Choledocholithiasis, Ascending Cholangitis and Gallstone Pancreatitis | Gallbladder | Gastroenterology

Med Clin N Am 92 (2008) 925–960

Choledocholithiasis, Ascending Cholangitis, and Gallstone Pancreatitis
Siriboon Attasaranya, MD, Evan L. Fogel, MD, Glen A. Lehman, MD*
Division of Gastroenterology/Hepatology, Department of Medicine, Indiana University Medical Center, 550 N. University Boulevard, UH 4100, Indianapolis, IN 46202, USA

Gallstone disease is one of the most common and most costly digestive diseases that require hospitalization in the United States with an estimated annual direct cost of $5.8 billion [1]. Gallstone disease is newly diagnosed in more than 1 million people annually in the United States, and cholecystectomy is performed in 700,000 cases [2]. The prevalence of gallstones has ethnic variability, with prevalence rates of approximately 10% to 15% in the United States and Europe [3]. The clinical spectrum of cholelithiasis ranges from an asymptomatic state to fatal complications. Patients who have asymptomatic gallstones carry an annual risk of approximately 1% for biliary colic [4,5], of 0.3% for acute cholecystitis [4–6], of 0.2% for symptomatic choledocholithiasis [5,6], and of 0.04% to 1.5% for gallstone pancreatitis (GSP) [7,8]. These small percentages, however, represent a large number of patients, given the overall prevalence of gallstones. Gallstone pathophysiology Gallstones are classified into cholesterol stones and pigment stones. Stones composed mostly of cholesterol account for 80% to 90% of patients undergoing cholecystectomy in Western countries [9]. In normal bile, cholesterol is soluble in the form of mixed micelles with an optimal concentration of bile salts and phospholipids. With disproportionate concentrations, bile becomes supersaturated, and the excess cholesterol precipitates as monohydrate crystals. These crystals embed in the gallbladder mucin gel with

* Corresponding author. E-mail address: (G.A. Lehman). 0025-7125/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2008.03.001



et al

bilirubinate to form biliary sludge, which can aggregate eventually into a gallbladder stone [10]. Black pigment stones make up a small proportion of gallstones. These stones consist of polymerized calcium bilirubinate, precipitated as a result of exceeding the solubility of calcium and unconjugated bilirubin. Conditions that create excessive unconjugated bilirubin, such as chronic hemolysis in hemoglobinopathies, cirrhosis [11], ineffective erythropoiesis, and ileal diseases [12], predispose a patient to the formation of black pigment stones. Brown pigment stones are formed primarily in the bile duct. They result from bacterial infection that releases b-glucuronidase to hydrolyze glucuronic acid from bilirubin. This process leads to decreased solubility of deconjugated bilirubin and formation of brown pigment stones. Risk factors for gallstones Risk factors for gallstone formation may be modifiable or nonmodifiable (Box 1). Environmental factors and genetic predisposition probably play interactive roles in gallstone formation. An inflammatory immune response may contribute to a patient’s susceptibility to cholesterol stone formation [13].

Box 1. Risk factors of gallstones Nonmodifiable factors Increasing age Female gender Ethnicity Genetics, family history Modifiable factors Pregnancy and parity Obesity Low-fiber, high-calorie diet Prolonged fasting Drugs: clofibrate, ceftriaxone Oral contraceptives Low-level physical activities Rapid weight loss (> 1.5 kg/wk) Hypertriglyceridemia/low high-density lipoprotein Metabolic syndrome Gallbladder stasis Specific diseases (ie, cirrhosis, Crohn’s disease with severe ileal involvement/resection)



Role of genetics Geographic variations and ethnic differences in prevalence suggest a genetic role in the formation of gallstones. The prevalence of gallstones is increased in families and in identical twins of patients who have gallstones [3]. The genes responsible for biliary lipid transport across the hepatic canaliculi [10,14] and for lipid metabolism [3] have been identified. Role of gallbladder stasis Impaired gallbladder contractility has been noted in some patients who have gallbladder stones. Although gallbladder dysfunction can result from gallstone disease or from excessive cholesterol infiltration into gallbladder smooth muscle [10], gallbladder stasis, by itself, can contribute to gallbladder stone formation. Gallbladder stasis frequently is evident in patients who have risk factors for cholelithiasis, including obesity, pregnancy, rapid weight loss, and prolonged fasting [15]. Furthermore, gallbladder dysmotility seems to be an independent risk factor for recurrent gallstones in patients treated with extracorporeal shockwave lithotripsy (ESWL) [16]. Prevention of gallstones Moderate physical activity and dietary management (high fiber intake and avoidance of saturated fatty acids) can lower the risk of cholelithiasis [17]. Daily administration of cholecystokinin in patients receiving prolonged total parenteral nutrition was shown to prevent the formation of gallbladder sludge in one small series [18]. Oral ursodeoxycholic acid (UDCA) has been demonstrated to help prevent cholelithiasis during rapid weight loss and in patients requiring long-term somatostatin therapy [17]. For secondary prevention, there currently are insufficient data to support the use of medical therapy, such as UDCA, for prevention of biliary colic or for prevention of complications in patients who have gallstones who are awaiting cholecystectomy or who are unfit for surgery [17,19]. Choledocholithiasis: special consideration Primary versus secondary bile duct stones In the Western world, most stones in the common bile duct arise from the passing of gallbladder stones into the common bile duct. Stones in the common duct occur in 10% to 15% of people who have gallbladder stones. Concomitant gallbladder stones and bile duct stones occur more frequently in elderly, Asian patients and in patients who have chronic bile duct

Newer techniques of biliary imaging have simplified the diagnosis of bile duct stones. fever. Severe episodes commonly require emergency medical visits and must be differentiated from cardiac or other potentially lifethreatening events. They are more prevalent in Asian populations. Given the potential serious complications of bile duct stones. parasitic infestation) and. Infrequently. It is difficult to determine whether the existing bile duct stones are asymptomatic in patients who present with biliary pain alone. and jaundice. hypothyroidism [20]. Symptomatic bile duct stones Patients who have symptomatic bile duct stones are at high risk of experiencing further symptoms or complications if left untreated. as determined in one study by cholangiograms using an in situ cholangiogram catheter [25]. Atypical as well as typical clinical symptoms should be recognized. specific therapy generally is indicated regardless of symptoms. because the pain can originate from either the gallbladder stones or bile duct stones. Clinical spectrum Coexisting bile duct stones and gallbladder stones Bile duct stones can be discovered incidentally during the evaluation of gallbladder stones. with an estimated prevalence of 5% to 12% [23. Acute ascending cholangitis and acute pancreatitis are two serious. These stones usually are brown pigment stones. life-threatening complications. Pain is variably mild to severe at onset. a clinically oriented approach remains paramount. Primary bile duct stones are formed in the intrahepatic or extrahepatic bile ducts.22]. More than one half of patients who had retained bile duct stones experienced recurrent symptoms during a follow-up period of 6 months to 13 years [26]. and 25% of patients developed serious complications [27].24]. Approximately one third of patients have spontaneous bile duct stone passage based on stone disappearance 6 weeks after diagnosis.928 ATTASARANYA et al inflammation (such as sclerosing cholangitis. probably. patients present with painless jaundice and weight loss that mimics pancreatobiliary malignancy. Biliary pain confined to the epigastrium or right upper quadrant of the abdomen is the most common presentation. Noninvasive . Common clinical symptoms and signs include pain. Bacterial colonization of bile and bile stasis play important roles in the pathogenesis of these stones [21. Diagnosis of bile duct stones Although advanced technologies have become more widely available.

