Acute and chronic cholecystitis

DISEASES OF THE GALLBLADDER AND BILE DUCTS - Norton J. Greenberger, Gustav Paumgartner

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PHYSIOLOGY OF BILE PRODUCTION AND FLOW

Bile Secretion and Composition Bile formed in the hepatic lobules is secreted into a complex network of canaliculi, small bile ductules, and larger bile ducts that run with lymphatics and branches of the portal vein and hepatic artery in portal tracts situated between hepatic lobules. These interlobular bile ducts coalesce to form larger septal bile ducts that join to form the right and left hepatic ducts, which in turn unite to form the common hepatic duct. The common hepatic duct is joined by the cystic duct of the gallbladder to form the common bile duct (CBD), which enters the duodenum (often after joining the main pancreatic duct) through the ampulla of Vater.

Hepatic bile is an isotonic fluid with an electrolyte composition resembling blood plasma. The electrolyte composition of gallbladder bile differs from that of hepatic bile because most of the inorganic anions, chloride and bicarbonate, have been removed by reabsorption across the gallbladder epithelium.

Major components of bile by weight include water (82%), bile acids (12%), lecithin and other phospholipids (4%), and unesterified cholesterol (0.7%). Other constituents include conjugated bilirubin, proteins (IgA, metabolites of hormones, and other proteins metabolized in the liver), electrolytes, mucus, and, often, drugs and their metabolites.

The total daily basal secretion of hepatic bile is approximately 500 to 600 mL. Many substances taken up or synthesized by the hepatocyte are secreted into the bile canalculi. The canalicular membrane forms microvilli and is associated with microfilaments of actin, microtubules, and other contractile elements. Prior to their secretion into the bile, many substances that are taken up into the hepatocyte are conjugated, while others such as phospholipids, a portion of primary bile acids, and some cholesterol are synthesized de novo in the hepatocyte. Three mechanisms are important in regulating bile flow: (1) active transport of bile acids from hepatocytes into the bile canaliculi, (2) active transport of other organic anions, and (3) cholangiocellular secretion. The last is a secretin-mediated and cyclic AMP-dependent mechanism that ultimately results in the secretion of a sodium- and bicarbonate-rich fluid into the bile ducts.

Active vectorial secretion of biliary constituents from the portal blood into the bile canaliculi is driven by a distinct set of polarized transport systems at the basolateral (sinusoidal) and the canalicular plasma membrane domains of the hepatocyte. Two sinusoidal bile salt uptake systems have been cloned in humans, the Na+/taurocholate cotransporter and the organic anion transporting protein, which also transports a large variety of non-bile salt organic anions. Four ATP-dependent canalicular transport systems ("export pumps") have been identified: a bile salt export pump (BSEP), which was formerly called "sister of P-glycoprotein"; a conjugate export pump (MRP2), also called the canalicular multispecific organic anion transporter, which mediates the canalicular excretion of various amphiphilic conjugates formed by phase II conjugation (e.g., bilirubin diglucuronide); a multidrug export pump (MDR1) for hydrophobic cationic compounds; and a phospholipid export pump (MDR3). The canalicular membrane also contains ATP-independent transport systems such as the Cl-/HCO3-anion exchanger isoform 2 for canalicular bicarbonate secretion. For some of these transporters, genetic defects have been identified that are associated with various forms of cholestasis or defects of biliary excretion. BSEP is defective in progressive familial intrahepatic cholestasis (PFIC) type 2. Mutations of MRP2 cause the Dubin-Johnson syndrome, an inherited form of conjugated hyperbilirubinemia. A defective MDR3 results in PFIC-3. The cystic fibrosis transmembrane regulator located on bile duct epithelial cells is defective in cystic fibrosis, which may be associated with impaired cholangiocellular bile formation and chronic cholestatic liver disease.

The Bile Acids The primary bile acids, cholic acid and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver, conjugated with glycine or taurine, and excreted into the bile. Secondary bile acids, including deoxycholate and lithocholate, are formed in the colon as bacterial metabolites of the primary bile acids. However, lithocholic acid is much less efficiently absorbed from the colon than deoxycholic acid. Another secondary bile acid, found in low concentration is ursodeoxycholic acid (UDCA), a stereoisomer of CDCA. In normal bile, the ratio of glycine to taurine conjugates is about 3:1.

