Crohn disease; approximately one-third of those with inflammatory involvement of the terminal ileum have gallstones due to disruption of bile salt resorption that results in decreased solubility of the bile. Drugs such as clofibrate, octreotide, and ceftriaxone can cause gallstones. In contrast, aspirin and other nonsteroidal anti-inflammatory drugs may protect against gallstones. Prolonged fasting (over 5–10 days) can lead to formation of biliary “sludge” (microlithiasis), which usually resolves with refeeding but can lead to gallstones or biliary symptoms. Pregnancy, particularly in obese women and those with insulin resistance, is associated with an increased risk of gallstones and of symptomatic gallbladder disease. Hormone replacement therapy appears to increase the risk of gallbladder disease and need for cholecystectomy; the risk is lower with transdermal than oral therapy.

 

 

 

 

Gender:

  • Cholelithiasis is more common in women than in men at all ages.

     

     

     

Race:

  • NHANES III showed some ethnic groups have higher prevalence, particularly in women. Mexican American women have the highest prevalence, followed by non-Hispanic white women, and then black women. Data from Asian populations suggest a lower prevalence. Mexican American and non-Hispanic white men have approximately the same prevalence; black men the lowest prevalence
  • In addition, 75% of female Pima Indians aged older than 25 years have gallstones, as do 35% of the Mapuche Indians of Chile

Genetics:

  • A family history of gallstones increases the risk for gallstones
  • A mutation in the gene that encodes the hepatocanalicular phosphatidylcholine transporter in the ABCB4 gene appears to be a risk factor for symptomatic gallstone disease. This mutation results in enhanced cholesterol precipitation and gallstone formation as a result of low biliary levels of phosphatidylcholine

Geography:

  • Cholelithiasis appears to be less common in Asian populations

 

 

Gallstone disease represents a considerable health problem in Western industrialized countries. With a prevalence of 10–15% in adults in the United States and in Europe, it is one of the most common digestive diseases. In the United States, it is the gastrointestinal disorder that, after gastroesophageal reflux disease, accounts for the second-highest costs. The clinical manifestations of gallstones include episodic abdominal pain, acute cholecystitis, obstructive jaundice, cholangitis, and pancreatitis.

In Western industrialized countries, >90% of gallstones consist mainly of cholesterol. Thus, in the majority of patients, cholelithiasis may be regarded as a disturbance of cholesterol disposal. A complex solubilizing system in bile is required to keep cholesterol in solution. If this system fails, or if its capacity is exceeded by hypersecretion of cholesterol into bile, cholesterol precipitates and gallstones may develop.

Epidemiology and Genetics

In the third National Health and Nutrition Examination Survey (NHANES III), a large epidemiologic survey that compiled data including gallbladder ultrasonography findings, the overall prevalence of gallstones in the United States was 7.9% in men and 16.6% in women, with a progressive increase after age 20. The prevalence was high in Mexican Americans (8.9% in men, 26.7% in women), intermediate for non-Hispanic whites (8.6% in men, 16.6% in women), and low for African Americans (5.3% in men, 13.9% in women). Overall prevalence rates in Europe, from large ultrasonic surveys in adults aged 30–69, are similar to those in the NHANES III study. The prevalence of gallstone disease is lower in Asians (ranging from 3% to 15%) and very low (<5%) in Africans. Certain ethnic groups are particularly susceptible; among Native Americans in the western United States, the prevalence of gallstones is over 75%.

Epidemiologic surveys and family clustering point to the critical role of genetics in determining susceptibility to gallstones. The genetic component in the pathogenesis of symptomatic gallstone disease in the Swedish population has been estimated to be about 25%. A single nucleotide polymorphism that leads to the amino acid substitution p.D19H and confers an increased risk of gallstone formation has been identified in the hepatic cholesterol transporter ABCG5/G8 of patients with gallstones. In a recent genome-wide analysis of serum bilirubin levels, the uridine diphosphate-glucuronyltransferease 1A1 (UGT1A1) Gilbert syndrome gene variant was associated with gallstone disease and with the presence of bilirubin in gallstones in men. Since most gallstones associated with theUGT1A1 variant were cholesterol stones, this finding points to the role of pigment particles in the pathogenesis of gallbladder stones, possibly as nucleation factors.