CT scanning has a similarly low sensitivity in the detection of bile duct stones and is used primarily to document biliary dilation. Table 1 summarizes the clinical . a mass lesion). Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) are less invasive than endoscopic retrograde cholangiography (ERC) but can detect bile duct stones with comparable accuracy.48]. as occurs with viral syndromes. however. if present. in the appropriate clinical setting is predictive of bile duct stones.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 929 methods have the lowest risk. Recently. such as the presence of gallstones or biliary ductal dilation. (2) suboptimal ductal contrast opacification in the presence of significant jaundice (bilirubin more than two or three times the upper limits of normal) or in a patient who has undergone cholecystectomy [43. Gallbladder stones. these levels tend to decline rapidly over several days [29] rather than slowly over several weeks.31]. use of multidetector CT. Although this accuracy is comparable to that of MRCP.47]. generally are well visualized if the gallbladder is adequately distended and not obscured by luminal gas or obesity. Elevations of serum alkaline phosphatase and gamma-glutamyl transpeptidase levels were detected in more than 90% of symptomatic patients [28]. and (3) limited visualization of intrahepatic duct branches. because most bile duct stones cause intermittent and incomplete biliary obstruction. Indirect evidence. The serum bilirubin level typically is less than 15 mg/dL. Blood tests Patients who have cholangitis or pancreatitis associated with abnormal serum liver function tests are at increased risk of having bile duct stones. degree of jaundice. In this clinical setting sequential follow-up of the pattern of liver function tests may be helpful diagnostically. With biliary stones. but the obstructed bile duct may not be dilated with acute obstruction. has been reported to have a sensitivity of 85% to 97% and specificity of 88% to 96% in the diagnosis of bile duct stones [43–46]. to exclude other causes of biliary obstruction (eg. mimicking acute viral hepatitis. TUS has low sensitivity (25%– 60%) for the detection of bile duct stones . in conjunction with oral or intravenous contrast and with reconstruction of axial and three-dimensional images. and to detect local complications such as liver abscess. and serum levels of these tests can fluctuate over time. The intensity of pain. Rarely. Imaging studies for diagnosis of bile duct stones Transabdominal ultrasound (TUS) is the most commonly used initial diagnostic tool for suspected biliary stones. this method is limited by (1) relatively frequent allergic reactions to the contrast agents. as high as 15% in one series using intravenous iotroxate [45]. but it has a very high specificity [30. the serum transaminase levels can be elevated profoundly (up to 2000 IU/L). whereas invasive techniques have the greatest accuracy. particularly when using oral contrast agents [45.

endoscopic retrograde cholangiography. . liver parenchymal lesions.31] Detection of concomitant intrahepatic duct stones. MRC.31] Specificity (%) 95–100 [30. EUS. flow artifact. transabdominal ultrasound.36] High accuracy Therapeutic potential ATTASARANYA Sensitivity (%) 25–63 [30.36] 95–100 [35. and pancreatic lesions MRC 85 [32] 93 [32] High accuracy for duct stone detection Noninvasive intrahepatic and extrahepatic duct evaluation Expensive Time consuming Limited value in stones ! 6 mm [37] Impacted stone at the ampulla [38]. duodenal diverticula. TUS. a Including pneumobilia. magnetic resonance cholangiography.31] 97 [30.31] Advantages Inexpensive Safe Widely available Portable Disadvantages Low sensitivity Radiation exposure Operator dependent Contrast allergy Renal impairment Higher risk than EUS False positives (air bubbles) False negatives with small stones in dilated duct Unsuccessful cannulation et al Abbreviations: ERC.930 Table 1 Imaging studies for diagnosis of common bile duct stones Characteristic TUS CT 71–75 [30. dilated bile duct O 10 mm [39] Claustrophobia Ferromagnetic implant Artifact interferencea [40–42] EUS 93–98 [32–34] 97–100 [32–34] High accuracy for duct stone detection Less invasive than ERC Detects small stones in a nondilated duct [30] Operator dependent High cost of equipment Insensitive for proximal common hepatic duct / intrahepatic duct stones ERC 90–97 [35. endoscopic ultrasound.

overlooked retained/residual stones from the prior therapy. In this setting. MRCP seems to have limited value in detecting stones in an air-filled duct [51]. It remains uncertain. Because of potential significant procedure-related risks and the availability of the other. The bile duct may be dilated persistently despite removal of all bile duct stones. in fact. Recurrence is thought to be caused mainly by bile stasis and bacterobilia. intraductal EUS. papillary stenosis. Table 2 Risk classification of probability of bile duct stones based on clinical presentation and transabdominal ultrasound evaluation Parameters Jaundice Liver function tests Cholangitis Pancreatitis Common bile duct diameter Ductal stones seen High Risk (O 50%) Current Persistently elevated Current Current Dilated bile duct (R 10 mm) Yes Moderate Risk (10%–50%) History of jaundice Declining History of fever History of pancreatitis Borderline dilated Questionable (with small gallbladder stones) Low Risk (! 5%) No history of jaundice Normal No history of fever No history of pancreatitis Normal None (with large gallbladder stones) . ERC now is reserved for patients who have confirmed bile duct stones or who are at high risk for bile duct stones (Table 2) who probably will require therapeutic intervention [49]. Detection of bile duct stones after endoscopic therapy After biliary endoscopic sphincterotomy (BES). however. is essential to prevent recurrence. less invasive.50]. what proportion of these recurrent stones are. These two factors may decrease the accuracy of imaging tests in detecting residual/recurrent stones after endoscopic therapy. perhaps resulting from increased biliary stasis. accurate imaging modalities. Main duct dilation (R 13 mm) and the presence of a periampullary diverticulum are common risk factors for recurrent stones [42. the biliary system frequently is filled with air. Stones even can recur in patients after gallbladder removal.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 931 applications and limitations of imaging studies in the diagnosis of bile duct stones. Identification and treatment of correctable risk factors. has been reported to detect stones in the dilated duct with a greater accuracy than achieved with ERC alone [52]. in conjunction with ERC. Recurrent bile duct stones Bile duct stones recur in about 4% to 24% of patients during a follow-up period of 15 years [42]. ERC is considered the reference standard for the diagnosis of bile duct stones and provides an opportunity for therapy. and gallstones in patients who have gallbladder in situ. such as biliary strictures.

An electrohydraulic lithotripsy system consists of a bipolar probe and a charge generator. the overall complication rate was 8%. Mechanical lithotripsy is the simplest and most widely used technique for fragmenting stones. preliminary results have been encouraging [58]. inadequate space to open the basket). and perforation in 0. . bleeding in 2%. cholecystitis in 0.5 cm. or are located proximal to strictures [54]. including pancreatitis in 5. Recently.56]. The lithotripter unit is designed as either an integrated device or a salvage device that consists of a metal sheath with a handle applicable to lithotripsy-compatible wire baskets. Electrohydraulic lithotripsy can be operated under either fluoroscopic or direct cholangioscopic guidance. multicenter trial. BES has supplanted surgery as the standard therapy for bile duct stones. are impacted. A disadvantage of using cholangioscopy for electrohydraulic lithotripsy is the need for two operators and the use of a fragile intraductal miniscope. The most common reason for unsuccessful mechanical lithotripsy is inability to capture the stones (eg. Mechanical lithotripsy usually is successful only in stones smaller than 3 cm [55]. Alternative therapies have been used to manage these difficult bile stones. Direct visualization is preferred to permit deployment of the probe at the surface of the stone to ensure the highest efficacy and to avoid ductal injury. procedure-related cholangitis in 1%. In a large. Treatment of difficult bile duct stones Approximately 10% to15% of patients have bile duct stones that cannot be removed using standard BES and balloon/basket extraction techniques. In the subgroup of 1600 patients who had common duct stones. These stones generally are larger than 1. About 85% to 90% of bile duct stones can be removed by balloon/basket extraction following BES. single-operator cholangioscopy has been used to direct electrohydraulic lithotripsy therapy for bile duct stones.4%.932 ATTASARANYA et al Therapy of bile duct stones Biliary endoscopic sphincterotomy Since its introduction in 1974. This technique seems to be helpful in patients who have concomitant intrahepatic duct stones or biliary strictures [57]. mechanical lithotripsy successfully removed 85% to 90% of ‘‘difficult’’ bile duct stones [55.8% in 2347 patients. Fragmentation of stones Mechanical lithotripsy. the overall complication rate of BES was 9.5%.3% [53]. In two studies. Electrohydraulic lithotripsy. Initiation of a spark causes expansion of the surrounding fluid that generates shock waves to fragment stones.