Bile acids are detergents that in aqueous solutions and above a critical concentration of about 2 m M form molecular aggregates called micelles. Cholesterol alone is poorly soluble in aqueous environments, and its solubility in bile depends on both the total lipid concentration and the relative molar percentages of bile acids and lecithin. Normal ratios of these constituents favor the formation of solubilizing mixed micelles, while abnormal ratios promote the precipitation of cholesterol crystals in bile.

In addition to facilitating the biliary excretion of cholesterol, bile acids are necessary for the normal intestinal absorption of dietary fats via a micellar transport mechanism (Chap. 286). Bile acids also serve as a major physiologic driving force for hepatic bile flow and aid in water and electrolyte transport in the small bowel and colon.

Enterohepatic Circulation Bile acids are efficiently conserved under normal conditions. Unconjugated, and to a lesser degree also conjugated, bile acids are absorbed by passive diffusion along the entire gut. Quantitatively much more important for bile salt recirculation, however, is the active transport mechanism for conjugated bile acids in the distal ileum (Chap. 286). The reabsorbed bile acids enter the portal bloodstream and are taken up rapidly by hepatocytes, reconjugated, and resecreted into bile (enterohepatic circulation).

The normal bile acid pool size is approximately 2 to 4 g. During digestion of a meal, the bile acid pool undergoes at least one or more enterohepatic cycles, depending on the size and composition of the meal. Normally, the bile acid pool circulates approximately 5 to 10 times daily. Intestinal absorption of the pool is about 95% efficient, so fecal loss of bile acids is in the range of 0.3 to 0.6 g/d. This fecal loss is compensated by an equal daily synthesis of bile acids by the liver, and thus the size of the bile acid pool is maintained. Bile acids returning to the liver suppress de novo hepatic synthesis of primary bile acids from cholesterol by inhibiting the rate-limiting enzyme cholesterol 7a-hydroxylase. While the loss of bile salts in stool is usually matched by increased hepatic synthesis, the maximum rate of synthesis is approximately 5 g/d, which may be insufficient to replete the bile acid pool size when there is pronounced impairment of intestinal bile salt reabsorption.

Gallbladder and Sphincteric Functions In the fasting state, the sphincter of Oddi offers a high-pressure zone of resistance to bile flow from the common bile duct into the duodenum. This tonic contraction serves to (1) prevent reflux of duodenal contents into the pancreatic and bile ducts and (2) promote bile filling of the gallbladder. The major factor controlling the evacuation of the gallbladder is the peptide hormone cholecystokinin (CCK), which is released from the duodenal mucosa in response to the ingestion of fats and amino acids. CCK produces (1) powerful contraction of the gallbladder, (2) decreased resistance of the sphincter of Oddi, (3) increased hepatic secretion of bile, and thus (4) enhanced flow of biliary contents into the duodenum.

Hepatic bile is "concentrated" within the gallbladder by energy-dependent transmucosal absorption of water and electrolytes. Almost the entire bile acid pool may be sequestered in the gallbladder following an overnight fast for delivery into the duodenum with the first meal of the day. The normal capacity of the gallbladder is 30 to 50 mL of bile.

DISEASES OF THE GALLBLADDER

CONGENITAL ANOMALIES

Anomalies of the biliary tract may be found in 10 to 20% of the population, including abnormalities in number, size, and shape (e.g., agenesis of the gallbladder, duplications, rudimentary or oversized "giant" gallbladders, and diverticula). Phrygian cap is a clinically innocuous entity in which a partial or complete septum (or fold) separates the fundus from the body. Anomalies of position or suspension are not uncommon and include left-sided gallbladder, intrahepatic gallbladder, retrodisplacement of the gallbladder, and "floating" gallbladder. The latter condition predisposes to acute torsion, volvulus, or herniation of the gallbladder.

GALLSTONES

Pathogenesis Gallstones are quite prevalent in most western countries. In the United States, autopsy series have shown gallstones in at least 20% of women and in 8% of men over the age of 40. It is estimated that 16 to 20 million persons in the United States have gallstones and that approximately 1 million new cases of cholelithiasis develop each year.

