CALCULOUS BILIARY DISEASE

CALCULOUS BILIARY DISEASE

  1. 1
    Current Diagnosis

    • True biliary colic is characterized by the abrupt onset and cessation of severe mid-epigastric or, less commonly, right upper quadrant pain.

    • Pain commonly starts 1 to 2 hours after eating and can be localized or radiate to the back, right shoulder, or chest.

    •   The onset of biliary colic commonly occurs during sleep.

    •   Nausea and vomiting commonly follow the onset of pain.

    • Elevations of total and conjugated bilirubin, ALP and GGT with modest elevations in AST and ALT support a suspected diagnosis of choledocholithiasis.

    • A normal serum biochemistry profile has a negative predictive value of 97% for ruling out choledocholithiasis.

    • Transabdominal ultrasonography is a useful and cost-effective test for diagnosing cholelithiasis; however, it has significantly lower utility for choledocholithiasis.

    • For intermediate-risk patients with suspected choledocholithiasis, examination of the common bile duct with magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasonography (EUS) is warranted.

  2. 2
    Current Therapy

    • The treatment of choice for symptomatic cholelithiasis is laparoscopic cholecystectomy. Elective laparoscopic cholecystectomy should only be performed for true biliary colic. Vague symptoms such as bloating, dyspepsia, and atypical abdominal pain are not commonly related to gallstone disease and thus are not an indication for gallbladder removal.

    • Laparoscopic cholecystectomy should generally take place within 72 hours of presentation for acute cholecystitis in appropriate surgical candidates.

    • Laparoscopic cholecystectomy is recommended in pregnant patients with symptomatic cholelithiasis and acute cholecystitis. This is best done by experienced surgeons in the second or early third trimesters.

    • Patients who should undergo preoperative ERCP for choledocholithiasis include those with high risk stratification and those deemed intermediate risk in whom a common bile duct stone is identified on MRCP or endoscopic ultrasonography.

  3. 3
    Cholelithiasis

    Epidemiology

    Gallstone disease is common in Western populations, affecting 10% to 15% of adults. It is estimated that 6.3 million men and 14.2 million women in the United States have gallstones. Although the vast majority of patients remain asymptomatic throughout their lifetime, roughly one third develop symptoms or complications.

    Pathophysiology

    Gallstones can be categorized based on their composition. Of patients with gallstone disease in the Western world, 80% to 90% have cholesterol stones or cholesterol-predominant stones (mixed stones). Pigment gallstones account for the remaining 5% to 10%. Patients with hemolytic disorders are prone to pigment stone formation, and therefore the correspondence with disorders such as sickle cell anemia, hereditary spherocytosis, and Gilbert’s syndrome is high.

    Risk Factors

    Risk factors for gallstone disease include female gender, age greater than 40 years, white, Latin American, and Native American descent, family history, obesity, rapid weight loss, starvation, total parenteral nutrition, bariatric surgery, diabetes mellitus, and hypertriglyceridemia.

    Clinical Manifestations

    The typical symptomatic presentation of gallstone disease is biliary colic. This is described as severe pain located in the mid-epigastrium or, less commonly, the right upper quadrant, that begins and ceases abruptly. The pain is typically constant, occurring 1 to 2 hours following a meal, and can either be localized or radiate to the back or right shoulder. Often the onset of pain occurs during sleep. Nausea and vomiting commonly accompany biliary pain, and as with most surgical entities, pain typically precedes the onset of these symptoms. Biliary colic can also manifest as chest pain and is occasionally mistaken for cardiac angina. Prolonged episodes of pain localized to the right upper quadrant often herald cholecystitis rather than biliary colic. A clinical history containing the cardinal features of biliary colic carries a high diagnostic accuracy.

    Diagnosis

    Transabdominal ultrasonography is the preferred initial imaging test for cholelithiasis. The sensitivity for detecting the presence of gallstones within the gallbladder lumen on ultrasonography is 97%.

    Biliary Sludge

    Biliary sludge is often diagnosed on transabdominal ultrasonography. It appears as low-amplitude nonshadowing echoes that layer in dependent portions of the gallbladder. The clinical course of biliary sludge varies from patient to patient. Some patients remain asymptomatic and others develop overt biliary colic. A fraction of patients demonstrate resolution of biliary sludge on repeat imaging.

    Symptomatic biliary sludge should be treated the same as cholelithiasis. Similarly, patients with asymptomatic biliary sludge should be managed expectantly.

    Treatment

    In patients with symptomatic cholelithiasis, treatment should be aimed at acute pain control and prevention of recurrent episodes. In patients without contraindications, cholecystectomy is the preferred choice for treatment of symptomatic uncomplicated cholelithiasis.