additional clinical experience is necessary. This success rate. A liquid or tissue medium is required to prevent energy attenuation. The success rates of bile duct stone clearance with laser lithotripsy have been reported at 64% to 97% [27]. Although this combined technique seems to be attractive. or electromagnetic systems. general anesthesia or. Laser lithotripsy. rescue BES. less frequently. with a remarkably low rate of pancreatitis of 2. Patients who have concomitant gallbladder and bile duct stones are treated ideally with a single procedure: laparoscopic cholecystectomy and laparoscopic bile duct exploration. however. consisting of a gaseous collection of ions and free electrons.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 933 Extracorporeal shockwave lithotripsy. occasionally. and. seems to require more ERCP sessions. a nasobiliary tube may be required before ESWL. a single-stage laparoscopic procedure can achieve a stone clearance . Most cases require several endoscopic procedures to remove the fragmented stones. this technique had a success rate of 92% and a complication rate of 7. A recent-generation device can differentiate between the light reflection patterns of the bile duct wall and those of stones.2% [63]. Surgery Laparoscopic bile duct exploration. In expert hands. This low rate of pancreatitis is attributed to the separate pancreatic and biliary orifices following BES. ESWL generates a shockwave originating outside the body using piezoelectric. An oscillating plasma. Use of a large-diameter (12–20 mm) dilation balloon as an adjunctive tool to enlarge an inadequate BES orifice can aid in the removal of large or difficult bile duct stones. conscious sedation is required. Most importantly. Because ESWL is painful. two meta-analyses have shown that the rate of pancreatitis is significantly higher with EBD than with BES [61. In a recent multicenter study of 103 patients.62]. more frequent use of mechanical lithotripsy. however. so that the pancreatic orifice is avoided during biliary balloon dilation. Complete stone clearance rates of 83% to 90% have been reported [59.60]. electrohydraulic. Supplemental large-diameter biliary orifice balloon dilation Endoscopic biliary orifice dilation (EBD) using a 6. In laser lithotripsy. Experience with this modality is limited. Because most bile duct stones are not radiopaque and are not visualized by fluoroscopy before contrast injection at endoscopic retrograde cholangiopancreatography (ERCP). The laser beam is stopped immediately when bile ductal tissue is contacted to prevent bile duct injury. is created to induce wave-mediated fragmentation of 8-mm diameter balloon to remove bile duct stones has a reported success rate comparable to that of BES.6%. Laser lithotripsy is performed under direct visualization using the cholangioscope or under fluoroscopic guidance. laser light at a particular wavelength is focused on the surface of a stone to achieve stone fragmentation.

Internal and external pigtail stents are preferred to straight stents because they migrate less frequently and maintain the patency of the biliary orifice better. The main goal is to prevent the impaction of stones. and. occasionally. however. Sump syndrome. including bile duct injury. is associated with significant mortality. Straight stents may be used selectively for stones associated with a biliary stricture. however. life-threatening condition requiring emergent intervention. Alternatively. new bile duct stones can occur in patients who had inadvertent long-term stent placement following therapy for bile duct stones [72]. occurs in 1% of such cases and is managed by endoscopic therapy. Long-term biliary stenting Whenever stones cannot be removed completely endoscopically. Acute ascending cholangitis Acute cholangitis. pancreatitis. biliary stents should be placed to ensure adequate biliary drainage and to prevent recurrent symptoms as well as biliary sepsis while awaiting further therapy. choledochoenterostomy or sphincteroplasty can be performed. The clinical presentation ranges from a mild.69]. Moreover. self-limited process to a serious. Long-term biliary stenting.934 ATTASARANYA et al rate comparable to that of ERCP.71]. Bile duct stones are the most common cause of acute . long-term biliary stenting is used in patients who have severe comorbid medical conditions that preclude surgery or who have had repeated endoscopic interventions for definitive therapy of bile duct stones [65–68]. ranging from 6% to 16%. which occurs when debris or food particles enter a side-to-side choledochoduodenostomy and block the distal bile duct. long-term stenting should be reserved as a definitive therapy for patients who are at extremely high risk for endoscopic or surgical procedures or who have a short life expectancy. This procedure is technically demanding. long-term stenting can promote stone fragmentation. spontaneous passage of stones [65. Additionally. and stricture [64]. and with morbidity of up to 40% during 3 years of follow-up [70. The reported success rates range from 80% to 98%. Open common bile duct exploration. leading to decreased stone size. Additionally. The former procedure is preferable for stones larger than 2 cm. with complication rates of 4% to 16%. infection. or infection of the biliary tree. occurs as a consequence of biliary tract obstruction. and only a minority of surgeons perform laparoscopic bile duct exploration. In summary. Open common bile duct exploration generally is performed only if endoscopic and laparoscopic approaches are unsuccessful. Either a transcystic approach (for stones ! 8–10 mm) or direct choledochostomy with choledoschoscopy (for larger or multiple stones) can be performed. mainly from cholangitis.

83]. Bile cultures are positive in 80% to 100% of patients who have cholangitis. Increasing intraductal pressure leads to disruption of hepatocellular tight junctions. These conditions are beyond the scope of this discussion.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 935 cholangitis in Western countries [73]. or AIDSrelated cholangiopathy. Enteric . Pathophysiology Bacterobilia occurs commonly in patients who have bile duct stones.76]. and jaundice. with or without GSP [81]. is uncommon and occurs in only 5% to 7% of cases [79.80]. orthotopic liver transplantation. and abnormal liver function tests is highly suggestive. Pancreatic enzyme elevations suggest that bile duct stones caused the cholangitis. The more severe form. secondary to biliary stricture from biliary surgery. this triad occurs in 56% to 70% of patients who have cholangitis [78]. is relatively mild and intermittent. often in the absence of clinical cholangitis. The presence of fever. unlike the pain secondary to bile duct stones in the absence of infection. The occurrence of bacteremia or endotoxemia is correlated directly with the intrabiliary pressure [75. in 1877. Fever is the most common presenting symptom. found in 90% of patients. Elderly and immunocompromised patients can present with atypical symptoms and signs. and blood cultures are positive in 21% to 71% [82. Indeed. Laboratory tests Leukocytosis and an elevated C-reactive protein level and erythrocyte sedimentation rate are found commonly but are nonspecific. the portal venous and periportal lymphatic systems serve as the portal of entry in a minority of cases [74]. Typically. with subsequent translocation (reflux) of bacteria and biliary toxins into the bloodstream. with a widely variable range. Liver function tests invariably are elevated. characterized by the additional clinical features of hypotension and alteration of consciousness (Reynold’s pentad). primary sclerosing cholangitis. Acute cholangitis is occurring increasingly. previous therapy probably is the second most common cause of acute cholangitis. the main entry route of bacteria is ascending from the duodenum [73]. The pain in patients who have cholangitis. Diagnosis and clinical manifestations Charcot. Malignant obstruction rarely presents with cholangitis do novo but can cause cholangitis after manipulation of stent occlusion from the biliary tree. biliary obstruction plays a critical role in the pathogenesis of cholangitis. leukocytosis. right upper abdominal pain. Biliary obstruction promotes bile stasis and bacterial growth and also may compromise host immune defense mechanisms [77]. described a triad of fever. In the presence of bacterobilia.