Gallstones are formed by concretion or accretion of normal or abnormal bile constituents. They are divided into three major types; cholesterol and mixed stones account for 80% of the total, with pigment stones comprising the remaining 20%. Mixed and cholesterol gallstones usually contain more than 50% cholesterol monohydrate plus an admixture of calcium salts, bile pigments, proteins, and fatty acids. Pigment stones are composed primarily of calcium bilirubinate; they contain less than 20% cholesterol.

Cholesterol and Mixed Stones and Biliary Sludge Cholesterol is essentially water insoluble and requires aqueous dispersion into either micelles or vesicles, both of which require the presence of a second lipid to "liquefy" the cholesterol. Cholesterol and phospholipids are secreted into bile as unilamellar bilayered vesicles, which are converted into mixed micelles consisting of bile acids, phospholipids, and cholesterol by the action of bile acids. If there is an excess of cholesterol in relation to phospholipids and bile acids, unstable cholesterol-rich vesicles remain, which aggregate into large multilamellar vesicles from which cholesterol crystals precipitate (Fig. 302-1).

There are several important mechanisms in the formation of lithogenic (stone-forming) bile. The most important is increased biliary secretion of cholesterol. This may occur in association with obesity, high-caloric and cholesterol-rich diets, or drugs (e.g., clofibrate) and may result from increased activity of HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis, and increased hepatic uptake of cholesterol from blood. In patients with gallstones, dietary cholesterol increases biliary cholesterol secretion. This does not occur in non-gallstone patients on high-cholesterol diets. In addition to environmental factors such as high-caloric and cholesterol-rich diets, genetic factors play an important role in cholesterol hypersecretion and gallstone formation. A high prevalence of gallstones is found among first-degree relatives of gallstone carriers and in certain ethnic populations such as American Indians as well as Chilean Indians and Chilean Hispanics. A common genetic trait has been identified for some of these populations by mitochondrial DNA analysis. A genetic defect in the control of cholesterol secretion also exists in certain strains of inbred mice who develop gallstones under a lithogenic diet. In some patients, impaired hepatic conversion of cholesterol to bile acids may also occur, resulting in an increase of the lithogenic cholesterol/bile acid ratio. Lithogenic bile may also result from conditions affecting the enterohepatic circulation of bile acids (e.g., prolonged parenteral alimentation or ileal disease or resection). In addition, most patients with gallstones may have reduced activity of hepatic cholesterol 7a-hydroxylase, the rate-limiting enzyme for primary bile acid synthesis.

Thus an excess of biliary cholesterol in relation to bile acids and phospholipids is primarily due to hypersecretion of cholesterol, but hyposecretion of bile acids may contribute. Two additional disturbances of bile acid metabolism that are likely to contribute to supersaturation of bile with cholesterol are (1) reduction of the bile acid pool and (2) enhanced conversion of cholic acid to deoxycholic acid, with replacement of the cholic acid pool by an expanded deoxycholic acid pool. The first disorder may be caused by more rapid loss of primary bile acid from the small intestine into the colon. The second disturbance may result from enhanced dehydroxylation of cholic acid and increased absorption of newly formed deoxycholic acid. An increased deoxycholate secretion is associated with hypersecretion of cholesterol into bile. While supersaturation of bile with cholesterol is an important prerequisite for gallstone formation, it is not sufficient by itself to produce cholesterol precipitation in vivo. Most people with supersaturated bile do not develop stones because the time required for cholesterol crystals to nucleate and grow is longer than the time bile spends in the gallbladder.

A second important mechanism is nucleation of cholesterol monohydrate crystals, which is greatly accelerated in human lithogenic bile; it is this feature rather than the degree of cholesterol supersaturation that distinguishes lithogenic from normal gallbladder bile. Accelerated nucleation of cholesterol monohydrate in bile may be due to either an excess of pronucleating factors or a deficiency of antinucleating factors. Mucin and certain non-mucin glycoproteins appear to be pronucleating factors, while apolipoproteins AI and AII and other glycoproteins appear to be antinucleating factors. Cholesterol monohydrate crystal nucleation and crystal growth probably occur within the mucin gel layer. Vesicle fusion leads to liquid crystals, which, in turn, nucleate into solid cholesterol monohydrate crystals. Continued growth of the crystals occurs by direct nucleation of cholesterol molecules from supersaturated unilamellar or multilamellar biliary vesicles.