    This is preferably done via laparoscopy, which offers lower rates of complications and postoperative pain along with better cosmetic results when compared to open cholecystectomy.

    Because of the high incidence of cholelithiasis, true biliary colic should be identified before a decision is made to proceed with laparoscopic cholecystectomy. Vague symptoms such as bloating or atypical abdominal pain are not typical of gallstone disease and thus often persist after surgery. In cases of asymptomatic uncomplicated cholelithiasis, elective cholecystectomy is not recommended unless the patient is diabetic or is undergoing an operation such as gastric bypass surgery after which there is an increased risk of gallstone formation.

    There is a very limited role for medical management of gallstone disease. Nonoperative management of symptomatic cholelithiasis involves bile dissolution with ursodeoxycholic acid (Actigall). The use of medical therapy is limited based on poor efficacy and high rates of recurrence and thus should be reserved only rarely for nonsurgical candidates.

    Analgesia is an important adjunct in the treatment of symptomatic cholelithiasis. In patients with severe symptoms requiring narcotic pain medication, meperidine (Demerol) is preferred over morphine because it has less effect on the sphincter of Oddi. Nonsteroidal antiinflammatory drugs (NSAIDs) are another mainstay of therapy. Parenterally administered ketorolac (Toradol) is perhaps the most commonly used agent for biliary colic in the acute care setting. Studies have shown that NSAIDs are beneficial in the management of pain due to gallstones, and at least one study has suggested that early administration of NSAIDs might decrease the progression to acute cholecystitis.

    Complications

    Complications that can potentially arise from cholelithiasis include acute cholecystitis, cholangitis, pancreatitis, obstructive jaundice, and, rarely, gallstone ileus.

  4. 4
    Choledocholithiasis

    Choledocholithiasis often manifests concomitantly with symptomatic gallstone disease and is a finding in 5% to 10% of patients undergoing laparoscopic cholecystectomy for symptomatic cholelithiasis. The work-up for suspected choledocholithiasis combines history, physical examination, laboratory data, and various imaging modalities. If the clinical history and physical examination are suggestive, the clinician should obtain serum liver biochemistry tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and fractionated bilirubin, alkaline phosphatase (ALP), and γ-glutamyl transpetidase (GGT).

    The typical pattern of serum biochemistry is one of cholestasis. A conjugated hyperbilirubinemia along with high levels of GGT and ALP are seen often in the setting of modest elevation of the transaminases. ALP is usually elevated out of proportion to the transaminases; however, extreme levels of AST and ALT have been described. Transaminase levels greater than 1000 U/L, although rare in gallstone disease, should not dissuade the clinician from a diagnosis

    of choledocholithiasis. Serum biochemistries provide the most utility in ruling out common bile duct stones. A normal biochemical profile has a negative predictive value of 97%. Clinical predictors for assessing the likelihood of choledocholithiasis in patients with symptomatic cholelithiasis are listed in Box 1.

     

    Box 1
    Proposed Strategy to Assign Risk of Choledocholithiasis in Patients with Symptomatic Cholelithiasis, Based on Clinical Predictors
    Predictors of Choledocholithiasis

    Very Strong

    Common bile duct stone on transabdominal ultrasound Clinical ascending cholangitis

    Total bilirubin > 4 mg/dL

    Strong

    Dilated common bile duct on transabdominal ultrasound (> 6 mm with gallbladder in situ)

    Total bilirubin 1.8–4 mg/dL

    Moderate

    Abnormal liver biochemistry test other than bilirubin Age older than 55 years

    Clinical gallstone pancreatitis

    Likelihood of Choledocholithiasis Based on Clinical Predictors

    Presence of any very strong predictor: High Presence of both strong predictors: High No predictors present: Low

    All other patients: Intermediate

    From ASGE Standards of Practice Committee, Maple JT, Ben-Menachem T, Anderson MA, et al: The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endosc 2010;71:1–9, with  permission.

     

    Diagnosis

    A variety of modalities are available for diagnosing choledocholithiasis. Perhaps the least expensive and most widely available test is transabdominal ultrasound. While the sensitivity for cholelithiasis is quite high with transabdominal ultrasound, identifying stones in the common bile duct (Figure 1) is more difficult. Prospective studies have reported sensitivities ranging from 22% to 55% for detecting common bile duct stones; however, in our clinical experience the sensitivity is much lower. Other indirect indicators of  choledocholithiasis such as common bile duct dilatation (77%–88% sensitivity) can provide additional diagnostic clues. Based on the high false-negative rates for common bile duct stones and dilatation, a negative transabdominal ultrasound cannot rule out choledocholithiasis. CT scan has a higher sensitivity for choledocholithiasis than transabdominal ultrasound. Levels of radiation and cost have limited its use as a first-line diagnostic tool.