Antibiotic therapy Antibiotics should be given early when acute cholangitis is suspected. local susceptibility pattern. including host factors (renal function. Medical therapy alone is effective in approximately 80% of patients. preferably within 24 to 48 hours. to control bacteremia and sepsis. and the presence of prior biliary intervention or surgery. Broad-spectrum antibiotics with adequate biliary excretion such as ampicillin/sulbactam. or have severe disease [84. . A treatment algorithm is suggested in Fig. Patients who have had recent biliary surgery or who have indwelling stents are more likely to harbor Enterococcus or hospital-acquired organisms such as Pseudomonas species. Medical therapy Initially. Patients who have mild disease are managed initially with medical therapy. antibiotics as well as supportive therapy. prompt additional biliary drainage is required in the others to control the clinical symptoms. Staphylococcus and Streptococcus are isolated infrequently. even before it is definitively established. including adequate hydration and correction of coagulopathy and metabolic derangements. are isolated more commonly in polymicrobial infections in patients who have had prior biliary-enteric surgery. and Enterococcus are isolated from bile commonly. 1.85]. allergic reactions). Anaerobic bacteria. severity of disease. Close monitoring and reassessment of the treatment response are important to guide the therapy. Management of cholangitis Early diagnosis and prompt appropriate therapy are essential. Imaging tests The choices in imaging are the same as for the diagnosis of bile duct stones but must be done more urgently in patients who have acute cholangitis. such as Clostridium and Bacteroides. must be provided. or fungi [86].936 ATTASARANYA et al gram-negative organisms including Escherichia coli. community versus hospital-acquired infection. methicillin-resistant Staphylococcus aureus. Delay in securing biliary drainage in this subgroup may produce a fatal outcome. Patients who have severe or progressive disease require urgent biliary drainage in addition to medical therapy [87]. are elderly [73]. Klebsiella. Patients who respond promptly to medical therapy should undergo biliary decompression and/or definitive therapy for bile duct stones as early as practical. An early CT scan is recommended to evaluate for biliary dilation and simultaneous liver abscesses. including antibiotics and supportive medical care. vancomycin-resistant Enterococcus. The choice of empiric antibiotics is based on several considerations.

One small retrospective study reported that a 3-day duration of antibiotic therapy following biliary drainage seemed to be effective in selected patients who respond promptly (with resolution of fever) to drainage procedures [88]. or surgical approaches or by multimodal therapy. Algorithm for management of patients who have acute cholangitis. 1. third. or prior enterobiliary surgery. antibiotics generally are continued for 5 to 7 days. severe disease. randomized trials. The optimal duration of antibiotic therapy following biliary drainage has not been well defined in prospective. the antibiotics should be adjusted to cover the identified micro-organism and to avoid the emergence of antibiotic-resistant micro-organisms. The duration of antibiotic therapy is based on the clinical response and the presence of bacteremia. switching from intravenous to oral administration usually is appropriate. and carbapenems are preferred. Decompression can be performed by endoscopic.or fourth-generation cephalosporins. percutaneous. Early biliary decompression is essential to restore good biliary penetration of the antibiotics and to drain purulent bile.g. Biliary drainage Biliary decompression is essential in patients who have cholangitis. quinolones. After a clinical response. For patients who have a positive blood culture. piperacillin/tazobactam. For mild disease. . a 10. Once the micro-organisms have been identified and their susceptibility has been determined.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 937 Acute cholangitis Assess clinical status. prompt 14-day course of antibiotics is recommended. hydration. gastric bypass surgery) unfavorable response/ technical failure Elective ERCP with definitive therapy (if not previously done) Percutaneous drainage Fig. particularly in patients who have severe disease. however [83]. correct metabolic derangement Mild Severe /unstable Intensive care Close monitoring/reassess in 6-12 hours Favorable response Refractory/Progressive Urgent ERCP with biliary decompression Elective ERCP with definitive therapy of bile duct stones (within 24-48 hours) ± definitive therapy favorable response altered anatomy (e. a biliary stent in situ. Antibiotics with enterococcal and anaerobic coverage may be added in patients who have advanced age. Biliary excretion of most antibiotics is compromised in the presence of biliary obstruction.

Definitive therapy (BES with removal of stones) is pursued in a stable patient who has confirmed bile duct stones. Evaluation before endoscopic retrograde cholangiopancreatography. Then limited contrast can be injected to fill only the extrahepatic ductal system to define the cause and location of obstruction. randomized trial. and the mortality with the endoscopic procedure was one third that of the open approach (10% versus 32%) [90]. Appropriate periprocedural and intraprocedural monitoring is needed. including defining ductal anatomy. Concomitant BES facilitates the placement of a larger stent (10–11. morbidity and mortality in elderly patients are lower with EBD than with percutaneous drainage [91]. in one prospective. Prolonging the procedure to attempt definitive therapy in an unstable patient may increase the morbidity and mortality. unless intrahepatic bile duct pathology is suspected. care must be taken to avoid aggravating the existing high intraductal pressure. The patient’s condition is stabilized as much as possible before the procedure.90]. Endoscopic biliary decompression therefore is the procedure of choice. Critically ill patients may require emergency ERCP using a mobile fluoroscopic unit at the bedside in the ICU. definitive therapy can be performed subsequently once the patient is stable. collecting bile for microbiologic study. however. and allowing definitive therapy in most cases. In an unstable patient. Similarly. providing tissue sampling. A large multicenter trial. identifying simultaneous pathology (such as biliary strictures or choledochal cysts).5 F) or multiple stents for more effective drainage and with a minimal risk of stent migration. and percutaneous or surgical drainage is reserved as an alternative when endoscopic therapy is technically impossible or is unsuccessful. EBD can be achieved with plastic biliary stents or with nasobiliary catheter drainage (NBD) with or without BES. Adequate hydration and prompt administration of systemic antibiotics are essential. Contrast injection during biliary cannulation should be minimized. noted that the risk . Details of prior surgeries that alter ERCP access should be identified.938 ATTASARANYA et al Endoscopic biliary decompression An endoscopic approach offers several benefits. In severe cholangitis biliary decompression and bile duct clearance by ERCP has lower morbidity and mortality rates than open surgery with bile duct exploration [89. Once deep cannulation is successful. EBD without fluoroscopy has been performed successfully in the ICU [92]. Endoscopic techniques of biliary drainage in acute cholangitis. 20 to 40 mL of bile should be aspirated to decompress the bile duct and to provide a sample of bile for microbiologic analysis. In patients who have severe cholangitis. every effort should be made to shorten the procedure time while providing adequate biliary drainage. When ERCP is performed in the presence of active cholangitis and purulent bile. the morbidity of the endoscopic procedure was one half that of open surgery (34% versus 66%).

larger stents should provide better drainage. Because most patients who have acute cholangitis undergo definitive therapy for bile duct stones several days or weeks following successful biliary decompression. Because BES is needed for placement of larger stents. Furthermore. Percutaneous transhepatic biliary drainage In percutaneous transhepatic biliary drainage a biliary drainage catheter is placed under ultrasound or fluoroscopic guidance into an intrahepatic . which otherwise could result in post-ERCP pancreatitis. even in the absence of coagulopathy [53]. controlled trials have compared outcomes between straight or pigtail biliary stents or among different stent sizes (7 F versus larger size) in patients who have acute cholangitis. BES can avoid compression of the pancreatic orifice by the stents. It is. less used frequently because of patient discomfort. BES also may facilitate stent placement through the tight stricture. Theoretically.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 939 of postsphincterotomy bleeding is correlated significantly with the presence of acute ascending cholangitis. particularly if thick. By separating the biliary and pancreatic orifices. the risk of BES-related bleeding needs to be weighed against the potential benefit. mainly from bleeding or cholecystitis [93]. the type or size of stent is likely to have no effect on treatment outcomes. In patients who have cholangitis in whom ERCP is performed but no bile duct stones are identified. BES has been shown to improve outcomes compared with no therapeutic intervention. the possibility of inadvertent dislodgment of the nasobiliary catheter.97]. purulent bile and stone debris are present. BES with long-term placement of multiple stents may be a reasonable alternative. the decision whether BES should be performed is tailored to the individual patient. BES may be performed when placement of a large (R 10 F) or multiple stents is required. the risk of kinking with inadequate drainage. or if the patient is unstable. with a faster recovery and shorter hospitalization [95]. NBD provides the advantage of active decompression by intermittent or continuous negative pressure suction and the opportunity for sequential bacteriologic bile cultures. generally is recommended for short-term drainage and produces satisfactory results [93. In patients who have debilitating comorbid conditions. Two prospective studies demonstrated no difference in treatment outcomes between biliary stenting and NBD in patients who had acute cholangitis [96. No randomized. Overall. for months) or may be unsuccessful. in whom the definitive therapy for bile duct stones is anticipated to be delayed (ie. and the potential for electrolyte disturbances secondary to the external diversion of bile. one study comparing decompression by NBD alone (n ¼ 73) versus NBD with BES (n ¼ 93) showed comparable success rates but significantly more complications in the BES group (12% versus 2%). placement of a biliary drainage tube alone (preferably a 7-F biliary stent or NBD). If coagulopathy is present.94]. without BES. In patients who have a concomitant biliary stricture that requires dilation. however.