Although in the vast majority of patients, the predisposition to gallstones appears to be polygenic, rare forms of monogenic gallstone disease exist. For example, a single gene defect, namely, a mutation in the gene encoding the canalicular phospholipid transporter (ABCB4) of the hepatocyte, has been identified in a rare form of cholesterol cholelithiasis, the low phospholipid-associated cholelithiasis (LPAC) syndrome. This gene defect is associated with extremely low phosphatidylcholine levels in bilecausing cholesterol precipitation.

 

 

Prophylactic cholecystectomy with certain exceptions i.e., hereditary spherocytosis, is not recommended because the risks of biliary colic, complications, and gallbladder cancer are low.1

Content 2

Content 3

 

 

Sixty to eighty percent of persons with asymptomatic gallstones remain asymptomatic over follow-up periods of up to 25 years. The probability of developing symptoms within 5 years after diagnosis is 2–4% per year and decreases in the years thereafter to 1–2%. The yearly incidence of complications is about 0.1–0.3%. Treatment of patients with asymptomatic gallstones does not prolong life expectancy, because the risk of complications caused by the stones is counterbalanced by the operative risks. Finally, the costs of expectant management without prophylactic cholecystectomy until symptoms or complications occur are lower than those of an active approach.

In countries with a low prevalence of gallbladder carcinoma, the slightly elevated risk of gallbladder carcinoma does not justify surgical intervention in patients with asymptomatic gallstones. Additionally, in diabetic patients, asymptomatic gallstones should be left alone. (????)

  • Most asymptomatic patients with cholelithiasis do not require cholecystectomy or surveilance.
    • Rationale: A landmark study from the University of Michigan followed the course of 123 faculty members identified as having asymptomatic gallstones during a routine health examination. After >2 decades of follow-up, 14 (11%) patients went on to develop complications requiring surgery.
    • Hemolytic conditions such as hereditary spherocytosis remain one indication to consider prophylactic cholecystectomy during other abdominal operations such as splenectomy.

       

    2. Symptomatic Cholelithiasis

  • Approximately 10% of patients with asymptomatic stones will develop symptoms in the first 5 years after diagnosis and approximately 1% to 2% of patients per year will develop complications from the stones.
  • Once patients become symptomatic, laparoscopic cholecystectomy is indicated because the incidence of future recurrent pain and complications is high. Gallstones remain asymptomatic unless they cause obstruction of the cystic duct, biliary tree, pancreatic duct, or erode through the wall of the gallbladder causing a fistula to the intestine.
  • Dissolution of gallstones with medication, lithotripsy, and other techniques are generally futile

    The primary treatment of symptomatic cholelithiasis is laparoscopic cholecystectomy.

    [Prophylactic cholecystectomy has been proposed for patients with small gallstones (≤5 mm in size) and preserved gallbladder motility, because they may have a high risk for acute pancreatitis. However, further studies are needed to support this recommendation. Some practitioners also consider prophylactic cholecystectomy in patients with a high risk of becoming symptomatic, such as children who will be exposed to the risks of the stones for a long time.]

    2. Symptomatic gallstones

    Patients with symptomatic gallstones should receive treatment. In addition to analgesic therapy, surgical or medical options must be offered. Elective laparoscopic cholecystectomy is the standard method of cholecystectomy in patients with symptomatic gallstones. It provides a permanent cure for nearly all patients. It is cost-effective if compared with open cholecystectomy. Today, more than 93% of all cholecystectomies are started by laparoscopy and only 4–7% have to be converted to open cholecystectomy. A meta-analysis of randomized studies comparing laparoscopic and open cholecystectomy shows identical complication rates for both methods, but on the average 3-day shorter hospital stays and 3-week shorter convalescences. This is reflected by the costs, which are 18% lower for laparoscopic than for open cholecystectomy. A historic comparison shows that complications (bile leakage, 0.4–1.5%; wound infection, 1.3–1.8%; pancreatitis, 0.3%; bleeding, 0.2–1.4%) are lower after laparoscopic than after open cholecystectomy. The rate of bile duct injuries is low and comparable for the two procedures, ranging from 0.2% to 0.6%.

    In patients with liver cirrhosis (Child class A or B) and portal hypertension, laparoscopic cholecystectomy seems to be superior to open cholecystectomy. Laparoscopic cholecystectomy should not be performed if advanced gallbladder carcinoma is suspected.