    FIGURE 1    A large gallstone in the common bile duct (CBD)  with dilatation of the CBD proximally. The endoscopic ultrasound probe is visualized in the top of the image, and a large cone-shaped shadow is cast distal to the gallstone.

    Three nonsurgical modalities offer true visualization of the common bile duct with comparable sensitivities: Magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasonography (EUS). MRCP has a diagnostic sensitivity of 85% to 92% for detecting choledocholithiasis, and although it is useful for helping determine which intermediate-risk patients would benefit from preoperative ERCP, small and distal common bile duct stones are often missed.

    EUS and ERCP are both minimally invasive techniques useful in the diagnosis and management of choledocholithiasis. Owing to the proximity of the extrahepatic bile duct to the proximal duodenum, EUS provides high sensitivity (89%–94%) for detecting common bile duct stones and is especially useful for detecting stones less than 5 mm in diameter. ERCP provides similar diagnostic sensitivity; however, ERCP offers therapeutic capability. Because of the reasonably high risk of complications including pancreatitis (1.3%– 15.1%), infection (0.6%–5.0%), gastrointestinal hemorrhage (0.3%– 2.0%), and perforation (0.1%–1.1%), ERCP as an initial modality should be reserved for patients who have a high pretest probability for choledocholithiasis and particularly for those with complications such as acute cholangitis or severe pancreatitis.

    Research has evaluated the use of ultrasound-guided ERCP with the goal of avoiding unnecessary bile duct cannulation, and reserving its use for therapeutic purposes only. A systematic review from 2009 showed that compared to ERCP alone, the use of EUS avoided unnecessary ERCP in 67.1% of patients in whom no common bile duct stone was identified. As more gastroenterologists become trained in this modality, EUS-guided ERCP might prove to be the preferred diagnostic modality in intermediate-risk patients for the diagnosis and initial therapy of choledocholithiasis.

    Treatment

    Patients with choledocholithiasis should be treated to avoid recurrent symptoms and development of complications. Stones can be extracted from the common bile duct via ERCP or laparoscopic cholecystectomy with bile duct exploration. Studies have shown similar efficacies without significant differences in morbidity or mortality; however, clinical expertise varies widely with the laparoscopic approach.

    Ultimately, cholecystectomy should be performed to prevent recurrence in surgical candidates. In patients undergoing laparoscopic cholecystectomy for suspected choledocholithiasis, perioperative management differs based upon the risk stratification of the patient (see Box 1). High risk patients should proceed directly to ERCP before surgery for attempted stone extraction. In intermediate-risk patients, a preoperative MRCP or EUS should be performed, and if the results

    are positive the patient should undergo ERCP as a prelude to surgery. For suspected choledocholithiasis in low-risk patients, surgery should be performed without further imaging of the common bile duct.

    Complications

    The two most common adverse complications of choledocholithiasis are gallstone pancreatitis and acute cholangitis. Gallstone pancreatitis develops in 3% to 7% of patients with gallstones and is the most common cause of acute pancreatitis in the United States. The diagnosis and management of acute pancreatitis is discussed in a separate chapter.

    Acute cholangitis is caused by obstruction and stasis of the biliary tract with complicating bacterial infection. The syndrome is characterized by fever, jaundice, and abdominal pain, also known as Charcot’s triad. Patients who develop hypotension and changes in mental status (Reynold’s pentad) have a poorer prognosis. Elderly patients often do not demonstrate the classic signs of acute cholangitis, but they can develop a delayed-sepsis–like syndrome of which hypotension is the most pronounced feature. High biliary pressures promote the translocation of bacteria from the portal circulation into the biliary tree. The most common bacterial organism seen in acute cholangitis is Escherichia coli (25%–50%), followed by Klebsiella, Enterobacter, and Enterococcus species.

    Treatment for acute cholangitis should focus on antimicrobial therapy and biliary drainage. Empiric antibiotic regimens should provide adequate activity against gram-negative and anaerobic organisms. Common regimens include monotherapy with ampicillin and sulbactam (Unasyn) or pipercillin and tazobactam (Zosyn) or combination therapy with a fluoroquinolone plus metronidazole (Flagyl).

    Patients without hypotension or mental status changes commonly show initial improvement after empiric antibiotics are administered, and thus biliary drainage can be done nonurgently. In patients demonstrating signs of sepsis or severe infection, emergent biliary drainage via ERCP is warranted. Patients who are not candidates for ERCP may undergo percutaneous transhepatic biliary drainage as an alternative.