Nausea and/or vomiting frequently occur. The disease recurs. An elevated serum amylase and/or lipase . Potential serious complications include sepsis. some patients have a severe. complicated course that entails substantial mortality. possibly with biliopancreatic reflux. when appropriate. Multiple small gallstones (! 5 mm). In expert centers. Management of patients who have severe disease is complex and has been debated for nearly a century. and pancreatitis [98]. Although GSP usually is mild and self-limited. intraperitoneal hemorrhage. in comparison with 10% of controls [105]. that occurred when the bile duct stone passed or was impacted at the ampulla. Most stones pass spontaneously into the duodenum. Anatomic variations such as a long common channel [103] or a nonpatent accessory duct [104] may be contributing risk factors. Because of the operative risks. The option of definitive therapy can be determined later. The incidence of GSP is increased in women more than 60 years old [99]. T-tube placement) should be performed to shorten the procedure time. the overall success rate of percutaneous drainage approaches 95% to 98% in patients who have biliary ductal dilation and is 70% to 80% in patients who do not have biliary dilation [98]. peritonitis. Clinical presentation Patients typically present with a sudden onset of unrelenting upper abdominal pain. the simplest procedure (eg. Discovery of fecal stones has been reported in about 90% of patients suspected of having GSP. which radiates into the back in about 50% of cases. a dilated cystic duct. Percutaneous transhepatic biliary drainage generally is reserved for patients in whom endoscopic biliary drainage is unsuccessful or who have altered anatomy such as prior gastric bypass surgery.940 ATTASARANYA et al duct and/or common bile duct. In severely ill patients. however. emergency surgical decompression rarely is performed. Surgical drainage Either open or laparoscopic common duct exploration may be performed. and good postprandial gallbladder emptying are putative factors for GSP [100–102]. Gallstone pancreatitis Gallstones are the most common cause of acute pancreatitis in Western countries. The pathogenesis is believed to be related to increased pancreatic ductal pressure. it is reserved for patients in whom both endoscopic and percutaneous approaches have been unsuccessful or who have altered anatomy that precludes such approaches. with the tip downstream in the duodenum. in approximately one third to two thirds of patients as early as 3 months after the initial episode if the underlying biliary stones are left untreated [106].

In selected cases. abdominal trauma/surgery. other potentially life-threatening conditions. known gallstone disease. previous/current medication use. such as a perforated viscus or bowel ischemia. As noted earlier.108]. other serious conditions should be considered and need to be excluded (Box 2). and weight loss that suggests a malignant process should be obtained. additional blood tests to exclude autoimmune pancreatitis (anti-nuclear antibodies. with a positive predictive value of 95% [109]. and specific therapy of bile duct stones is essential to prevent recurrence. and the serum calcium level also should be obtained at presentation. IgG4) or genetically related pancreatitis (cystic fibrosis. or biliary dilation in the absence of other causes [107. When patients experience sudden severe abdominal pain.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 941 level three times the upper limit of normal or higher in the typical clinical setting is diagnostic. Suspicion of GSP is increased in patients who have acute pancreatitis associated with abnormal liver function tests. Diagnosis Recognition of GSP is crucial. A history of excessive alcohol use. can produce modest elevation of the serum amylase or lipase level. Differential diagnosis of acute pancreatitis Gastrointestinal diseases Perforation of hollow viscus Mesenteric ischemia/infarction Intestinal obstruction Acute cholecystitis Acute cholangitis Non-gastrointestinal diseases Acute inferior wall myocardial infarction Dissecting abdominal aortic aneurysm Ectopic pregnancy . the diagnosis of acute pancreatitis is based on the characteristic pain and elevated serum amylase or lipase levels. because urgent endoscopic intervention may prevent complications and mortality in selected cases. hereditary pancreatitis) should be considered. Liver function tests. Any elevation of liver function tests in patients who have acute pancreatitis should Box 2. previous episodes of pancreatitis. documented gallbladder stones. triglyceride levels. Notably. family history. Liver function tests Elevation of alanine aminotransferase more than three times the upper limit of normal within 1 to 2 days after onset is the single best predictor of biliary pancreatitis.

Furthermore. Moreover. . Abdominal plain roentgenograms Abdominal plain roentgenograms contribute little to the diagnosis. peaks at 24 hours and may remain elevated for several days [112]. because of overlapping values. A normal alanine aminotransferase level does not exclude GSP. Imaging studies In patients suspected of having acute pancreatitis. ! 4 mm) may be missed by TUS [116]. or opaque gallbladder stones are detected rarely. imaging studies may be required to determine the potential cause (gallstones. Clinical use of the height of the serum amylase/lipase is limited. fluid collection) in patients who have severe pancreatitis. and daily monitoring of these levels is of limited value in predicting the progression or prognosis of acute pancreatitis [114]. Although TUS is highly accurate for the diagnosis of gallstones in the absence of pancreatitis. because the sensitivity rate is only 48% [109]. Serum lipase. initial imaging studies are useful mainly in confirming the diagnosis and in excluding other abdominal emergencies. The serum amylase level tends to be higher with GSP than with alcoholic pancreatitis [113]. liver function tests are entirely within the normal range in 10% of cases [110].942 ATTASARANYA et al raise the possibility of GSP. the amount of the serum amylase/lipase elevation is not correlated with disease severity. In patients who have a firm diagnosis. indicating underlying chronic pancreatitis. Transabdominal ultrasound TUS is the first line of investigation for GSP because of its low cost. The ‘‘sentinel loop’’ of distended small bowel is rare and does not affect management. The primary value of TUS for acute pancreatitis is to document the presence of gallbladder stones and/or bile duct dilation. it is only 60% to 80% sensitive in detecting gallstones during an attack of acute pancreatitis. its availability. and its portability for bedside examination of the critically ill patient. Serum amylase/lipase The serum amylase level rises within 2 to 12 hours after the onset of symptoms and normalizes within 3 to 5 days [111]. however. The primary value of plain roentgenograms is to exclude other abdominal emergencies such as intestinal perforation or obstruction. underlying chronic pancreatitis. Pancreatic calcifications. derived mainly from pancreatic acinar cells. EUS or an interval TUS may help in this situation. however. or neoplastic process) and to detect local complications (pancreatic necrosis. bile duct dilation. small gallstones (mean size. In particular. suggesting GSP.115]. presumably because of overlying bowel gas [114.

