Hepatology

Gallbladder and
Biliary Tract Disease

David S. Barnes

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Gallbladder diseases

Gallbladder diseases considered here include gallstones, tumors, and acute acalculous cholecystitis.

Gallstones and Cholecystitis

Definition and Etiology

Gallbladder stones are an extremely common disorder and are usually asymptomatic. Some patients experience biliary colic, an intermittent and often severe pain in the epigastrium or right upper quadrant, and at times between the scapula because of temporary obstruction of the cystic duct with a gallstone. If the cystic duct obstruction persists, the gallbladder becomes inflamed and the patient develops cholecystitis, an acute inflammation and infection of the gallbladder.

Prevalence and Risk Factors

It is estimated that there are 20.5 million cases of gallbladder disease in the United States, 14.2 million of whom are in women.1 More than 600,000 cholecystectomies per year are performed in the United States, most of which are for symptomatic gallstone disease. Epidemiologic studies have shown variations in the prevalence of gallstones in different ethnic populations, with particularly high rates in Native Americans. In addition to ethnic background, other risk factors for the development of gallstones include diabetes, rapid weight loss, morbid obesity, cirrhosis, and conditions associated with infrequent gallbladder emptying, such as total parenteral nutrition.

Pathophysiology and Natural History

Most gallstones are composed primarily of cholesterol, with smaller amounts of mucus, calcium bilirubinate, and protein. Pigment stones, a result of hemolysis, are less common and are made primarily of calcium bilirubinate. Symptoms occur with gallstones when the gallbladder contracts, often after a meal, resulting in occlusion of the cystic duct with a stone that produces symptoms, typically pain.

Signs and Symptoms

The vast majority of patients with gallstones are asymptomatic. Symptomatic gallstones typically manifest with right upper quadrant abdominal pain, often accompanied by nausea and vomiting. The pain is often severe, may abate over several hours (biliary colic), or may progress to cholecystitis, with persistent pain and fever. On examination, there is pain to palpation in the right upper quadrant (Murphy's sign).

Diagnosis

The imaging study of choice is a right upper quadrant ultrasound, which, in the presence of cholecystitis, typically shows the presence of gallstones, a thickened gallbladder wall, and pericholecystic fluid. In those patients with symptomatic gallstones and a negative ultrasound examination, endoscopic ultrasound may be helpful.2 To confirm the suspicion of cholecystitis, a hydroxyiminodiacetic acid (HIDA) scan can be useful. The radionuclide material is concentrated in the liver and excreted into the bile but does not fill the gallbladder because of cystic duct obstruction.

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Summary: Acute Cholecystitis

  • Right upper quadrant abdominal pain, nausea, and vomiting
  • Ultrasound reveals
  • Thickened gallbladder wall
  • Pericholecystic
  • HIDA scan reveals nonvisualized gallbladder
Treatment

The primary treatment for symptomatic gallstone disease is cholecystectomy. Prophylactic cholecystectomy for silent gallstones is not warranted.3 Most cholecystectomies in the United States are done laparoscopically. A patient with an acute episode that resolves should see a surgeon within a few weeks and elective cholecystectomy should be considered. Patients who have persistent right upper quadrant tenderness and develop fever or an elevated white blood cell count should be seen more urgently.

Common bile duct stones can accompany acute cholecystitis in up to 10% of cases. These stones can be removed endoscopically before or after cholecystectomy, or surgically at the time of laparoscopic or open cholecystectomy.

Most good-risk patients who undergo elective laparoscopic cholecystectomy are sent home within 24 hours. Patients who undergo open cholecystectomy may require hospitalization for several days. It is estimated that 95% of patients experience relief of pain after cholecystectomy. The remaining patients probably had symptoms not related to gallbladder disease before surgery.

Practice guidelines for the treatment of gallstones and gallbladder disease are available from the Society for Surgery of the Alimentary Tract (SSAT). These guidelines (available at http://www.ssat.com/cgi-bin/guidelines.cgi) review the symptoms and diagnosis of gallstone disease and make treatment recommendations regarding surgical consultation and indications for surgery. They review the risks of cholecystectomy, both laparoscopic and open, and the expected outcomes. There are also recommendations for the treatment of common duct stones.

Gallbladder Tumors

Benign and malignant tumors can occur in the gallbladder. Benign tumors consist of papillomas, adenomyomas, or cholesterol polyps. Malignant tumors of the gallbladder are uncommon. The most common malignant tumor of the gallbladder is adenocarcinoma, although squamous cell carcinoma, cystadenocarcinoma, and adenoacanthomas have been reported. Adenocarcinoma of the gallbladder is associated with chronic cholecystitis; exposure to rubber or petroleum products has also been suggested as a cause. It occurs more commonly in women and those older than 50 years.

