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.

Although the exact mechanism of acalculous cholecystitis is unclear, several theories exist. Injury may be the result of retained concentrated bile, an extremely noxious substance. In the presence of prolonged fasting, the gallbladder never receives a cholecystokinin (CCK) stimulus to empty; thus, the concentrated bile remains stagnant in the lumen. [2, 3] A study by Cullen et al demonstrated the ability of endotoxin to cause necrosis, hemorrhage, areas of fibrin deposition, and extensive mucosal loss, consistent with an acute ischemic insult.[4] Endotoxin also abolished the contractile response to CCK, leading to gallbladder stasis.

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, 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, including myocardial infarction Sickle cell disease Salmonella infections Diabetes mellitus[] Patients with AIDS who have cytomegalovirus, cryptosporidiosis, or microsporidiosis Patients who are immunocompromised are at increased risk of developing cholecystitis from a number of different infectious sources. Idiopathic cases exist.

Epidemiology
An estimated 10-20% of Americans have gallstones, and as many as one third of these people develop acute cholecystitis. Cholecystectomy for either recurrent biliary colic or acute cholecystitis is the most common major surgical procedure performed by general surgeons, resulting in approximately 500,000 operations annually.

Age distribution for cholecystitis

The incidence of cholecystitis increases with age. The physiologic explanation for the increasing incidence of gallstone disease in the elderly population is unclear. The increased incidence in elderly men has been linked to changing androgen-to-estrogen ratios. Go to Pediatric Cholecystitis for more complete information on this topic.

Sex distribution for cholecystitis

Gallstones are 2-3 times more frequent in females than in males, resulting in a higher incidence of calculous cholecystitis in females. Elevated progesterone levels during pregnancy may cause biliary stasis, resulting in higher rates of gallbladder disease in pregnant females. Acalculous cholecystitis is observed more often in elderly men.

Prevalence of cholecystitis by race and ethnicity

Cholelithiasis, the major risk factor for cholecystitis, has an increased prevalence among people of Scandinavian descent, Pima Indians, and Hispanic populations, whereas cholelithiasis is less common among individuals from sub-Saharan Africa and Asia.[6, 7] In the United States, white people have a higher prevalence than black people.

Prognosis
Uncomplicated cholecystitis has an excellent prognosis, with very low mortality. Most patients with acute cholecystitis have a complete remission within 1-4 days. However, 25-30% of patients either require surgery or develop some complication. Once complications such as perforation/gangrene develop, the prognosis becomes less favorable. Perforation occurs in 10-15% of cases. Patients with acalculous cholecystitis have a mortality ranging from 10-50%, which far exceeds the expected 4% mortality observed in patients with calculous cholecystitis. In patients who are critically ill with acalculous cholecystitis and perforation or gangrene, mortality can be as high as 50-60%.

Patient Education
Patients diagnosed with cholecystitis must be educated regarding causes of their disease, complications if left untreated, and medical/surgical options to treat cholecystitis.

Cholelithiasis Background
Gallstones are concretions that form in the biliary tract, usually in the gallbladder. Cholelithiasis is the presence of gallstones in the gallbladder (see the image below).

Cholelithiasis. A gallbladder filled with gallstones (examined extracorporally after laparoscopic cholecystectomy [LC]).

Gallstones develop insidiously, and they may remain asymptomatic for decades. Migration of gallstones may lead to obstruction of the cystic duct (biliary colic), with subsequent inflammation (acute cholecystitis). Cholangitis occurs when a gallstone obstructs the biliary or hepatic ducts, causing inflammation and infection. Obstruction of pancreatic duct can cause acute pancreatitis.[1, 2]

Choledocholithiasis is the presence of a gallstone in the common bile duct (see the image below). Choledocholithiasis complicates the workup and management of cholelithiasis, necessitates additional diagnostic and therapeutic procedures, and adds to the morbidity and mortality of gallstone disease.

Common bile duct stone (choledocholithiasis). The sensitivity of transabdominal ultrasonography for choledocholithiasis is approximately 75% in the presence of dilated ducts and 50% for nondilated ducts. Image courtesy of DT Schwartz.