     

3. Biliary sludge

  • Biliary sludge is most often asymptomatic, but it can be associated with biliary colic (9.1% incidence), pancreatitis (3.1%), and acute acalculous cholecystitis (7.1%). The natural history of biliary sludge is not fully known.

 

 

 

 

4. Gallstones and gallbladder polyps

Patients with gallstones and gallbladder polyps larger than 1 cm should be cholecystectomized irrespective of symptoms. For polyps larger than 1 cm, the probability of neoplastic alteration is markedly increased and a carcinoma may be found in up to 50%. For polyps with a diameter of less than 1 cm, the risk is considerably lower, but in patients aged 50 or older, cholecystectomy should be considered.

In patients with asymptomatic gallstones who undergo surgery for morbid obesity, prophylactic cholecystectomy should be considered, because they have a 10–15% risk of becoming symptomatic or developing complications after surgery for obesity. During large abdominal surgery (eg, surgery for obesity, extended bowel resections for Crohn disease, and radical gastrectomy with removal of lymph nodes), simultaneous cholecystectomy for asymptomatic stones may be performed.

Although asymptomatic patients in general should be managed expectantly, litholytic therapy may be considered if the stones appear to be ideal for dissolution by oral bile acid therapy with ursodeoxycholic acid (UDCA), psychosocial factors favor an active approach, or medical factors are present creating a high risk for surgery.?????

3. Preoperative diagnostic studies

Preoperative ultrasonography must be performed not only for diagnosis of gallbladder stones but also for detection of potential complications. Preoperative determination of liver enzymes (GGT, alkaline phosphatase, transaminases) and serum bilirubin is mandatory to assess the likelihood of simultaneous bile duct stones or preexisting liver disease. The likelihood of simultaneous bile duct stones is high if the diameter of the common bile duct is greater than 6–8 mm and GGT, alkaline phosphatase, or serum bilirubin is elevated. It is low if the diameter of the common bile duct is normal and serum enzymes indicative of cholestasis are not elevated (see Table 54–3). (See also “Complications,” earlier.) In case of uncertainty an endoscopic ultrasound or an MRC should be performed.

Lammert  F, Neubrand  MW, Bittner  R  et al. S3-guidelines for diagnosis and treatment of gallstones. German Society for Digestive and Metabolic Diseases and German Society for Surgery of the Alimentary Tract. Z Gastroenterol. 2007;45:971–1001. 
[PubMed: 17874360] 

B. Nonsurgical Therapy

1. Oral bile acid dissolution

In selected patients who have symptomatic gallbladder stones without complications and have mild and infrequent episodes of biliary pain, stone dissolution with UDCA may be employed. The patient must, however, be informed about the high risk of recurrent stones. UDCA reduces cholesterol saturation of bile and also produces a lamellar liquid crystalline phase in bile that allows dispersion of cholesterol from stones by physical-chemical means. In carefully selected patients with radiolucent stones smaller than 5–10 mm in diameter in a functioning gallbladder, complete dissolution can be achieved with UDCA in about 50% of patients. In general, 6–18 months of therapy are required to achieve complete dissolution of stones 5–10 mm in diameter, as gallstone dissolution occurs at a mean rate of 0.7-mm decrease in diameter per month. For good results within a reasonable time period, this therapy should be limited to radiolucent stones smaller than 5 mm in diameter. The dose of UDCA should be 10–15 mg/kg/day. Stones larger than 15 mm in size rarely dissolve. Pigment stones are not responsive to UDCA therapy. Recurrence of stones in 30–50% of patients within 3–5 years after stone dissolution has reduced the role of gallstone dissolution to patients who want to avoid or are unfit for cholecystectomy. A report from Japan that UDCA may reduce the risk of biliary pain independently from dissolution of the stones has not been confirmed in a recent study, which could not demonstrate a decrease of the incidence of biliary symptoms in gallstone patients awaiting elective cholecystectomy.

2. Extracorporeal shock wave lithotripsy

Following the introduction of laparoscopic cholecystectomy, this nonsurgical therapeutic modality has been abandoned mainly because of high rates of stone recurrence (11–29% at 2 years, 60–80% at 10 years). Extracorporeal shock wave lithotripsy has maintained a limited role in the treatment of bile duct stones resistant to endoscopic extraction.

