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Cholecystitis Background

Cholecystitis is defined as inflammation of the gallbladder that occurs most commonly because of an obstruction of the cystic duct from cholelithiasis. Ninety percent of cases involve stones in the cystic duct (ie, calculous cholecystitis), with the other 10% of cases representing acalculous cholecystitis.[1] Risk factors for cholecystitis mirror those for cholelithiasis and include increasing age, female sex, certain ethnic groups, obesity or rapid weight loss, drugs, and pregnancy. Although bile cultures are positive for bacteria in 50-75% of cases, bacterial proliferation may be a result of cholecystitis and not the precipitating factor. Acalculous cholecystitis is related to conditions associated with biliary stasis, including debilitation, major surgery, severe trauma, sepsis, long-term total parenteral nutrition (TPN), and prolonged fasting. Other causes of acalculous cholecystitis include cardiac events; sickle cell disease;Salmonella infections; diabetes mellitus; and cytomegalovirus, cryptosporidiosis, or microsporidiosis infections in patients with AIDS. (See Etiology.) Go to Acalculous Cholecystopathy for more complete information on this topic. Uncomplicated cholecystitis has an excellent prognosis, with a very low mortality rate. Once complications such as perforation/gangrene develop, the prognosis becomes less favorable. Some 25-30% of patients either require surgery or develop some complication. (See Prognosis.) The most common presenting symptom of acute cholecystitis is upper abdominal pain. The physical examination may reveal fever, tachycardia, and tenderness in the RUQ or epigastric region, often with guarding or rebound. However, the absence of physical findings does not rule out the diagnosis of cholecystitis. (See Clinical Presentation.) Delays in making the diagnosis of acute cholecystitis result in a higher incidence of morbidity and mortality. This is especially true for ICU patients who develop acalculous cholecystitis. The diagnosis should be considered and investigated promptly in order to prevent poor outcomes. (See Diagnosis.) Initial treatment of acute cholecystitis includes bowel rest, intravenous hydration, correction of electrolyte abnormalities, analgesia, and intravenous antibiotics. For mild cases of acute cholecystitis, antibiotic therapy with a single broad-spectrum antibiotic is adequate. Outpatient treatment may be appropriate for cases of uncomplicated cholecystitis. If surgical treatment is indicated, laparoscopic cholecystectomy represents the standard of care. (See Treatment and Management.) Go to Workup: Imaging Studies in Cholecystitis and Biliary Colic for more complete information on this topic.

Pathophysiology
Ninety percent of cases of cholecystitis involve stones in the cystic duct (ie, calculous cholecystitis), with the other 10% of cases representing acalculous cholecystitis.[1] Acute calculous cholecystitis is caused by obstruction of the cystic duct, leading to distention of the gallbladder. As the gallbladder becomes distended, blood flow and lymphatic drainage are compromised, leading to mucosal ischemia and necrosis.

or microsporidiosis Patients who are immunocompromised are at increased risk of developing cholecystitis from a number of different infectious sources. Injury may be the result of retained concentrated bile. areas of fibrin deposition. resulting in approximately 500.[4] Endotoxin also abolished the contractile response to CCK. [2. In the presence of prolonged fasting. Etiology Risk factors for calculous cholecystitis mirror those for cholelithiasis and include the following:       Female sex Certain ethnic groups Obesity or rapid weight loss Drugs (especially hormonal therapy in women) Pregnancy Increasing age Acalculous cholecystitis is related to conditions associated with biliary stasis. Age distribution for cholecystitis The incidence of cholecystitis increases with age. thus. The increased incidence in elderly men has been linked to changing androgen-to-estrogen ratios. Sex distribution for cholecystitis . consistent with an acute ischemic insult. Go to Pediatric Cholecystitis for more complete information on this topic. the gallbladder never receives a cholecystokinin (CCK) stimulus to empty. 3] A study by Cullen et al demonstrated the ability of endotoxin to cause necrosis. and as many as one third of these people develop acute cholecystitis.Although the exact mechanism of acalculous cholecystitis is unclear. leading to gallbladder stasis. the concentrated bile remains stagnant in the lumen. cryptosporidiosis. and extensive mucosal loss. several theories exist. Cholecystectomy for either recurrent biliary colic or acute cholecystitis is the most common major surgical procedure performed by general surgeons.           Epidemiology An estimated 10-20% of Americans have gallstones.000 operations annually. to include the following: Critical illness Major surgery or severe trauma/burns Sepsis Long-term total parenteral nutrition (TPN) Prolonged fasting Other causes of acalculous cholecystitis include the following: Cardiac events. an extremely noxious substance. hemorrhage. The physiologic explanation for the increasing incidence of gallstone disease in the elderly population is unclear. including myocardial infarction Sickle cell disease Salmonella infections Diabetes mellitus[] Patients with AIDS who have cytomegalovirus. Idiopathic cases exist.