A third important mechanism in cholesterol gallstone formation is gallbladder hypomotility. If the gallbladder emptied all supersaturated or crystal-containing bile completely, stones would not be able to grow. A high percentage of patients with gallstones exhibits abnormalities of gallbladder emptying. Ultrasonographic studies show that gallstone patients have an increased gallbladder volume during fasting and also after a test meal (residual volume) and that fractional emptying after gallbladder stimulation is decreased. Gallbladder emptying is a major determinant of gallstone recurrence in patients who underwent biliary lithotripsy. Within 3 years, only 13% of patients with good but 53% of patients with poor gallbladder emptying form recurrent stones.

Biliary sludge is a thick mucous material that upon microscopic examination reveals lecithin-cholesterol crystals, cholesterol monohydrate crystals, calcium bilirubinate, and mucin thread or mucous gels. Biliary sludge typically forms a crescent-like layer in the most dependent portion of the gallbladder and is recognized by characteristic echoes on ultrasonography (see below). The presence of biliary sludge implies two abnormalities: (1) the normal balance between gallbladder mucin secretion and elimination has become deranged and (2) nucleation of biliary solutes has occurred. That biliary sludge may be a precursor form of gallstone disease is evident from several observations. In one study, 96 patients with gallbladder sludge were followed prospectively by serial ultrasound studies. In 18%, biliary sludge disappeared and did not recur for at least 2 years. In 60%, biliary sludge disappeared and reappeared; in 14%, gallstones (8% asymptomatic, 6% symptomatic) developed, and in 6%, severe biliary pain with or without acute pancreatitis occurred. In 12 patients, cholecystectomies were performed, 6 for gallstone-associated biliary pain and 3 in symptomatic patients with sludge but without gallstones who had prior attacks of pancreatitis; the latter did not recur after cholecystectomy. It should be emphasized that biliary sludge can develop with disorders that cause gallbladder hypomotility, i.e., surgery, burns, total parenteral nutrition, pregnancy, and oral contraceptives¾all of which are associated with gallstone formation.

Two other conditions are associated with cholesterol stone or biliary sludge formation: pregnancy and very low calorie diet. There appear to be two key changes during pregnancy that contribute to a "cholelithogenic state." First, the composition of the bile acid pool and the cholesterol-carrying capacity of bile change, with a resultant marked increase in cholesterol saturation during the third trimester. Second, ultrasonographic studies have demonstrated that gallbladder contraction in response to a standard meal is sluggish, resulting in impaired gallbladder emptying. That these changes are related to pregnancy per se is supported by several studies that show reversal of these abnormalities after delivery. During pregnancy, gallbladder sludge develops in 20 to 30% of women and gallstones in 5 to 12%. While biliary sludge is a common finding during pregnancy, it is usually asymptomatic and often resolves spontaneously after delivery. Gallstones, which are less common than sludge and frequently associated with biliary colic, may also disappear after delivery because of spontaneous dissolution related to bile becoming unsaturated with cholesterol post partum.

From 10 to 20% of people having rapid weight reduction through very low calorie dieting develop gallstones. In a study involving 600 patients who completed a 16-week, 520-kcal/d diet, UDCA in a dosage of 600 mg/d proved highly effective in preventing gallstone formation; gallstones developed in only 3% of UDCA recipients compared to 28% of placebo-treated patients.

To summarize, cholesterol gallstone disease occurs because of several defects, which include (1) bile supersaturation with cholesterol, (2) nucleation of cholesterol monohydrate with subsequent crystal retention and stone growth, and (3) abnormal gallbladder motor function with delayed emptying and stasis. Other important factors known to predispose to cholesterol stone formation are summarized in Table 302-1.