3. Medical prophylaxis of cholesterol gallstone disease

UDCA may prevent gallstone formation in obese patients during rapid weight loss. In patients who completed a 3-month, 520-kcal/day diet, UDCA at a dose of 600 mg/day proved highly effective in preventing gallstone formation; gallstones developed in only 3% of patients receiving UDCA compared with 28% receiving placebo. In a study of stone prophylaxis by UDCA in obese patients treated by gastric banding, 500 mg/day of UDCA reduced the risk of gallstone formation from 30% to 8% within a follow-up of 6 months. For prophylaxis of gallstone formation during rapid weight loss (>1.5 kg/week) a minimal dose of UDCA of 500 mg/day is recommended until constant body weight is attained.

4. Symptomatic treatment of biliary colic

In general, combinations of analgesics with spasmolytic drugs are used for relief of pain. As a first-line treatment, nonsteroidal antirheumatic drugs, such as diclofenac orindomethacin are recommended and may be used in combination with N-butylscopolamine. Often opiates such as pethidine or buprenorphine are required.Nitroglycerin may also be effective because it relaxes the sphincter of Oddi. The patient should be kept nothing by mouth (NPO). In case of vomiting, parenteral fluid and electrolyte replacement may be indicated.

Colli  A, Conte  D, Valle  SD  et al. Meta-analysis: nonsteroidal anti-inflammatory drugs in biliary colic. Aliment Pharmacol Ther. 2012;35:1370–1378. 
[PubMed: 22540869] 
Lammert  F, Neubrand  MW, Bittner  R  et al. S3-guidelines for diagnosis and treatment of gallstones. German Society for Digestive and Metabolic Diseases and German Society for Surgery of the Alimentary Tract. Z Gastroenterol. 2007;45:971–1001. 
[PubMed: 17874360] 
May  GR, Sutherland  LR, Shaffer  EA. Efficacy of bile acid therapy for gallstone dissolution: a meta-analysis of randomized trials. Aliment Pharmacol Ther. 1993;7:139–148. 
[PubMed: 8485266] 
Miller  K, Hell  E, Lang  B  et al. Gallstone formation prophylaxis after gastric restrictive procedures for weight loss: a randomized double-blind placebo-controlled trial. Ann Surg. 2003;238:697–702. 
[PubMed: 14578732] 
Paumgartner  G, Pauletzki  J, Sackmann  M. Ursodeoxycholic acid treatment of cholesterol gallstone disease. Scand J Gastroenterol Suppl. 1994;204:27–31. 
[PubMed: 7824875] 
Shiffman  ML, Kaplan  GD, Brinkman-Kaplan  V  et al. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet program. Ann Intern Med. 1995;122:899–905. 
[PubMed: 7755224] 
Stokes  CS, Gluud  LL, Casper  M  et al. Ursodeoxycholic acid and diets higher in fat prevent gallbladder stones during weight loss: a meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2014;12:1090–1100.  [PubMed: 24321208] 

C. Management of Complications

1. Cholecystitis

Patients with acute cholecystitis should undergo early elective laparoscopic cholecystectomy, ideally within 24 hours of hospital admission. Four randomized studies have compared early and late (>6 weeks after diagnosis) cholecystectomy in a total of 388 patients. A meta-analysis of these studies confirms the advantages of early elective laparoscopic cholecystectomy. Hospital stay for the late operation was 3 days longer, and 17.5% of the patients had to undergo emergency operation during the preoperative waiting period. Early operation did not increase the complication rate (13.1%) as compared with late cholecystectomy (17.8%).

A more recent multicenter randomized trial (ACDC study) including a total of 618 patients showed that laparoscopic cholecystectomy within 24 hours of hospital admission was superior to delayed laparoscopic cholecystectomy at days 7 to 45 concerning morbidity and costs.

From admission until operation the patient should be kept NPO and intravenously hydrated with careful control of serum electrolytes. Administration of broad-spectrum antibiotics early in the course is recommended, because secondary infection often supervenes in what is initially a noninfectious process.

After conservative therapy, about 75% of patients with acute cholecystitis will recover, but about one-third of them will be readmitted because of biliary pain or complications and about 20% will have a recurrence of cholecystitis within 1 year.