Patients with small gallbladder tumors may present with symptoms suggesting cholecystitis (e.g., abdominal pain, fever), whereas larger tumors may manifest late with jaundice and an abdominal mass. Computed tomography (CT) or ultrasound scans will reveal a gallbladder mass and, in the case of larger tumors, a mass in the liver and evidence of biliary obstruction. Patients with the incidental finding of gallbladder carcinoma at the time of cholecystectomy have a good prognosis. Otherwise, the 5-year survival rate of patients with gallbladder cancer is only about 5%.

Special mention should be made of the finding on ultrasound of polypoid lesions of the gallbladder, gallbladder polyps. Histologically, there are four types of polypoid lesions, including cholesterol polyps, adenomas, adenomyomatous hyperplasia, and malignant polyps. Although polyp size (larger than 10 mm) and patient age (older than 60 years) are more suggestive of malignancy, no radiologic test can distinguish benign from malignant polyps in the absence of metastatic or invasive cancer.4 Although there are no firm guidelines, cholecystectomy for patients with polyps larger than 10 mm seems warranted.4,5 Regular follow-up ultrasound examination for patients with polyps smaller than 10 mm has been suggested, but prospective studies confirming the benefit of such a surveillance program have not been done.4

Acute Acalculous Cholecystitis

Acute acalculous cholecystitis is an acute inflammatory disease of the gallbladder not associated with gallstones. About 10% of the 500,000 cholecystectomies performed each year in the United States are for acalculous cholecystitis. The pathogenesis is believed to be an ischemic injury to the gallbladder wall, compounded by chemical injury caused by bile acids. It is often seen in patients hospitalized for trauma or burns who have a superimposed sepsis and are on mechanical ventilation. It is also associated with patients with vascular disease and immunodeficiency.

Clinical manifestations can be similar to those seen with calculous cholecystitis (right upper quadrant pain, fever, and a positive Murphy sign [pain during inspiration associated with palpation of the right upper quadrant]) but are typically subtler in a ventilated patient in the intensive care unit, in whom usual clinical clues are absent. When acalculous cholecystitis is being considered, ultrasound is the diagnostic test of choice and shows a thickened gallbladder wall, pericholecystic fluid, and a sonographic Murphy's sign. Cholecystectomy, open or laparoscopic, is the definitive therapy. In patients who are a prohibitively high surgical risk, an ultrasound-guided percutaneous cholecystostomy tube provides drainage of the gallbladder without surgery. Another nonsurgical approach is transpapillary endoscopic drainage of the gallbladder.6 The outcome of patients with acalculous cholecystitis depends to a large extent on the underlying illness, but mortality can be as high as 30% when perforation of the gallbladder occurs as a complication.7

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Biliary tract diseases

Choledocholithiasis

Definition and Causes

One of the most common causes of extrahepatic biliary obstruction is choledocholithiasis, with one or more stones in the common bile duct or common hepatic duct causing biliary obstruction.

Prevalence and Risk Factors

Up to 10% of patients with gallstones have common bile duct stones. Common bile duct stones have been discovered days to several years after surgery in as many as 5% of patients who have undergone cholecystectomy.8 It is believed that the stones represent retained stones or stones that have formed de novo after the operation.

Pathophysiology and Natural History

Stones in the bile duct can cause biliary obstruction and cholestasis. This can lead to infection in the bile duct (bacterial cholangitis), which requires urgent medical therapy. The long-standing presence of stones in the bile duct can lead to secondary biliary cirrhosis. Choledocholithiasis can also lead to gallstone pancreatitis.

Signs and Symptoms

Most patients with choledocholithiasis report upper abdominal pain, although some patients may remain asymptomatic. Because complete obstruction of the bile duct by the stone may be intermittent, patients may report episodic jaundice.

The initial manifestation of choledocholithiasis can also be heralded by an episode of cholangitis. Gallstone pancreatitis manifests with typical features of pancreatitis, including epigastric pain, nausea, and vomiting.

Diagnosis

Several diagnostic tools can be used when evaluating patients suspected of having choledocholithiasis. Ultrasound is the preferred initial screening test because it is usually less expensive than CT or magnetic resonance imaging (MRI), does not use ionizing radiation, and is highly accurate in detecting gallbladder stones and bile duct dilation.9 MR cholangiography has gained acceptance as a tool for diagnosing choledocholithiasis. Its accuracy in detecting bile duct stones approaches that of endoscopic retrograde cholangiography.10 Abdominal CT scanning can also be helpful in evaluating patients with obstructive jaundice. It is as accurate as ultrasound in detecting common duct stones and may help localize the level of obstruction in the biliary tree.

Once biliary dilation or the presence of a common duct stone is noted on an imaging study, or biliary obstruction is strongly suspected on clinical grounds despite negative imaging studies, endoscopic retrograde cholangiopancreatography (ERCP) is recommended. ERCP provides a means of visualizing the biliary tree and the opportunity for therapy. Percutaneous transhepatic cholangiography can be a useful alternative when ERCP is not successful, although it is sometimes not successful in the absence of dilated bile ducts. Practice guidelines from the Society for Surgery of the Alimentary Tract for the treatment of gallstone and gallbladder diseases can be found online (www.ssat.com/cgi-bin/chole7.cgi).