Pigment Stones Gallstones composed largely of calcium bilirubinate are much more common in the Far East than in western countries. The presence of increased amounts of unconjugated, insoluble bilirubin in bile results in the precipitation of bilirubin, which may aggregate to form pigment stones or may form the nidus for growth of mixed cholesterol gallstones. In western countries, chronic hemolytic states (with increased conjugated bilirubin in bile) or alcoholic liver disease are associated with an increased incidence of pigment stones. Deconjugation of an excess of soluble bilirubin mono- and diglucuronide may be mediated by endogenous b-glucuronidase but may also occur by spontaneous alkaline hydrolysis. Sometimes, the enzyme is also produced when bile is chronically infected by bacteria. Pigment stone formation is especially prominent in Asians and is often associated with infections in the biliary tree (Table 302-1).

Diagnosis Procedures of potential use in the diagnosis of cholelithiasis and other diseases of the gallbladder are detailed in Table 302-2. The plain abdominal film may detect gallstones containing sufficient calcium to be radiopaque (10 to 15% of cholesterol and mixed stones and approximately 50% of pigment stones). Plain radiography may also be of use in the diagnosis of emphysematous cholecystitis, porcelain gallbladder, limey bile, and gallstone ileus.

Ultrasonography of the gallbladder is very accurate in the identification of cholelithiasis and has several advantages over oral cholecystography (Fig. 302-2 A). The gallbladder is easily visualized with the technique, and in fact, failure to image the gallbladder successfully in a fasting patient correlates well with the presence of underlying gallbladder disease. Stones as small as 2 mm in diameter may be confidently identified provided that firm criteria are used [e.g., acoustic "shadowing" of opacities that are within the gallbladder lumen and that change with the patient's position (by gravity)]. In major medical centers, the false-negative and false-positive rates for ultrasound in gallstone patients are about 2 to 4%. Biliary sludge is material of low echogenic activity that typically forms a layer in the most dependent position of the gallbladder. This layer shifts with postural changes but fails to produce acoustic shadowing; these two characteristics distinguish sludges from gallstones. Ultrasound can also be used to assess the emptying function of the gallbladder.

Oral cholecystography (OCG) is a useful procedure for the diagnosis of gallstones but has been largely replaced by ultrasound. However, OCG is still useful for the selection of patients for nonsurgical therapy of gallstone disease such as lithotripsy or bile acid dissolution therapy. In both these settings, OCG is used to assess the patency of the cystic duct and gallbladder emptying function. Further, OCG can also delineate the size and number of gallstones and determine whether they are calcified. Factors that may produce nonvisualization of the OCG are summarized in Table 302-2.

Radiopharmaceuticals such as 99mTc-labeled N -substituted iminodiacetic acids (HIDA, DIDA, DISIDA, etc.) are rapidly extracted from the blood and are excreted into the biliary tree in high concentration even in the presence of mild to moderate serum bilirubin elevations. Failure to image the gallbladder in the presence of biliary ductal visualization may indicate cystic duct obstruction, acute or chronic cholecystitis, or surgical absence of the organ. Such scans have their greatest application in the diagnosis of acute cholecystitis.

Symptoms of Gallstone Disease Gallstones usually produce symptoms by causing inflammation or obstruction following their migration into the cystic duct or CBD. The most specific and characteristic symptom of gallstone disease is biliary colic. Obstruction of the cystic duct or CBD by a stone produces increased intraluminal pressure and distention of the viscus that cannot be relieved by repetitive biliary contractions. The resultant visceral pain is characteristically a severe, steady ache or pressure in the epigastrium or right upper quadrant (RUQ) of the abdomen with frequent radiation to the interscapular area, right scapula, or shoulder.

Biliary colic begins quite suddenly and may persist with severe intensity for 30 min to 5 h, subsiding gradually or rapidly. An episode of biliary pain is sometimes followed by a residual mild ache or soreness in the RUQ, which may persist for 24 h or so. Nausea and vomiting frequently accompany episodes of biliary colic. An elevated level of serum bilirubin and/or alkaline phosphatase suggests a common duct stone. Fever or chills (rigors) with biliary colic usually imply a complication, i.e., cholecystitis, pancreatitis, or cholangitis. Complaints of vague epigastric fullness, dyspepsia, eructation, or flatulence, especially following a fatty meal, should not be confused with biliary colic. Such symptoms are frequently elicited from patients with gallstone disease but are not specific for biliary calculi. Biliary colic may be precipitated by eating a fatty meal, by consumption of a large meal following a period of prolonged fasting, or by eating a normal meal.