If a complication of cholecystitis, such as diffuse peritonitis with suspected perforation, gangrene, or empyema develops, an emergency operation should be performed within 24 hours. When the patient is prepared for surgery, it must be considered that the circulating blood volume is often reduced in patients with cholecystitis or cholangitis. Volume substitution with colloids or albumin solution may therefore be indicated to prevent renal complications. In patients older than 65 years or with markedly increased operative risk (American Society of Anesthesiologists [ASA] risk class ≥IV), percutaneous drainage of the gallbladder is feasible and associated with low mortality.

If, because of late diagnosis or other medical reasons (high operative risk), cholecystectomy cannot be performed within 1–5 days, it is generally performed within 6 weeks after acute cholecystitis has subsided.

Gutt  CN, Encke  J, Koninger  J  et al. Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, NCT00447304). Ann Surg. 2013;258:385–393.  [PubMed: 24022431] 
Johansson  M, Thune  A, Nelvin  L  et al. Randomized clinical trial of open versus laparoscopic cholecystectomy in the treatment of acute cholecystitis. Br J Surg. 2005;92:44–49. 
[PubMed: 15584058] 
Macrì  A, Scuderi  G, Saladino  E  et al. Acute gallstone cholecystitis in the elderly: treatment with emergency ultrasonographic percutaneous cholecystostomy and interval laparoscopic cholecystectomy. Surg Endosc. 2006;20:88–91. 
[PubMed: 16333552] 
Papi  C, Catarci  M, D’Ambrosio  L  et al. Timing of cholecystectomy for acute calculous cholecystitis: a meta-analysis. Am J Gastroenterol. 2004;99:147–155. 
[PubMed: 14687156] 

2. Choledocholithiasis

Symptomatic bile duct stones should be removed. Data on the natural history of bile duct stones show that symptomatic bile duct stones will cause recurrent colic in more than 50% of the patients and complications in about 25%. Asymptomatic bile duct stones seem to be more benign than symptomatic bile duct stones. Although long-term prospective data are not available, short-term prospective and long-term retrospective studies indicate that less than half of the patients become symptomatic and more than 20% of the stones pass spontaneously. From these data it may be concluded that patients with asymptomatic bile duct stones may be treated, but that treatment is not necessary for every patient. Spontaneous passage of stones into the bowel appears to be common, especially when the stones are small. Examination of the feces after extracorporeal shock wave lithotripsy of gallbladder stones has shown that stone fragments up to 8 mm in diameter can pass the papilla spontaneously without severe symptoms.

Patients with symptomatic bile duct stones who have had cholecystectomy previously should undergo endoscopic stone extraction. Patients with simultaneous gallbladder and bile duct stones undergo so-called therapeutic splitting. In this technique, ERC is performed before or after cholecystectomy. If the probability of simultaneous choledocholithiasis is high, preoperative endoscopic papillotomy (EPT) and stone extraction are preferred in most hospitals. EPT and cholecystectomy should not be performed on the same day to exclude complications of EPT before surgery. If the probability of choledocholithiasis is low, preoperative ERC should not be the standard; rather—depending on availability—less-invasive procedures should be used. Both endosonography and MRC have high sensitivity and specificity for the detection of bile duct stones. If bile duct stones are found, preoperative EPT with stone removal should be performed. In centers with high expertise, laparoscopic cholecystectomy may be combined with laparoscopic revision of the common duct and removal of the stones.

If endoscopic transpapillary therapy is not possible or fails, percutaneous, transhepatic, or surgical therapy of choledocholithiasis may be employed. In high-risk patients the placement of an endoprosthesis may be considered for primary therapy.

After successful endoscopic or percutaneous removal of bile duct stones in patients with gallbladder stones, cholecystectomy should be performed. This recommendation is based on a study randomizing patients (age >60) after endoscopic sphincterotomy and clearance of their bile duct stones to receive either expectant management or early laparoscopic cholecystectomy. Within a median follow-up of approximately 5 years, 24% of patients with the gallbladder left in situ returned with further biliary events (cholangitis, acute cholecystitis, biliary pain, and jaundice) as compared with only 7% (cholangitis, biliary pain) in the cholecystectomy group. Cholecystectomy should be performed early, preferably during the same hospital admission. A recent randomized study showed that recurrent biliary events occurred in 17 out of 47 patients (36.2%) whose laparoscopic cholecystectomy was delayed for 6–8 weeks, but only in 1 out of 49 patients who underwent early laparoscopic cholecystectomy within 72 hours after endoscopic sphincterotomy. Early laparoscopic cholecystectomy after sphincterotomy was safe and prevented the majority of biliary events in the period following sphincterotomy and removal of bile duct stones.