123]. patients who have peripancreatic fluid collections (grade D or E on the CT severity index) had a mortality of 14% and morbidity of 54%. CT grading of the extent of extrapancreatic inflammation (ascites. cohort study. Also. Occasionally. or C) had no mortality and only 4% morbidity [119]. an earlier CT scan may underestimate the severity of disease. Peripancreatic fat necrosis can occur from extravasation of activated pancreatic enzymes without pancreatic necrosis [117]. with appropriate technique. precluding an accurate evaluation of extent of necrosis. obstruction. or mesenteric infarction. a noncontrast multislice CT seems to be informative.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 943 CT scanning A dynamic contrast-enhanced CT scan is the optimal tool for detecting pancreatic parenchymal and peripancreatic inflammatory changes to confirm the diagnosis. In a retrospective. [117–119]. a high-quality CT scan. The optimal timing of the CT scan is important. is mandatory. MR imaging/magnetic resonance cholangiopancreatography Recent studies suggest that MR imaging and CT have comparable reliability in the evaluation of severity and local complications of acute pancreatitis [122. whereas patients who did not have fluid collections (grades A. MR imaging/MRCP may offer an advantage over Table 3 CT severity index with correlation to prognosis Degree of CT Severity Necrosis Index Complications Mortality Score (%) Score (range) (%) (%) 0 1 2 3 4 none none !30 30–50 O50 0 0 2 4 6 7–10 92 17 0–3 4–6 8 35 3 6 CT Grading A: normal pancreas B: edematous pancreatitis C: pancreatic/peripancreatic inflammation D: one peripancreatic fluid collection E: multiple peripancreatic fluid collections Data from Refs. Because pancreatic necrosis may not be appreciated by CT scan until at least 2 to 3 days after symptom onset [121]. B. In patients who have an uncertain diagnosis. pancreatic calcifications indicating chronic pancreatitis. a CT scan is helpful to identify other abdominal emergencies such as intestinal perforation. Balthazar and colleagues [117–119] have combined the extent of pancreatic/peripancreatic inflammatory changes and degree of pancreatic necrosis into a CT severity index that can predict reliably the severity of disease and the prognosis (Table 3). pleural effusion. . or a pancreatic neoplasm can be discovered. certain causes of pancreatitis such as common duct stones. When intravenous contrast is contraindicated. and retroperitoneal inflammation) was noted to predict local complications and persistent organ failure accurately [120].

These scoring criteria provide moderate overall . and biliary pancreatitis) [126. MR imaging reliably distinguishes a pancreatic fluid collection from liquefied necrosis [124]. Secretin-MRCP may help define pancreatic ductal anatomy. as well as pancreatic duct disruption undetected by CT scan [123]. whereas the accuracy of ERC alone is 87% to 90% [39. which carries a mortality rate of 1% to 3%. its technical infeasibility in critically ill patients. respectively [39]. with better detection of pancreatic hemorrhage [122] and bile duct stones. The APACHE-II score can be determined at admission and repeated at 24 or 48 hours. mortality approaches 30% [107]. Unlike CT scan. It does not obviate the need for ERCP. A normal EUS can obviate the need for ERCP because it has a high negative predictive value for the diagnosis of bile duct stones.127]. ! 3 days from admission) in 123 patients suspected of having GSP has been reported to be as high as 97. Determining severity and predicting prognosis Once acute pancreatitis has been diagnosed. Furthermore. Although most patients who have acute pancreatitis have mild. Several clinical scoring systems have been used to predict the severity of pancreatitis. One small. Glasgow criteria [128]. specificity. most commonly Ranson’s criteria (overall. The use of MR imaging has been limited by its lack of availability on an urgent basis. Both Ranson’s and Glasgow criteria require a 48-hour duration to complete the assessment. and APACHE-II [129]. most bile duct stones causing GSP are small (! 5 mm). EUS followed by ERCP. which is relatively long because organ failure may be evident by this time. if indicated. because ERCP is performed only if bile duct stones are confirmed by EUS. The technical success rate of early EUS (median. the severity of disease can be assessed to guide further management and to predict prognosis. self-limited disease (acute interstitial pancreatitis). such as pancreas divisum.5% [125]. about 15% to 25% of patients develop pancreatic necrosis. however. EUS may be useful in select patients (eg. postcholecystectomy) in whom the detection of stones at the time of ERCP guides therapy. and accuracy of MRCP in detection of bile duct stones in setting of GSP to be 80%. Because of its accuracy in detecting bile duct stones.944 ATTASARANYA et al CT scanning. prospective series reported the sensitivity. particularly in critically ill patients who have a borderline probability of bile duct stones. 83% and 81%.52]. less invasive means to detect biliary stones. Endoscopic ultrasound EUS is a very accurate. and its variable reliability between centers. and MRCP has limited accuracy in detection of these stones. Although it is available at only a few centers in the United States. seems o be a reasonable approach. If this necrotic tissue becomes infected. Intraductal EUS with ERC has been shown to increase the diagnostic accuracy of bile duct stones to 95% to 97%. EUS may serve as a useful guide about whether to proceed with therapeutic ERCP for GSP.

prevention of hypoxemia. although firm supportive evidence is lacking. correction of metabolic derangements. treatment in an ICU using a multidisciplinary team approach (consisting of . Oxygen supplementation generally is recommended because most patients require narcotic analgesia. early (! 72 hours after symptom onset). defined by a body mass index of 30 or higher. Close monitoring is needed to detect early deterioration of correctable conditions (eg. Moreover. Obesity. which can compromise ventilatory function. creatinine level O 2. polymorphonuclear elastase. A Ranson’s score of 3 or higher or an APACHE II score of 8 or higher also predicts severe pancreatitis. but the latter has been associated with a mortality of 36% and local complication rate of 77% [131]. such as interleukins. or systemic complications such as laboratory evidence of disseminated intravascular coagulation or a serum calcium level of 7. The authors’ group does not use a formal grading system to manage these patients. abscess or pseudocyst. Severe pancreatitis is defined by the presence of organ failure (systolic blood pressure ! 90 mm Hg. with a reported mortality greater than 50% in one study [132]. and pain control are the mainstays of supportive care. Because of the low prevalence of severe disease. Aggressive fluid resuscitation to preserve pancreatic microcirculation prevented or minimized pancreatic necrosis in an experimental model [134].0 mg/dL after rehydration. A distinction between transient organ failure (! 48 hours) and persistent organ failure (O 48 hours) is important [107] because the former can occur in patients who have interstitial pancreatitis with a low mortality. these clinical predictors yield a low positive predictive value (43%–49%) [107]. The clinically based Atlanta classification of acute pancreatitis is widely accepted [130]. hypoxia). have been evaluated in limited studies but are not used routinely. Elevated hematocrit and C-reactive protein [107] are correlated modestly with severe disease. progressive multiorgan organ failure is the most important predictive factor for mortality. Effective pain control is tailored to the individual patient. PaO2 % 60 mm Hg. In patients who have severe pancreatitis. Nasogastric tube decompression is needed only in patients who have significant ileus or vomiting. was associated with increased morbidity and mortality of acute pancreatitis in a recent meta-analysis of 739 patients from five studies [133]. and trypsinogen activation peptide. procalcitonin. local complications such as pancreatic necrosis. Treatment General Adequate hydration. and gastrointestinal bleeding O 500 cm3/24 hours). Several markers. Empiric proton-pump inhibitor therapy is reasonable to prevent stress-related mucosal injury.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 945 accuracy.5 mg/dL or higher.