Natural History Gallstone disease discovered in an asymptomatic patient or in a patient whose symptoms are not referable to cholelithiasis is a common clinical problem. The natural history of "silent" or asymptomatic gallstones has occasioned much debate. A study of predominantly male silent gallstone patients suggests that the cumulative risk for the development of symptoms or complications requiring surgery is relatively low¾10% at 5 years, 15% at 10 years, and 18% at 15 years. Patients remaining asymptomatic for 15 years were found to be unlikely to develop symptoms during further follow-up, and most patients who did develop complications from their gallstones experienced prior warning symptoms. Similar conclusions apply to diabetic patients with silent gallstones. Decision analysis has suggested that (1) the cumulative risk of death due to gallstone disease while on expectant management is small, and (2) prophylactic cholecystectomy is not warranted.

Complications requiring cholecystectomy are much more common in gallstone patients who have developed symptoms of biliary colic. Patients found to have gallstones at a young age are more likely to develop symptoms from cholelithiasis than are patients older than 60 years at the time of initial diagnosis. Patients with diabetes mellitus and gallstones may be somewhat more susceptible to septic complications, but the magnitude of risk of septic biliary complications in diabetic patients is incompletely defined. In addition, asymptomatic gallstone patients with nonvisualization of the gallbladder on OCG appear to have an increased tendency to develop symptoms and complications.

TREATMENT

Surgical Therapy In asymptomatic gallstone patients, the risk of developing symptoms or complications requiring surgery is quite small (in the range of 1 to 2% per year). Thus a recommendation for cholecystectomy in a patient with gallstones should probably be based on assessment of three factors: (1) the presence of symptoms that are frequent enough or severe enough to interfere with the patient's general routine; (2) the presence of a prior complication of gallstone disease, i.e., history of acute cholecystitis, pancreatitis, gallstone fistula, etc.; or (3) the presence of an underlying condition predisposing the patient to increased risk of gallstone complications (e.g., calcified or porcelain gallbladder and/or a previous attack of acute cholecystitis regardless of current symptomatic status). Patients with very large gallstones (over 2 cm in diameter) and patients having gallstones in a congenitally anomalous gallbladder might also be considered for prophylactic cholecystectomy. Although age under 50 years is a worrisome factor in asymptomatic gallstone patients, few authorities would now recommend routine cholecystectomy in all young patients with silent stones. Laparoscopic cholecystectomy is a minimal-access approach for the removal of the gallbladder together with its stones. Its advantages include a markedly shortened hospital stay as well as decreased cost, and it is the procedure of choice for most patients referred for elective cholecystectomy.

From several studies involving over 4000 patients undergoing laparoscopic cholecystectomy, the following key points emerge: (1) complications develop in about 4% of patients, (2) conversion to laparotomy occurs in 5%, (3) the death rate is remarkably low (i.e., <0.1%), and (4) bile duct injuries are unusual (i.e., 0.2 to 0.5%). These data indicate why laparoscopic cholecystectomy has become the "gold standard" for treating symptomatic cholelithiasis.

Medical Therapy¾Gallstone Dissolution UDCA decreases cholesterol saturation of bile and also appears to produce a lamellar liquid crystalline phase in bile that allows a dispersion of cholesterol from stones by physiochemical means. UDCA may also retard cholesterol crystal nucleation. In carefully selected patients with a functioning gallbladder and with radiolucent stones <10 mm in diameter, complete dissolution can be achieved in about 50% of patients within 6 months to 2 years with UDCA at a dose of 8 to 10 mg/kg per day. The highest success rate (i.e., >70%) occurs in patients with small (<5 mm) floating radiolucent gallstones. Probably no more than 10% of patients with symptomatic cholelithiasis are candidates for such treatment. However, in addition to the vexing problem of recurrent stones (30 to 50% over 3 to 5 years of follow-up), there is also the factor of taking an expensive drug for an indefinite period of time. The advantages and success of laparoscopic cholecystectomy have largely reduced the role of gallstone dissolution to patients who wish to avoid or are not candidates for elective cholecystectomy.