Lau  JY, Leow  CK, Fung  TM  et al. Cholecystectomy or gall-bladder in situ after endoscopic sphincterotomy and bile duct stone removal in Chinese patients.Gastroenterology. 2006;130:96–103. 
[PubMed: 16401473] 
Reinders  JS, Goud  A, Timmer  R  et al. Early laparoscopic cholecystectomy improves outcomes after endoscopic sphincterotomy for choledochocystolithiasis.Gastroenterology. 2010;138:2315–2320. 
[PubMed: 20206179] 
Schiphorst  AH, Besselink  MG, Boerma  D  et al. Timing of cholecystectomy after endoscopic sphincterotomy for common bile duct stones. Surg Endosc. 2008;22:2046–2050. 
[PubMed: 18270768] 

3. Cholangitis

Acute cholangitis caused by an obstructive gallstone should be treated as soon as possible (in septic patients, as an emergency procedure) by endoscopic removal of the stone. A randomized study has shown a significant advantage of the endoscopic versus the surgical approach with regard to complications and mortality. Immediate systemic antibiotic therapy is indicated to prevent septic complications. If stone extraction fails, nasobiliary drainage or a biliary stent should be placed. Nasobiliary drainage and a biliary stent are equally effective, but nasobiliary drainage offers the advantage of bile sampling for microbiological tests and flushing the bile duct.

Lai  EC, Mok  FP, Tan  ES  et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med. 1992;326:1582–1586. 
[PubMed: 1584258] 

4. Biliary pancreatitis

Management of biliary pancreatitis depends on its severity. Most cases of biliary pancreatitis are mild, resolve spontaneously, and may be managed expectantly. After resolution, patients with gallbladder or bile duct stones, or both, should undergo cholecystectomy and removal of bile duct stones prior to discharge from the hospital. If biliary pancreatitis is severe and is associated with choledocholithiasis and signs of cholestasis, ERC with papillotomy and stone extraction should be performed as soon as possible, in the presence of cholangitis within 24 hours.

In cases where surgery is not desired cholecystostomy may be considered.

 

A. Cholecystitis, Acute

 

Chronic cholecystitis is a chronic inflammation of the gallbladder wall that results from repeated attacks of acute and subacute cholecystitis or mechanical irritation of the gallbladder mucosa by gallstones. It may progress from asymptomatic to symptomatic.

In 10–30% of the patients with acute cholecystitis severe complications, such as gallbladder gangrene, empyema, or perforation, occur. Fistulization between gallbladder and bowel occur in less than 1% of all patients with gallstones. A biliodigestive fistula can manifest itself by ascending cholangitis or a bile acid malabsorption syndrome. In about 60% of cases, the fistulas are located between the gallbladder and the duodenum and remain asymptomatic. Passage of large stones through a fistula can cause gallstone ileus, especially in the terminal ileum. Aerobilia is an important sign of a biliodigestive fistula. Magnetic resonance cholangiography (MRC) may be valuable for diagnosis in this situation.

Mirizzi syndrome is a rare complication in which a gallstone becomes impacted in the neck of the gallbladder or cystic duct, causing compression of the common bile duct and obstructive jaundice.

B. Choledocholithiasis

Passage of gallstones into the common bile duct occurs in approximately 10–15% of patients with gallbladder stones. In up to 25% of elderly patients who undergo cholecystectomy, stones in the common duct are found. The large majority of them are cholesterol stones that originate in the gallbladder. Stones that primarily form in the bile ducts are usually pigment stones (see “Pathogenesis,” earlier). An exception is the formation of cholesterol gallstones in the bile ducts of patients with an ABCB4 gene defect causing impaired biliary phospholipid secretion. Most patients with common bile duct stones present with biliary pain accompanied by abnormal liver tests with or without jaundice. Major complications of choledocholithiasis are obstructive jaundice, cholangitis, pancreatitis, and secondary biliary cirrhosis.