pancreatobiliary surgeons.946 ATTASARANYA et al gastroenterologists. two prospective. Rather. Recently. Optimal timing for initiating oral intake is determined according to clinical status: improving pain scores. In the absence of ileus. interventional radiologists. Early enteral feeding within 48 hours after admission is well tolerated. Several randomized. double-blind. Nutrition In patients who have mild pancreatitis. Antibiotic prophylaxis to prevent infected pancreatic necrosis therefore is an attractive concept. its reliability has been questioned. selection criteria) included in this meta-analysis. Antibiotic prophylaxis Based on a recent guideline. Moreover. Because of the heterogenous studies (eg. In patients who have severe pancreatitis for whom prolonged pancreatic rest is expected. meropenem in the other) on reduction of pancreatic infection or mortality [139. and is less expensive than parenteral nutrition [135]. endoscopists with expertise in ERCP.140]. empiric antibiotics should be used only when infected necrosis is suspected and the work-up for sepsis is pending. is safer (with fewer infectious complications). adequate nutritional support is needed to meet metabolic requirements. Patients who have pancreatic necrosis have a significant risk of infectious complications. and absence of significant nausea or vomiting. Generally. return of appetite or active bowel function. One meta-analysis published in 2003 concluded that prophylactic antibiotics significantly reduced both mortality and pancreatic sepsis [138]. nutritional support is not necessary because rapid recovery is expected within several days. unblinded studies using either selective gut decontamination with oral antibiotics or systemic antibiotics with various regimens in patients who have pancreatic necrosis have shown conflicting results. . and a critical care team) is needed to optimize outcome. which constitute a major cause of death after 2 weeks of disease. Currently. antibiotic prophylaxis is recommended in patients who have suspected or confirmed bile duct obstruction undergoing ERCP [137]. superimposed fungal infection is a risk emerging from the prolonged use of broad-spectrum antibiotics [107]. jejunal feeding is preferable. placebo-controlled studies showed no beneficial effects of antibiotics (ciprofloxacin/metronidazole in one. different antibiotic regimens. Gastric feeding also seems to be feasible and safe [136]. routine use of prophylactic antibiotics seems to be unjustified and is not recommended [107]. although tube placement occasionally can be difficult. Parenteral nutrition may be considered in patients who cannot tolerate enteral feeding or when jejunal tube placement is not feasible technically. empiric antibiotic prophylaxis is given to patients who have GSP when early ERCP is indicated because these patients are likely to have retained or impacted bile duct stones.

Neoptolemos and colleagues [142] first reported a randomized trial comparing urgent ERCP within 72 hours of admission with conservative therapy plus selective ERCP after 5 days if indicated. and 9. persistent severe pain. Routine ERCP therefore is not recommended because of its low yield and significant risks. These predictors have variable accuracy [143. because the offending stone passes spontaneously into the duodenum in most patients. progressive rise of liver function tests or of the serum lipase/amylase level during the 24 to 48 hours after admission. patients who are likely to have retained bile duct stones requiring ERCP can be selected more precisely. Early ERCP was performed successfully in 90% of patients. ERCP is used in mild. and patients who have severe GSP are more likely to have retained/impacted stones [142]. uncomplicated course with mild to moderate disease. self-limited GSP when the findings of other noninvasive tests such as MRCP. In patients who had predicted severe GSP.145–147]. respectively). controlled trials have compared urgent ERCP with conservative therapy [142. Clinical studies of the role of urgent endoscopic retrograde cholangiopancreatography in gallstone pancreatitis Four landmark randomized. No significant difference in mortality was noted between the two groups. bile duct stones were discovered in 38%. This study demonstrated that an expert could perform ERCP safely in the setting of acute pancreatitis. to early ERCP within 24 hours after admission or to conservative therapy. Urgent ERCP was performed successfully in 88% of patients. Subgroup . 127 of whom had GSP. 18 of the patients (45%) who had predicted severe pancreatitis who were assigned to conservative therapy eventually had ERCP performed (for cholangitis/ septic shock) at a median of less than 72 hours after admission.35 mg/dL on day 2 of hospitalization have been used to predict retained bile duct stones in patients who have GSP. Urgent endoscopic retrograde cholangiopancreatography for acute biliary pancreatitis The extent of pancreatic injury is related to the duration of ampullary obstruction [141]. and an elevation of bilirubin to more than 1.5 days versus 17 days. Clinically.CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 947 Specific therapy Most patients who have GSP have a self-limited. or an intraoperative cholangiogram performed during the interval cholecystectomy indicate the need for definitive therapy of bile duct stones. EUS.144]. and biliary stones were documented in 19 patients (32%) in this group. Notably. Therefore early restoration of ampullary patency at ERCP is desirable to prevent further pancreatic injury. With the increasing availability of MRCP and EUS. early ERCP led to a significant reduction in the overall complication rate and hospital stay compared with the control group (24% versus 61%. Fan and colleagues [145] randomly assigned 195 patients who had pancreatitis.

the clinical applicability of this preliminary report is limited. The reduction in biliary sepsis was confined to those who were predicted to have severe pancreatitis. with the number needed to treat for avoidance of complication being 7. and some relevant data (eg.6. significantly reduces morbidity [149. Seventy-five patients were found to have impacted stones at the papilla and were treated immediately with BES. P ¼ . It is difficult to establish firm conclusions based on these meta-analyses because of the . This study has been criticized. The patients who had early ERCP (including the 75 patients who impacted stones. All patients underwent duodenoscopy within 24 hours of admission.03) in the early ERCP group. Patients assigned to early intervention had ERCP performed within 72 hours of symptom onset. The expertise of the participating centers also was questioned. who had a normal-appearing papilla. as reported in the earlier British study [142]. This study has not been fully published. This study confirmed the benefits of early ERCP in patients predicted to have severe GSP. reported by Folsch and colleagues [147]. the study was terminated prematurely because the interim analysis demonstrated an increased mortality (7.09). as was biliary sepsis (0% versus 12%).6 and the number needed to treat for avoidance of death being 25. Hence. Patients who had a bilirubin level greater than 5 mg/dL or high fever (O 39 C) were excluded. percentage of visualized bile duct stones) are not available. who were immediately treated) had significantly lower complication rates (17% versus 36%) and mortality (0% versus 7%) than the patients treated with conservative therapy.150]. A large preliminary study from Poland [146] evaluated 280 patients suspected of having GSP. were assigned randomly to early ERCP (! 24 hours after admission) or conservative therapy. The remainder of the patients. particularly in patients who have severe disease. however. evaluated ¨ 238 patients suspected of having GSP from 22 centers in Germany. Instead.948 ATTASARANYA et al analysis of the 127 patients who had GSP demonstrated that the rate of complications was significantly lower in the group receiving early ERCP than in the control group (16% versus 33%). A significant reduction in mortality was evident only when the Polish study was included in one meta-analysis [149].5%. Two subsequent meta-analyses concluded that early endoscopic therapy. criteria for severity. The benefit of early ERCP was significant regardless of the severity of GSP and was most pronounced in patients who had ERCP less than 24 hours after the onset of symptoms.6%) and a higher rate of respiratory failure (12% versus 4.9% versus 3. The fourth study. however. because 19 of the 22 centers contributed fewer than a mean of 2 patients per year to the trial [148]. This study did not demonstrate a significant benefit of early ERCP in reduction of either morbidity or mortality. P ¼ . There also was a trend toward lower mortality in the ERCP group (2% versus 8%. because of its higher rate of overall morbidity in comparison with the other three studies and an unclear association of early ERCP with respiratory distress.