[1. mortality can be as high as 50-60%. Cholelithiasis. Most patients with acute cholecystitis have a complete remission within 1-4 days. Gallstones develop insidiously. whereas cholelithiasis is less common among individuals from sub-Saharan Africa and Asia. Perforation occurs in 10-15% of cases. Cholelithiasis is the presence of gallstones in the gallbladder (see the image below). Elevated progesterone levels during pregnancy may cause biliary stasis. A gallbladder filled with gallstones (examined extracorporally after laparoscopic cholecystectomy [LC]). 2] . However. Cholangitis occurs when a gallstone obstructs the biliary or hepatic ducts. usually in the gallbladder. and Hispanic populations. Acalculous cholecystitis is observed more often in elderly men. Cholelithiasis Background Gallstones are concretions that form in the biliary tract. the prognosis becomes less favorable. and they may remain asymptomatic for decades. with very low mortality.[6. Pima Indians. 7] In the United States. resulting in higher rates of gallbladder disease in pregnant females. 25-30% of patients either require surgery or develop some complication. which far exceeds the expected 4% mortality observed in patients with calculous cholecystitis. Once complications such as perforation/gangrene develop. Patients with acalculous cholecystitis have a mortality ranging from 10-50%. the major risk factor for cholecystitis. Prognosis Uncomplicated cholecystitis has an excellent prognosis. Prevalence of cholecystitis by race and ethnicity Cholelithiasis. Patient Education Patients diagnosed with cholecystitis must be educated regarding causes of their disease.Gallstones are 2-3 times more frequent in females than in males. has an increased prevalence among people of Scandinavian descent. and medical/surgical options to treat cholecystitis. resulting in a higher incidence of calculous cholecystitis in females. Migration of gallstones may lead to obstruction of the cystic duct (biliary colic). Obstruction of pancreatic duct can cause acute pancreatitis. causing inflammation and infection. complications if left untreated. white people have a higher prevalence than black people. with subsequent inflammation (acute cholecystitis). In patients who are critically ill with acalculous cholecystitis and perforation or gangrene.

which then precipitate from solution as microscopic crystals. Image courtesy of DT Schwartz. Sludge in the gallbladder. and fuse to form macroscopic stones. Cholecystectomy is among the most frequently performed abdominal surgical procedures. it can become supersaturated with these substances. In some cases. Asymptomatic gallstones may be managed expectantly. Once gallstones become symptomatic. The sensitivity of transabdominal ultrasonography for choledocholithiasis is approximately 75% in the presence of dilated ducts and 50% for nondilated ducts. it may also cause disease in itself. Occlusion of the ducts by sludge and/or stones produces the complications of gallstone disease. .Choledocholithiasis is the presence of a gallstone in the common bile duct (see the image below). Common bile duct stone (choledocholithiasis). Ultrasonography is the procedure of choice in suspected gallbladder or biliary disease (see Workup). definitive surgical intervention with excision of the gallbladder (cholecystectomy) is usually indicated. This typically occurs in patients with prolonged illness. Although sludge may be a step in the formation of stones. Five to fifteen percent of patients with acute cholecystitis present without stones (acalculous cholecystitis). and adds to the morbidity and mortality of gallstone disease. aggregate. such as those with major trauma or with prolonged ICU stays. the crystals grow. necessitates additional diagnostic and therapeutic procedures. Chronic gallstone disease may lead to fibrosis and loss of function of the gallbladder. Image courtesy of DT Schwartz. The treatment of gallstones depends upon the stage of disease. producing gallbladder sludge (see the image below). When bile is concentrated in the gallbladder. Choledocholithiasis complicates the workup and management of cholelithiasis. Note the lack of shadowing. Over time. and it predisposes to gallbladder cancer. however. medical dissolution may be considered (see Treatment and Management) Pathophysiology Gallstone formation occurs because certain substances in bile are present in concentrations that approach the limits of their solubility. The crystals are trapped in gallbladder mucus.