Gallbladder stones may be fragmented by extracorporeal shock waves. While such shock wave lithotripsy combined with medical litholytic therapy is safe and effective in carefully selected patients with gallbladder calculi (radiolucent, solitary stone <2 cm in well-contracting gallbladder), the procedure is employed infrequently because of the emergence of laparoscopic cholystectomy as the procedure of choice for symptomatic cholelithiasis, the recurrence of gallstones in 30% of patients within 5 years after lithotripsy combined with medical litholytic therapy, and the cost of taking UDCA for a variable period after the procedure.

ACUTE AND CHRONIC CHOLECYSTITIS

Acute Cholecystitis Acute inflammation of the gallbladder wall usually follows obstruction of the cystic duct by a stone. Inflammatory response can be evoked by three factors: (1) mechanical inflammation produced by increased intraluminal pressure and distention with resulting ischemia of the gallbladder mucosa and wall, (2) chemical inflammation caused by the release of lysolecithin (due to the action of phospholipase on lecithin in bile) and other local tissue factors, and (3) bacterial inflammation, which may play a role in 50 to 85% of patients with acute cholecystitis. The organisms most frequently isolated by culture of gallbladder bile in these patients include Escherichia coli, Klebsiella spp., group D Streptococcus, Staphylococcus spp., and Clostridium spp.

Acute cholecystitis often begins as an attack of biliary colic that progressively worsens. Approximately 60 to 70% of patients report having experienced prior attacks that resolved spontaneously. As the episode progresses, however, the pain of acute cholecystitis becomes more generalized in the right upper abdomen. As with biliary colic, the pain of cholecystitis may radiate to the interscapular area, right scapula, or shoulder. Peritoneal signs of inflammation such as increased pain with jarring or on deep respiration may be apparent. The patient is anorectic and often nauseated. Vomiting is relatively common and may produce symptoms and signs of vascular and extracellular volume depletion. Jaundice is unusual early in the course of acute cholecystitis but may occur when edematous inflammatory changes involve the bile ducts and surrounding lymph nodes.

A low-grade fever is characteristically present, but shaking chills or rigors are not uncommon. The RUQ of the abdomen is almost invariably tender to palpation. An enlarged, tense gallbladder is palpable in one-quarter to one-half of patients. Deep inspiration or cough during subcostal palpation of the RUQ usually produces increased pain and inspiratory arrest (Murphy's sign). A light blow delivered to the right subcostal area may elicit a marked increase in pain. Localized rebound tenderness in the RUQ is common, as are abdominal distention and hypoactive bowel sounds from paralytic ileus, but generalized peritoneal signs and abdominal rigidity are usually lacking, absent perforation.

The diagnosis of acute cholecystitis is usually made on the basis of a characteristic history and physical examination. The triad of sudden onset of RUQ tenderness, fever, and leukocytosis is highly suggestive. Typically, leukocytosis in the range of 10,000 to 15,000 cells per microliter with a left shift on differential count is found. The serum bilirubin is mildly elevated [<85.5 umol/L (5 mg/dL)] in 45% of patients, while 25% have modest elevations in serum aminotransferases (usually less than a fivefold elevation). The radionuclide (e.g., HIDA) biliary scan may be confirmatory if bile duct imaging is seen without visualization of the gallbladder. Ultrasound will demonstrate calculi in 90 to 95% of cases.

Approximately 75% of patients treated medically have remission of acute symptoms within 2 to 7 days following hospitalization. In 25%, however, a complication of acute cholecystitis will occur despite conservative treatment (see below). In this setting, prompt surgical intervention is required. Of the 75% of patients with acute cholecystitis who undergo remission of symptoms, approximately one-quarter will experience a recurrence of cholecystitis within 1 year, and 60% will have at least one recurrent bout within 6 years. In view of the natural history of the disease, acute cholecystitis is best treated by early surgery whenever possible.