This study was aborted prematurely after recruiting 61 patients because the interim analysis demonstrated that morbidity (29% versus 7%. Subsequently. Early ERCP was successful in 92% of patients. These six studies are summarized in Table 4. most immediate complications in this study were classified as pancreatic phlegmons. which were not fully defined. and timing of intervention) among these randomized trials. Two recent prospective.2 mg/dL and distal bile duct diameter measured by TUS R 8 mm) without cholangitis. P ¼ . This study showed no significant benefit from early ERCP in reduction of organ failure. P ¼ . P ¼ 1). In patients who have severe. particularly if performed within 24 to 48 hours of admission or symptom onset in patients who have GSP and who have simultaneous acute cholangitis or persistent biliary obstruction (persistent severe pain and elevation of liver function tests). it is unclear how many patients in this study actually had evidence of bile duct obstruction. and rising bilirubin level measured every 6 hours) to early ERCP (within 48 hours of admission if obstruction persisted more than 24 hours) versus conservative therapy with selective ERCP after more than 48 hours. The timing of early ERCP (within 72 hours) was relatively delayed in this study as compared with the former study. The validity of their criteria for biliary obstruction is unknown. There were no deaths in this study. because the rate of documented bile duct stones seems to be similar to that of previous studies without the preset criteria of biliary obstruction [150. 2 had papillary edema).CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 949 lack of homogeneity (eg. early ERCP seems to be beneficial. Patients were assigned randomly to early ERCP (within 72 hours after admission) or to conservative therapy. In summary.151]. local complications (6% versus 6%). overall morbidity (21% versus 18%. randomized studies addressing the use of early ERCP to restore biliary patency in patients who have GSP have included only patients who met the preset criteria for ampullary obstruction [144. Ten percent of patients in each group had severe pancreatitis. bile-free gastric aspirate. Oria and colleagues [151] recruited 103 patients suspected of having GSP who met criteria for ampullary obstruction (bilirubin level O 1. The accuracy of TUS in measuring the distal bile duct also has been questioned. Ampullary obstruction was confirmed by early ERCP in 13 of 14 patients who met the criteria of persistent obstruction (11 had impacted stones at the ampulla.152]. P ¼ . Acosta and colleagues [144] randomly assigned patients suspected of having ampullary obstruction (defined by persistent severe pain.8). predictors of severity. . when overlying bowel gas commonly is present. and mortality (6% versus 2%. Notably. In addition. in selection criteria.04) and immediate complications (26% versus 3%. Bile duct stones were found in 66% of patients in the early ERCP group versus 40% in the conservative group (who underwent elective cholecystectomy with intraoperative cholangiogram). particularly in the setting of acute pancreatitis. rather than merely having bile duct stones.02) were significantly higher in the conservative group than in the early ERCP group.

950 Table 4 Prospective randomized.b 12/61a.b ATTASARANYA Fan et al [145] 195/127 (with GSP) Nowak et al [146] 280 On admission: serum urea O 45 mg/dL or plasma glucose O 198 mg/dL O Three Ranson’s criteria Not mentioned 24 hours after admission 90 38 16a/0a.5 days for ERCP versus 17 days for controls) Early ERCP significantly reduces morbidity in patients predicted to have severe GSP Decreased complication rate and mortality in both predicted mild and severe cases Study Neoptolemos 146 et al [142] 12/24a. controlled trials: urgent endoscopic retrograde cholangiopancreatography (ERCP) in gallstone pancreatitis (GSP) Number of patients Criteria of predicted severe GSP O Three modified Glasgow’s criteria Timing of ERCP 72 hours after admission Success rate of early ERCP (%) 88 Documented stones at early ERCP (%) 32 Complications (%) Mortality (%) ERCP Control ERCP Control Notes 2 8 Decreased morbidity in predicted severe GSP Shortened hospital stay (9.c 33a/12a 5 9 et al 24 hours after admission Not mentioned 42 (impacted stones) 17a 36a 2a 13a .

9 3.2 mg/dL on admission. Defined by distal bile duct measuring R 8 mm by ultrasound with a total bilirubin R 1. ! 72 hours 92 selected patients after onset with suspected of symptoms ampullary obstructione 66 21 18 6 2 Significantly higher rate of respiratory failure in the early ERCP group Excluded cholangitis (biliary sepsis) Main complication in control group was pancreatic phlegmon Excluded acute cholangitis CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS a b c d e Numbers are statistically significantly different.Folsch ¨ et al [147] 121 R Three Glasgow criteria 72 hours after 96 onset of symptoms 46 46 51 7. and elevated serum bilirubin. bile-free gastric aspirate.6 Acosta et al [144] 61 Ranson’s and ! 48 hours 100 (of 14 93 Acosta criteria. 951 . patients after selected patients admission with with suspected only if obstruction ampullary obstruction O 24 hours) obstructiond persists O 24 hours 29a 7a 0 0 Oria et al [151] 102 APACHE-II. Defined by severe persisting pain. Total complications/ biliary sepsis. All severity/ predicted severe.

Because of possibility of overlooking tiny bile duct stones. regardless of the presence or absence of bile duct stones [153].952 ATTASARANYA et al nonobstructive GSP. Practice varies among experts and centers. Patients who have spontaneously resolving liver function tests may not require urgent ERCP.153]. Finally. Early Gallstone pancreatitis (intact gallbladder with stones) Predicted/actual severe pancreatitis* yes Cholangitis no Predicted/actual mild pancreatitis Persistent/progressive severe pain Early ERCP ± biliary sphincterotomy (< 24-48 hours after admission) yes Persistent liver function tests > 48 hours no Surgical candidate no yes Surgical candidate Laparoscopic cholecystectomy with intraoperative cholangiogram (IOC) (in the same admission) no empirical Presence of bile duct stones? Elective laparoscopic cholecystectomy (when pancreatitis subsides) yes Follow up ERCP with biliary sphincterotomy no Follow up yes Fig. one guideline advocates BES in patients who have severe GSP. The authors perform urgent ERCP on selected cases in this situation when retained bile duct stones are suspected based on persistent elevation of liver function tests for more than 24 to 48 hours. performing BES empirically in severe GSP seems reasonable. and each case should be judged individually. Indeed.152. particularly in a dilated duct. and recommendations are inconsistent [49. Early laparoscopic cholecystectomy seems to be safe and effective in preventing recurrent attacks in patients who have mild GSP [154]. BES may prevent recurrent episodes of pancreatitis. whether BES should be performed when bile duct stones are not visualized is unclear. 2. Cholecystectomy for gallstone pancreatitis The primary objective of cholecystectomy is to prevent recurrent GSP. particularly if cholecystectomy cannot be performed in the near future or is impossible because of the high surgical risk.113. the benefit of urgent ERCP is controversial. 2. Algorithm of endoscopic therapy in acute gallstone pancreatitis. Furthermore. An algorithm for endoscopic intervention in acute GSP is proposed in Fig. .107.

a presumptive diagnosis of idiopathic pancreatitis should be made. .CHOLEDOCHOLITHIASIS AND GALLSTONE PANCREATITIS 953 cholecystectomy may be unsafe in patients who have severe disease. adequate monitoring/supportive care. however. other causes such as sphincter of Oddi dysfunction. should be considered to guide further management.122:1500–11. respectively) [155].5% and 47% versus 7%. et al. management of these patients should be undertaken by experienced hands. such as MRCP or EUS. less-invasive imaging methods. depending on the local expertise. when pancreatitis subsides. Everhart JE. Gastroenterology 2002. it currently is recommended that cholecystectomy should be performed in the same hospitalization. Appropriate noninvasive diagnostic studies. If any bile duct stones are documented. Less invasive investigations. Summary Gallstone disease is encountered commonly in clinical practice. References [1] Sandler RS. such as biliary and pancreatic manometry. The burden of selected digestive diseases in the United States. and for minor/major pancreatic sphincter therapy. Acute cholangitis and GSP are two major complications that require prompt recognition and timely intervention to limit morbidity and prevent mortality or recurrence. or within 2 to 4 weeks after discharge [152. and proper patient selection for invasive therapeutic procedures are elements of good clinical practice. The relatively invasive endoscopic techniques should be reserved for therapy and not used for diagnosis. Because of the high recurrence rate of GSP unless gallstones are removed. pancreas divisum. The diagnosis of biliary stones has become less problematic with current. because overall complication rates and sepsis were significantly higher in those undergoing early surgery than in those undergoing delayed surgery (44% versus 5. If these tests do not confirm the presence of common duct stones. and pancreatic neoplasms need to be excluded. Gallstone pancreatitis after cholecystectomy In patients who have had cholecystectomy. Further discussion of this issue is beyond the scope of this article. fully normalized serum liver chemistries) may proceed directly to laparoscopic cholecystectomy and intraoperative cholangiogram. they can be managed by intraoperative or postoperative ERCP or by laparoscopic bile duct exploration. Donowitz M. and because of the high frequency of serious procedure-related complications.153]. Patients who have little evidence of retained ductal stones (resolved pain. Because of the frequent need for complex biliary procedures.

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