which form almost exclusively in the gallbladder. Thus. phosphate. but a small proportion consists of unconjugated bilirubin. possibly related to liver fluke infestation. a yellow pigment derived from the breakdown of heme. progressive dissolution of vesicles may lead to a state in which the cholesterol-carrying capacity of the micelles and residual vesicles is exceeded. the main factors that determine whether cholesterol gallstones will form are (1) the amount of cholesterol secreted by liver cells. which are quite water soluble and stable. mixed micelles have a lower carrying capacity for cholesterol (about 1 molecule of cholesterol for every 3 molecules of lecithin). which complex with calcium and precipitate from solution. termed unilamellar vesicles. and cholesterol monohydrate crystals may form. At this point. Most of the bilirubin in bile is in the form of glucuronide conjugates. unconjugated bilirubin may be present in bile at higher than normal concentrations. and pigment gallstones Bilirubin. bilirubin. Calcium. it may become colonized with bacteria. Liver cells secrete cholesterol into bile along with phospholipid (lecithin) in the form of small spherical membranous bubbles. like fatty acids. Compared with vesicles (which can hold up to 1 molecule of cholesterol for every molecule of lecithin). The resulting concretions have a claylike consistency and are termed brown pigment stones. and (2) the degree of concentration and extent of stasis of bile in the gallbladder. The bacteria hydrolyze conjugated bilirubin. Bile is normally sterile. In situations of high heme turnover. such as chronic hemolysis or cirrhosis. tends to form insoluble precipitates with calcium. Over time. where bile is concentrated by reabsorption of electrolytes and water. and other anions. carbonate. Liver cells also secrete bile salts. but in some unusual circumstances (eg.The 2 main substances involved in gallstone formation are cholesterol and calcium bilirubinate. Bacterial hydrolysis of lecithin leads to the release of fatty acids. and the resulting increase in unconjugated bilirubin may lead to precipitation of calcium bilirubinate crystals. Calcium enters bile passively along with other electrolytes. is actively secreted into bile by liver cells. Brown pigment stones are unusual in the United States but are fairly common in some parts of Southeast Asia. then as bile is concentrated. Unlike cholesterol or black pigment stones. various oxidations cause the bilirubin precipitates to take on a jet-black color. which are powerful detergents required for digestion and absorption of dietary fats. above a biliary stricture). bile is supersaturated with cholesterol. Black pigment stones represent 10-20% of gallstones in the United States. relative to lecithin and bile salts. If bile contains a relatively high proportion of cholesterol to begin with. This happens mainly in the gallbladder. brown pigment stones often form de novo in the bile ducts. Mixed gallstones . Unconjugated bilirubin. Calcium bilirubinate may then crystallize from solution and eventually form stones. Cholesterol gallstones More than 80% of gallstones in the United States contain cholesterol as their major component. and stones formed in this manner are termed black pigment stones. Bile salts in bile dissolve the unilamellar vesicles to form soluble aggregates called mixed micelles.

(Images of CBD stones are shown below. insulin resistance. producing mixed gallstones. and increasing age. cholesterol stones may accumulate a substantial proportion of calcium bilirubinate and other calcium salts. Cholesterol gallstones Cholesterol gallstones are associated with female sex. hypertension. prolonged fasting with total parenteral nutrition. Etiology Cholesterol gallstones. over time. and brown pigment gallstones have different pathogeneses and different risk factors.) Obstruction of the CBD by gallstones leads to symptoms and complications that include pain. black pigment gallstones. Lytic enzymes from bacteria and leukocytes hydrolyze bilirubin conjugates and fatty acids. Progesterone reduces gallbladder contractility. Intraoperative cholangiogram demonstrating a distal common bile duct stone with dilatation. and sepsis. Large stones may develop a surface rim of calcium resembling an eggshell that may be visible on plain x-ray films. A major contributing factor is thought to be the high progesterone levels of pregnancy. cholangitis. and hyperlipidemia is associated with increased hepatic cholesterol secretion and is a major risk factor for the development of cholesterol gallstones. As a result. jaundice. and rapid weight loss . type II diabetes mellitus. Intraoperative cholangiogram demonstrating a distal common bile duct stone without dilatation. Other risk factors include the following:      Obesity Pregnancy Gallbladder stasis Drugs Heredity The metabolic syndrome of truncal obesity. Cholesterol gallstones are more common in women who have experienced multiple pregnancies. Other causes of gallbladder stasis associated with increased risk of gallstones include high spinal cord injuries. European or Native American ancestry. leading to prolonged retention and greater concentration of bile in the gallbladder. pancreatitis. Common bile duct stones Choledocholithiasis occurs as a result of either the primary formation of stones in the common bile duct (CBD) or the passage of gallstones from the gallbladder through the cystic duct into the CBD.Cholesterol gallstones may become colonized with bacteria and can elicit gallbladder mucosal inflammation.