Acalculous Cholecystitis In 5 to 10% of patients with acute cholecystitis, calculi obstructing the cystic duct are not found at surgery. In over 50% of such cases, an underlying explanation for acalculous inflammation is not found. An increased risk for the development of acalculous cholecystitis is especially associated with serious trauma or burns, with the postpartum period following prolonged labor, and with orthopedic and other nonbiliary major surgical operations in the postoperative period. Other precipitating factors include vasculitis, obstructing adenocarcinoma of the gallbladder, diabetes mellitus, torsion of the gallbladder, "unusual" bacterial infections of the gallbladder (e.g., Leptospira, Streptococcus, Salmonella, or Vibrio cholerae), and parasitic infestation of the gallbladder. Acalculous cholecystitis may also be seen with a variety of other systemic disease processes (sarcoidosis, cardiovascular disease, tuberculosis, syphilis, actinomycosis, etc.) and may possibly complicate periods of prolonged parenteral hyperalimentation.

Although the clinical manifestations of acalculous cholecystitis are indistinguishable from those of calculous cholecystitis, the setting of acute gallbladder inflammation complicating severe underlying illness is characteristic of acalculous disease. Ultrasound, computed tomography (CT) scanning, or radionuclide examinations demonstrating a large, tense, static gallbladder without stones and with evidence of poor emptying over a prolonged period may be diagnostically useful in some cases. The complication rate for acalculous cholecystitis exceeds that for calculous cholecystitis. Successful management of acute acalculous cholecystitis appears to depend primarily on early diagnosis and surgical intervention, with meticulous attention to postoperative care.

Acalculous Cholecystopathy Disordered motility of the gallbladder can produce recurrent biliary pain in patients without gallstones. Infusion of an octapeptide of CCK can be used to measure the gallbladder ejection fraction during cholescintigraphy. In a representative study, CCK cholescintigraphy using 99mTc-diisopropyl iminodiacetic acid (DIDA) identified 21 patients with an abnormal gallbladder ejection fraction (<40% at 45 min); 10 of 11 patients who underwent surgery became asymptomatic; all 10 showed abnormalities, i.e., chronic cholecystitis, gallbladder muscle hypertrophy, and/or a markedly narrowed cystic duct. From this and other similar studies, the following criteria can be used to identify patients with acalculous cholecystopathy: (1) recurrent episodes of typical RUQ pain characteristic of biliary tract pain, (2) abnormal CCK cholescintigraphy demonstrating a gallbladder ejection fraction of less than 40%, and (3) infusion of CCK reproduces the patient's pain. An additional clue would be the identification of a large gallbladder on ultrasound examination. Finally, it should be noted that sphincter of Oddi dysfunction can also give rise to recurrent RUQ pain and CCK-scintigraphic abnormalities.

Emphysematous Cholecystitis So-called emphysematous cholecystitis is thought to begin with acute cholecystitis (calculous or acalculous) followed by ischemia or gangrene of the gallbladder wall and infection by gas-producing organisms. Bacteria most frequently cultured in this setting include anaerobes, such as C. welchii or C. perfringens, and aerobes, such as E. coli. This condition occurs most frequently in elderly men and in patients with diabetes mellitus. The clinical manifestations are essentially indistinguishable from those of nongaseous cholecystitis. The diagnosis is usually made on plain abdominal film by the finding of gas within the gallbladder lumen, dissecting within the gallbladder wall to form a gaseous ring, or in the pericholecystic tissues. The morbidity and mortality rates with emphysematous cholecystitis are considerable. Prompt surgical intervention coupled with appropriate antibiotics is mandatory.

Chronic Cholecystitis Chronic inflammation of the gallbladder wall is almost always associated with the presence of gallstones and is thought to result from repeated bouts of subacute or acute cholecystitis or from persistent mechanical irritation of the gallbladder wall. The presence of bacteria in the bile occurs in more than one-quarter of patients with chronic cholecystitis. Although the presence of infected bile in a patient with chronic cholecystitis undergoing elective cholecystectomy probably adds little to the operative risk, intraoperative Gram's staining and routine culturing of bile have been advocated to identify those patients whose gallbladder is colonized with Clostridium spp. Appropriate antibiotics intra- and postoperatively are recommended in such patients because colonization with these organisms may be associated with devastating septic complications following surgery. Chronic cholecystitis may be asymptomatic for years, may progress to symptomatic gallbladder disease or to acute cholecystitis, or may present with complications (see below).

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