     

  5. 5
    Acute Cholecystitis

    Acute cholecystitis is a syndrome defined by right upper quadrant pain, fever, and leukocytosis in the setting of gallbladder inflammation. Nausea and vomiting often occur as concurrent symptoms. Patients commonly have a positive Murphy’s sign on physical examination, which is defined as abrupt cessation of inspiration upon deep palpation of the gallbladder fossa, just beneath the liver edge. Approximately 95% of patients with acute cholecystitis have gallstones. In these instances, cholecystitis is thought to be precipitated by obstruction of the cystic duct and by local irritation of the gallbladder wall. Local inflammation is followed by release of pro- inflammatory prostaglandins. Superimposed bacterial infection might or might not complicate acute cholecystitis. As with cholangitis, the main bacteria responsible for infections during acute cholecystitis are

    1. coli and Klebsiella, Enterobacter, and Enterococcus species.

    Diagnosis

    The diagnosis of acute cholecystitis can often be made on physical examination alone. The most common laboratory finding in acute cholecystitis is leukocytosis. Mild elevations in AST and ALT can also be seen. Elevations of bilirubin and ALP are typical of biliary obstruction and are not commonly seen in acute cholecystitis. These abnormalities, if present, should raise suspicion for other conditions such as choledocholithiasis, cholangitis, or Mirizzi’s syndrome.

    Mirizzi’s syndrome is a rare cause of obstructive jaundice characterized by an impacted cystic duct stone that causes mass effect and compression of the common bile duct or common hepatic duct.

    The initial imaging study of choice for acute cholecystitis is transabdominal ultrasound. Findings suggestive of cholecystitis include cholelithiasis, pericholecystic fluid (Figure 2) and a sonographic Murphy’s sign (Figure 3). Thickening of the gallbladder wall supports a diagnosis of acute cholecystitis, but is a nonspecific finding. Transabdominal ultrasound has a sensitivity of 88% for diagnosing acute cholecystitis. Hepatobiliary cholescintigraphy (HIDA scan) (Figure 4) is recommended if the suspicion of cholecystitis remains after a negative transabdominal ultrasound. MRCP and CT scan are typically not necessary for the diagnosis, although CT scan can be useful if complications from cholecystitis such as perforation are suspected.

    FIGURE 2    Computed tomography (CT) scan demonstrating  acute cholecystitis. The outline arrow indicates gallstones within the gallbladder lumen. The two solid arrows highlight mural thickening of the gallbladder wall and small amounts of pericholecystic fluid. (Image courtesy of Richard M. Gore, MD, Department of Radiology, NorthShore University Health System, Evanston, IL.)

    FIGURE 3    Acute cholecystits: ultrasound. Gallbladder (g)  is distended, with mural thickening (arrowhead) and a stone in the gallbladder neck (arrow). Positive sonographic Murphy sign was present.

    FIGURE 4    Hepatobiliary iminodiacetic Acid (HIDA)  scan demonstrating acute cholecystitis. There is nonfilling of the gallbladder (outline arrow), with isotope noted in the stomach and duodenum (solid arrows). (Image courtesy of Richard M. Gore, MD, Department of Radiology, NorthShore University Health System, Evanston, IL.)

    Treatment

    The treatment for acute cholecystitis involves supportive care, analgesia, antibiotics, and either surgery or percutaneous gallbladder drainage. If treatment is delayed or inadequate, numerous potential complications can result. These include emphysematous or gangrenous cholecystitis and gallbladder perforation. All patients with acute cholecystitis should be admitted to the hospital and given supportive care including intravenous fluids. NSAIDs and opioid analgesics are typically used for pain control.

    Although bacterial etiologies complicate less than half of all episodes, empiric antibiotics are commonly administered to patients with acute cholecystitis. Appropriate antibiotic regimens are the same as those used in the setting of acute cholangitis (see the discussion of complications of choledocholithiasis).

    In patients who are adequate surgical candidates, cholecystectomy should be performed within 72 hours of initial presentation.

    Numerous prospective trials and a Cochrane Database review have evaluated early versus delayed (6–12 weeks) cholecystectomy. There is overwhelming consensus that early surgery carries no increase in complications or perioperative morbidity and is associated with shorter hospital stays. Furthermore, early laparoscopic cholecystectomy eliminates the risk of recurrent episodes of acute cholecystitis.