ileal resection. Estrogens administered for contraception or for treatment of prostate cancer increase the risk of cholesterol gallstones. a high-fat diet. portal hypertension leads to splenomegaly. Bacterial or parasitic infections from organisms that contain B -glucuronidase. this combination is most often encountered in patients with postsurgical biliary strictures or choledochal cysts. diet. At least a dozen genes may contribute to the risk. Clofibrate and other fibrate hypolipidemic drugs increase hepatic elimination of cholesterol via biliary secretion and appear to increase the risk of cholesterol gallstones. increase the risk for pigmented stones. In the United States. an enzyme that deconjugates bilirubin glucuronide. increase cholesterol secretion and gallstone formation. intraductal formation of brown pigment stones accompanies multiple strictures throughout intrahepatic and extrahepatic bile ducts. particularly associated with a South American diet. The etiology is unknown. hereditary spherocytosis. causes red cell sequestration. but liver flukes have been implicated. More than one third of patients develop gallstones after bariatric surgery. About 25% of the predisposition to cholesterol gallstones appears to be hereditary. Weight loss greater than 25% is the best predictor for the gallstone formation. Prerequisites for formation of brown pigment gallstones include colonization of bile with bacteria and intraductal stasis.[4] A rare syndrome of low phospholipid–associated cholelithiasis occurs in individuals with a hereditary deficiency of the biliary transport protein required for lecithin secretion. Diosgenin-rich beans. Black pigment gallstones Black pigment gallstones occur disproportionately in individuals with high heme turnover. and beta-thalassemia. In hepatolithiasis. once symptomatic. gallstones include sickle cell In cirrhosis.associated with severe caloric and fat restriction (eg. though the mechanism is unclear. Cirrhosis carries major multifactorial risks for gallstone formation and gallbladder disease. In most cases. gastric bypass surgery). patients with diabetes are prone to more severe complications. This condition causes recurrent cholangitis and predisposes to biliary cirrhosis and cholangiocarcinoma. leading to a modest increase in hemoglobin turnover. Disorders of hemolysis associated with pigment anemia. Rapid weight loss mobilizes tissue cholesterol stores and increases the saturation of bile. Reduced hepatic synthesis and transport of bile salts. Other comorbidities Diabetes mellitus is associated with an increased risk of gallstone. a condition encountered mainly in rice-growing regions of East Asia. About half of all cirrhotic patients have pigment gallstones. as judged from studies of identical and fraternal twins. This. hyperestrogenemia. in turn. no risk factor can be identified. impaired . or other diseases of the ileum decrease bile salt reabsorption and increase the risk of gallstone formation. however. Somatostatin analogues appear to predispose to gallstones by decreasing gallbladder emptying.[3] Obesity. and hypertriglyceridemia are strongly associated with the formation of gallstones. Crohn disease.

Bile duct stones Primary common bile duct stones are caused by conditions leading to bile stasis and chronic bactibilia. In Western populations. sclerosing cholangitis. The sludge also contains mucin and bacterial cytoskeletons. which further aid in stone formation. about 20 million people (10-20% of adults) have gallstones.000 people develop symptoms or complications of gallstones requiring cholecystectomy. International statistics . and bile acids leads to the formation of insoluble calcium bilirubinate particles. Bactibilia is also common in these instances. About 7000 deaths are attributable to acute gallstone complications. and genetics. Some authors have suggested that the stones are formed because of the bactibilia alone and that the parasites' presence is just a coincidence. contribute to the formation of gallstones (typically pigment stones) in cirrhosis. approximately 500. In Asian populations. to decreased enteral stimulation of the gallbladder with resultant biliary stasis and stone formation. deconjugated bilirubin. in the United States. biliary stasis is secondary to factors such as sphincter of Oddi dysfunction. and major trauma. use of total parenteral nutrition.gallbladder contraction. ICU care. infestation with Ascaris lumbricoides and Clonorchis sinensis may promote stasis by either blocking the biliary ducts or by damaging the duct walls. comorbidities. cholecystectomy is a very common procedure. thus releasing fatty acids from biliary phospholipids. probably secondary to episodic portal bacteremia. paralysis. Each year. Bile stasis promotes growth of bacteria.000 deaths per year in the United States. resulting in the formation of biliary sludge. Choledocholithiasis complicates 10-15% of cholelithiasis cases. such as acute pancreatitis. and its rare complications result in several hundred deaths each year. The presence of free fatty acids. Escherichia coli) produce beta-glucuronidase in amounts sufficient to deconjugate bilirubin diglucuronide. resulting in stricture formation. including ethnicity. About 2000-3000 deaths are caused by gallbladder cancers (80% of which occur in the setting of gallstone disease with chronic cholecystitis). Gallstone disease is responsible for about 10. benign biliary strictures. This is due. cholesterol becomes insoluble. With the loss of bile acids. in general. Although gallstone surgery is relatively safe. and cystic dilatation of the bile ducts. The duct epithelium and/or bacteria (eg. Other illnesses or states that predispose to gallstone formation include burns. among other factors. and increased biliary stasis. Epidemiology The prevalence of cholelithiasis is affected by many factors. which produce phospholipase A1. Every year 1-3% of people develop gallstones and about 1-3% of people become symptomatic. United States statistics In the United States. gender. Up to 90% of patients with brown pigment CBD stones have bile culture results positive for bacteria.