Chronic gallstone disease may lead to fibrosis and loss of function of the gallbladder, and it predisposes to gallbladder cancer. Ultrasonography is the procedure of choice in suspected gallbladder or biliary disease (see Workup). The treatment of gallstones depends upon the stage of disease. Asymptomatic gallstones may be managed expectantly. Once gallstones become symptomatic, definitive surgical intervention with excision of the gallbladder (cholecystectomy) is usually indicated. Cholecystectomy is among the most frequently performed abdominal surgical procedures. In some cases, 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. 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 (see the image below). Over time, the crystals grow, aggregate, and fuse to form macroscopic stones. Occlusion of the ducts by sludge and/or stones produces the complications of gallstone disease.

Sludge in the gallbladder. Note the lack of shadowing. Image courtesy of DT Schwartz.

Although sludge may be a step in the formation of stones, it may also cause disease in itself. Five to fifteen percent of patients with acute cholecystitis present without stones (acalculous cholecystitis). This typically occurs in patients with prolonged illness, such as those with major trauma or with prolonged ICU stays.

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 with 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 as bile is concentrated, 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 cholesterol monohydrate crystals may form. Thus, the main factors that determine whether cholesterol gallstones will form are (1) the amount of cholesterol secreted by liver cells, relative to lecithin and bile salts, and (2) the degree of concentration and extent of 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 is normally 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 fluke infestation.

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.

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. (Images of CBD stones are shown below.) Obstruction of the CBD by gallstones leads to symptoms and complications that include pain, jaundice, cholangitis, pancreatitis, and sepsis.
Intraoperative cholangiogram demonstrating a distal common bile duct stone with dilatation.

Intraoperative cholangiogram demonstrating a distal common bile duct stone without dilatation.

Etiology
Cholesterol gallstones, black pigment gallstones, and brown pigment gallstones have different pathogeneses and different risk factors.

Cholesterol gallstones
Cholesterol gallstones are associated with female sex, European or Native American ancestry, and increasing age. Other risk factors include the following:

Obesity Pregnancy Gallbladder stasis Drugs Heredity 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. 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. 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). More than one third of patients develop gallstones after bariatric surgery. Weight loss greater than 25% is the best predictor for the gallstone formation. Rapid weight loss mobilizes tissue cholesterol stores and increases the saturation of bile.[3] Obesity, a high-fat diet, and hypertriglyceridemia are strongly associated with the formation of gallstones. Diosgenin-rich beans, particularly associated with a South American diet, increase cholesterol secretion and gallstone formation. 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 analogues appear to predispose to gallstones by decreasing gallbladder emptying. 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.[4] A rare syndrome of low phospholipidassociated cholelithiasis occurs in individuals with a hereditary deficiency of the biliary transport protein required for lecithin secretion.

Black pigment gallstones

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 anemia, hereditary spherocytosis, and beta-thalassemia. gallstones include sickle cell

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.

Other comorbidities
Diabetes mellitus is associated with an increased risk of gallstone, though the mechanism is unclear; once symptomatic, patients with diabetes are prone to more severe complications. Crohn disease, ileal resection, or other diseases of the ileum decrease bile salt reabsorption and increase the risk of gallstone formation. Bacterial or parasitic infections from organisms that contain B -glucuronidase, an enzyme that deconjugates bilirubin glucuronide, increase the risk for pigmented stones. Cirrhosis carries major multifactorial risks for gallstone formation and gallbladder disease. Reduced hepatic synthesis and transport of bile salts, hyperestrogenemia, impaired

gallbladder contraction, and increased biliary stasis, among other factors, contribute to the formation of gallstones (typically pigment stones) in cirrhosis. Other illnesses or states that predispose to gallstone formation include burns, use of total parenteral nutrition, paralysis, ICU care, and major trauma. This is due, in general, to decreased enteral stimulation of the gallbladder with resultant biliary stasis and stone formation.