The presentation of acute obstruction of the common bile duct by a stone usually includes biliary pain, similar to the pain of cystic duct obstruction, and—if of sufficient duration—is followed by jaundice. Most patients with obstruction have elevated liver enzymes (alanine amino-transferase [ALT], aspartate aminotransferase [AST]) in the acute phase of obstruction. In the later course ALT and AST decrease toward normal even if the obstruction persists, whereas alkaline phosphatase rises, followed by bilirubin elevation and eventually jaundice.

Transcutaneous abdominal ultrasonography has only moderate diagnostic accuracy for the detection or exclusion of bile duct stones. Sensitivities between 38% and 82% have been reported. If the diameter of the common bile duct is larger than 6 mm, a bile duct stone must be suspected. Determination of γ-glutamyl transferase (GGT), alkaline phosphatase, ALT, and serum bilirubin levels is mandatory for differential diagnosis in this situation (Table 54–3).

Criteria for simultaneous choledocholithiasis in patients with gallbladder stones.

High probability for simultaneous bile duct stones

  • – Common bile duct dilated (>6–8 mm) + hyperbilirubinemia + elevated GGT, alkaline phosphatase and/or ALT

  • – Common bile duct >10 mm in presence of gallbladder stones

  • – Direct evidence of stone in bile ducts by ultrasound

Low probability for simultaneous bile duct stones

  • – Common bile duct not dilated

  • – GGT, alkaline phosphatase, and ALT within normal limits

ALT, alanine aminotransferase; GGT, γ-glutamyl transferase.

If direct proof or exclusion of bile duct stones by ultrasonography is not possible, clinical symptoms and signs of biliary obstruction guide the planning of further diagnostic measures. If there is high suspicion of the presence of a bile duct stone, endoscopic retrograde cholangiography (ERC) is indicated because it permits simultaneous therapeutic intervention (endoscopic papillotomy and stone extraction). Its sensitivity and specificity for the detection of bile duct stones are greater than 90%. However, a general recommendation for exclusion of bile duct stones with ERC prior to laparoscopic cholecystectomy would expose too many patients to unnecessary risks of this diagnostic procedure, because the prevalence of bile duct stones in patients with gallbladder stones, depending on age, ranges between 5% and 15% only. If findings are questionable and bile duct stones are suspected, endosonography or MRC (see Figure 9–36) should be performed prior to ERC. Endosonography has the highest sensitivity for the detection of stones in the common duct. It is associated with lesser risks than the diagnostic ERC, especially for small (<5 mm) and ampullary stones. A recent meta-analysis of five randomized controlled studies including a total of 301 patients did not find a significant difference between endoscopic ultrasound and MRCP with regard to sensitivity (93% vs 85%) and specificity (96% vs 93%) for the diagnosis of bile duct stones.

C. Cholangitis

The characteristic presentation of cholangitis involves biliary pain, jaundice, and spiking fevers with chills (the Charcot triad). Leukocytosis is typical, and blood cultures are positive in about 75% of patients.

D. Biliary Pancreatitis

Biochemical evidence of pancreatic inflammation complicates acute cholecystitis in about 15% and choledocholithiasis in about 30% of patients. The common cause appears to be passage of stones through the common duct.

 

 

 

Complications from these stones include:

  • Acute cholecystitis, gallbladder inflammation resulting from obstruction of the cystic duct. In 50% of patients there is no evidence of bacterial infection in the gallbladder bile
  • Biliary colic, resulting from intermittent obstruction of the cystic or bile ducts
  • Cholangitis, infection within the bile ducts, most commonly caused by obstruction. Symptoms frequently include right upper quadrant tenderness, fever, and jaundice (Charcot triad). Cholangitis is a serious medical problem and may require early duct decompression to prevent sepsis
  • Gallstone ileus, which occurs when a large gallstone erodes through the wall of the gallbladder and into adjacent, adherent structures. Most commonly this is the duodenum, but it may also be the stomach or colon. A large gallstone may obstruct the small intestine, most commonly near the terminal ileum

After the first manifestation of biliary pain, about 30% of patients do not have another episode, but the majority of patients suffer from further attacks of pain, and the rate of complications is 1–3% per year. By contrast, the rate of complications for a carrier of a gallstone that has never had a biliary colic is only 0.1–0.3% per year. If there are no further episodes of biliary colic within 5 years after the first attack, the natural history of the patient may be regarded as that of asymptomatic gallstone disease.

 

Content 11

 

USMLE Reviewer (Subscription Required)