The lifetime risk of developing gallstones in whites is 50% for women and 30% for men. in men. After age 15 years. 20% of women had stones. A Swedish epidemiologic study found that the incidence of gallstones was 1.[5] In a study of randomly selected individuals aged 35-85 years in a general population who had been screened previously with ultrasonography and found to have no gallbladder stones. and age-related demographics Prevalence of gallstones is highest in fair-skinned people of northern European descent and in Hispanic populations and Native American populations. Beginning at puberty. The incidence rate of choledocholithiasis is higher internationally than in the United States. Gallstone development was related to length of follow-up and low-density lipoprotein (LDL) cholesterol levels. The mortality rate for an elective cholecystectomy is 0.5% with less than 10% morbidity. . Gallstones are uncommon in children.4% per year until late in life. 8.[6] Prevalence of gallstones is low in Asians and African Americans. the rate is less.8% for men and 4.39 per 100 person-years. On reexamination. especially during their reproductive years. and the prevalence is greatest at advanced age.3% (42/503) had developed gallstones. The mortality rate for an emergent cholecystectomy is 3-5% with 30-50% morbidity. however. about 0. biliary malformation and disease. Women are more likely to develop cholesterol gallstones than men. but it appears to be somewhat lower in Asia and Africa. the prevalence of gallstones in US women increases by about 1% per year. Race-. Prognosis Less than half of patients with gallstones become symptomatic. The difference appears to be attributable mainly to estrogen. but new stone formation in men and women continues at a rate of about 0. Children with gallstones are more likely to have congenital anomalies. and 14% of men had stones. the concentration of cholesterol in bile increases.[7] Pigment gallstones affect men and women equally. The incidence in women falls with menopause.5% per year. Halldestam et al reexamined 503 study subjects after a minimum interval of 5 years.8% for women. compared with 15-60% of patients older than 60 years. 8-15% of patients younger than 60 years have common bile duct stones. African Americans with sickle cell disease have gallstones early in life secondary to associated hemolysis. sex-. Gallstones continue to form throughout adult life. which increases biliary cholesterol secretion. when the incidence of gallstones in women is 2 to 3 times that in men. gallstone prevalence in persons aged 60 years was 12.[5] In an Italian study. mainly because of the additional problem of primary common bile duct stones caused by parasitic infestation with Ascaris lumbricoidesand Clonorchis sinensis.4% for women. and inversely related to alcohol consumption. In a Danish study.The prevalence of cholesterol cholelithiasis in other Western cultures is similar to that in the United States. gallstone prevalence in persons aged 30 years was 1. Among individuals undergoing cholecystectomy for symptomatic cholelithiasis. or hemolytic pigment stones.9% for men and 22. Risk of developing gallstones increases with age.

The prognosis in patients with choledocholithiasis depends on the presence and severity of complications. If pain is severe or persists for more than an hour. stones may recur in the bile duct.Following cholecystectomy. Alarm symptoms include persistent epigastric pain lasting for greater than 20 minutes. while 55% experience varying degrees of complications. Of all patients who refuse surgery or are unfit to undergo surgery. . the patient should seek immediate medical attention. 45% remain asymptomatic from choledocholithiasis. or fever. especially if accompanied by nausea. Patient Education Patients with asymptomatic gallstones should be educated to recognize and report the symptoms of biliary colic and acute pancreatitis. vomiting. Approximately 10-15% of patients have an associated choledocholithiasis.