Bile duct stones

Primary common bile duct stones are caused by conditions leading to bile stasis and chronic bactibilia. Up to 90% of patients with brown pigment CBD stones have bile culture results positive for bacteria. In Western populations, biliary stasis is secondary to factors such as sphincter of Oddi dysfunction, benign biliary strictures, sclerosing cholangitis, and cystic dilatation of the bile ducts. Bile stasis promotes growth of bacteria, which produce phospholipase A1, thus releasing fatty acids from biliary phospholipids. The duct epithelium and/or bacteria (eg, Escherichia coli) produce beta-glucuronidase in amounts sufficient to deconjugate bilirubin diglucuronide. The presence of free fatty acids, deconjugated bilirubin, and bile acids leads to the formation of insoluble calcium bilirubinate particles. With the loss of bile acids, cholesterol becomes insoluble, resulting in the formation of biliary sludge. The sludge also contains mucin and bacterial cytoskeletons, which further aid in stone formation. In Asian populations, infestation with Ascaris lumbricoides and Clonorchis sinensis may promote stasis by either blocking the biliary ducts or by damaging the duct walls, resulting in stricture formation. Bactibilia is also common in these instances, probably secondary to episodic portal bacteremia. Some authors have suggested that the stones are formed because of the bactibilia alone and that the parasites' presence is just a coincidence.

Epidemiology
The prevalence of cholelithiasis is affected by many factors, including ethnicity, gender, comorbidities, and genetics.

United States statistics

In the United States, about 20 million people (10-20% of adults) have gallstones. Every year 1-3% of people develop gallstones and about 1-3% of people become symptomatic. 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. Choledocholithiasis complicates 10-15% of cholelithiasis cases.

International statistics

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. A Swedish epidemiologic study found that the incidence of gallstones was 1.39 per 100 person-years.[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, Halldestam et al reexamined 503 study subjects after a minimum interval of 5 years. On reexamination, 8.3% (42/503) had developed gallstones. Gallstone development was related to length of follow-up and low-density lipoprotein (LDL) cholesterol levels, and inversely related to alcohol consumption.[5] In an Italian study, 20% of women had stones, and 14% of men had stones. In a Danish study, gallstone prevalence in persons aged 30 years was 1.8% for men and 4.8% for women; gallstone prevalence in persons aged 60 years was 12.9% for men and 22.4% for women. The incidence rate of choledocholithiasis is higher internationally than in the United States, mainly because of the additional problem of primary common bile duct stones caused by parasitic infestation with Ascaris lumbricoidesand Clonorchis sinensis.

Race-, sex-, 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.[6] Prevalence of gallstones is low in Asians and African Americans; however, African Americans with sickle cell disease have gallstones early in life secondary to associated hemolysis. The lifetime risk of developing gallstones in whites is 50% for women and 30% for men. Women are more likely to develop cholesterol gallstones than men, especially during their reproductive years, when the incidence of gallstones in women is 2 to 3 times that in men. The difference appears to be attributable mainly to estrogen, which increases biliary cholesterol secretion.[7] Pigment gallstones affect men and women equally. Risk of developing gallstones increases with age. Gallstones are uncommon in children. Children with gallstones are more likely to have congenital anomalies, biliary malformation and disease, or hemolytic pigment stones. 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. Gallstones continue to form throughout adult life, and the prevalence is greatest at advanced age. The 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. Among individuals undergoing cholecystectomy for symptomatic cholelithiasis, 8-15% of patients younger than 60 years have common bile duct stones, compared with 15-60% of patients older than 60 years.

Prognosis
Less than half of patients with gallstones become symptomatic. The mortality rate for an elective cholecystectomy is 0.5% with less than 10% morbidity. The mortality rate for an emergent cholecystectomy is 3-5% with 30-50% morbidity.

Following cholecystectomy, stones may recur in the bile duct. Approximately 10-15% of patients have an associated choledocholithiasis. The prognosis in patients with choledocholithiasis depends on the presence and severity of complications. Of all patients who refuse surgery or are unfit to undergo surgery, 45% remain asymptomatic from choledocholithiasis, while 55% experience varying degrees of complications.

Patient Education
Patients with asymptomatic gallstones should be educated to recognize and report the symptoms of biliary colic and acute pancreatitis. Alarm symptoms include persistent epigastric pain lasting for greater than 20 minutes, especially if accompanied by nausea, vomiting, or fever. If pain is severe or persists for more than an hour, the patient should seek immediate medical attention.