    Acute Acalculous Cholesystitis

    An estimated 5% to 10% of cases of acute cholecystitis develop without the presence of gallstones. Acute acalculous cholecystitis is often seen in the setting of serious medical illness, complicated surgery, severe blunt trauma, and burn injuries. Other conditions such as diabetes mellitus, vasculitis, AIDS, and congestive heart failure have also been implicated as risk factors. Acute acalculous cholecystitis carries major risks of gangrene (50%) and perforation (10%), and mortality ranges from 30% to 50%. Numerous organisms have been associated with acute acalculous cholecystitis, including bacterial, viral, fungal, and parasitic infections.

    The diagnosis is difficult. Patients are often critically ill and unable to elicit their symptoms. Transabdominal ultrasound is the best modality to evaluate acute acalculous cholecystitis in the critically ill patient owing to its availability, cost, and ease of performance.

    Hepatobiliary iminodiacetic acid (HIDA) and computed tomography (CT) scanning can have a role in difficult-to-diagnose acute acalculous cholecystitis and should be considered if ultrasound is nondiagnostic. Whereas false positive tests can occur, a normal HIDA scan has a high negative predictive value in evaluating acute acalculous cholecystitis.

    Because of the high rate of gangrene and perforation, early cholecystectomy should be performed in patients who are surgical candidates. In patients too ill to undergo surgery, biliary drainage with percutaneous cholecystostomy should be considered.

  6. 6
    Gangrenous Cholecystitis, Emphysematous Cholecystitis and Gallbladder Perforation

    Gangrenous cholecystitis is most often seen in elderly patients and diabetics along with patients who delay seeking medical treatment for their symptoms. It is the most common complication of acute cholecystitis and carries a high mortality. Emphysematous cholecystitis is caused by gas-forming bacteria that infect the gallbladder. E coli and Clostridium species are most commonly implicated. Gas in the gallbladder may be seen on imaging, particularly CT or magnetic resonance imaging (MRI). Patients with gangrenous or emphysematous cholecystitis are at an elevated risk for gallbladder perforation. Early empiric antibiotics and cholecystectomy are crucial in the management of these complications to minimize mortality and prevent perforation of the gallbladder, a condition that carries a mortality rate of 42% to 60%.

  7. 7
    Gallbladder Disease in Pregnancy

    Pregnancy is a major risk factor for cholesterol gallstone formation. Because of anatomic changes secondary to the gravid uterus, biliary colic can be difficult to delineate from other causes of abdominal pain. Pregnant patients often have gallstones on transabdominal ultrasound, and thus a detailed history and physical examination are needed to diagnose a patient’s abdominal pain as biliary. Patients with other symptoms including bloating or dyspepsia should be evaluated for other etiologies.

    In pregnant patients with recurrent symptomatic cholelithiasis, laparoscopic cholecystectomy remains the treatment of choice. The second and early third trimesters are the best times to perform cholecystectomy owing to ease and lower rates of complications.

    Nonsurgical management of gallstones is limited in pregnancy. NSAIDs are generally avoided late in pregnancy owing to the risk of premature closure of the ductus arteriosis, especially after 30 to 32 weeks of gestation.

    After appendicitis, acute cholecystitis is the second most common nonobstetric surgical emergency during pregnancy. As with nonpregnant patients, pregnant women with acute cholecystitis should be treated with cholecystectomy in addition to medical management. Early surgery for pregnant patients with acute cholecystitis has been found to decrease relapse rates and hospital readmissions. No differences in maternal or fetal morbidity and mortality have been found in patients treated conservatively versus surgically for acute cholecystitis during pregnancy.

  8. 8
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    ASGE Standards of Practice Committee, Maple J.T., Ben- Menachem T., Anderson M.A., et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endosc. 2010;71:1–9.

    ASGE Standards of Practice Committee, Maple J.T., Ikenberry S.O., Anderson M.A., et al. The role of endoscopy in the management of choledocholithiasis. Gastrointest Endosc.

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    Dhupar R., Smaldone G.M., Hamad G.G. Is there a benefit to delaying cholecystectomy for symptomatic gallbladder disease during pregnancy? Surg Endosc. 2010;24:108–112.

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    Freitas M.L., Bell R.L., Duffy A.J. Choledocholithiasis: Evolving standards for diagnosis and management. World J Gastroenterol. 2006;12:3162–3167.

    Gore R.M., Thakrar K.H., Newmark G.M., et al. Gallbladder imaging. Gastroenterol Clin North Am. 2010;39:265–267.

    Gurusamy K.S., Samraj K. Early versus late laparoscopic cholecystectomy for acute cholecystitis. Cochrane Database Syst Rev. 2006;18: CD005440.

    Papi C., Catarci M., Ambrosio D., et al. Timing of cholecystectomy for acute calculous cholecystitis: A meta-analysis. Am J Gastroenterol. 2004;99:147–155.

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