Treatment

The goals of therapy for choledocholithiasis are to remove the stones from the biliary tree and to decompress the biliary tree urgently if bacterial cholangitis is present. Stone extraction can be accomplished with ERCP, often preceded by an endoscopic sphincterotomy. In the presence of bacterial cholangitis, when a stone cannot be removed for technical reasons—for example, because of its large size—an endoscopically placed biliary stent can be useful for decompressing the biliary tree. An alternative to ERCP for the treatment of choledocholithiasis is percutaneous transhepatic cholangiography (PTHC). PTHC can be used for emergent drainage of the biliary tree in the presence of cholangitis. Passage of a wire into the duodenum via a percutaneous approach can also help guide an endoscopist when performing an ERCP with stone extraction if ERCP had previously failed because of technical factors.

Cholangiocarcinoma

Definition

Cholangiocarcinoma is an adenocarcinoma of the intrahepatic or extrahepatic bile duct.

Prevalence and Risk Factors

There are 2000 to 3000 new cases per year of cholangiocarcinoma in the United States, accounting for 10% to 15% of all primary hepatobiliary malignancies.11 It is most common in middle-aged men. Primary sclerosing cholangitis (PSC) is a major risk factor for the development of cholangiocarcinoma. In a large Swedish study, 8% of patients with PSC developed cholangiocarcinoma over a mean follow-up period of 5 years.12 However, this study might have underestimated the actual incidence of PSC-associated cholangiocarcinoma. Other diseases associated with the development of cholangiocarcinoma include choledochal cysts and infection with liver flukes, including Opisthorchis (formerly Clonorchis) sinensis, O. felineus, and O. viverrini.

Pathophysiology and Natural History

Cholangiocarcinoma is a malignant transformation of the bile ducts, including the ducts in the intrahepatic, perihilar, or extrahepatic biliary tree. A commonly used classification system for cholangiocarcinoma is based on the anatomic location of the tumor.13 The natural history is one of progression, with a poor 5-year survival rate, lower than 5%. A tissue diagnosis is often difficult to obtain and, in the absence of obviously metastatic disease or extensive local spread, surgical exploration is the only way to determine resectability.

Signs and Symptoms

Patients typically present with jaundice and pruritus and more generalized symptoms, such as weight loss, anorexia, and fatigue. Cholangiocarcinoma should always be suspected in a previously stable patient with PSC who has a rapid clinical decline.

Diagnosis

Initial diagnostic testing for cholangiocarcinoma is similar to that used for other causes of cholestasis. Laboratory testing typically shows an elevated level of alkaline phosphatase of liver origin, with or without an elevation of the bilirubin level. Ultrasound examination, MRI, or CT scanning may reveal areas of focal biliary dilation. MRI is the optimal imaging study when cholangiocarcinoma is suspected.14 Direct cholangiography with ERCP or PTHC cholangiography with brush cytology of the biliary tree can be useful for diagnosis, although the sensitivity for detecting malignancy with brush cytology is less than 75%.15

Blood testing for cancer antigens, particularly CA19-9, has been shown to be useful in detecting cholangiocarcinoma, as has an index using CA19-9 and carcinoembryonic antigen (CEA).16-18 Neither method is highly sensitive or specific but can help confirm suspected cholangiocarcinoma.

Treatment

Surgical resection of cholangiocarcinoma has resulted in a 5-year survival rate of 16% to 44%.19,20 Liver transplantation for cholangiocarcinoma is not offered by most transplantation centers because of a high recurrence rate after transplantation. Some centers have had a more favorable outcome with radiation and chemotherapy followed by liver transplantation in patients with early-stage disease.21,22 Palliative therapy includes percutaneously or endoscopically placed biliary stenting. Photodynamic therapy has also been used with some success.23

Miscellaneous Conditions Causing Biliary Tract Obstruction

Benign Tumors

Although most bile duct tumors are malignant, some benign biliary lesions result in biliary obstruction and cholestasis. These include papillomas, adenomas, and cystadenomas.24

Ampullary Tumors

Tumors of the ampulla of Vater can be benign (adenomas) or malignant (ampullary carcinoma). Either can result in biliary obstruction and can be confused with cholangiocarcinoma and pancreatic adenocarcinoma. At presentation, patients are often jaundiced and may have a palpable gallbladder because of bile duct obstruction distal to the cystic duct. Laboratory findings typically show an elevation of alkaline phosphatase and bilirubin levels.

Imaging studies of the biliary tree will often show dilation, suggesting a distal bile duct obstruction. Further investigation with a side-viewing duodenoscope will reveal the presence of the ampullary tumor. Ampullary adenomas, often seen with familial adenomatous polyposis, can be treated with surgical excision of the ampulla.25,26 Whipple's procedure is the treatment of choice for those with resectable ampullary carcinoma.

The 5-year survival rate is as high as 60% in patients with tumor-free surgical margins.27 For patients who are not surgical candidates, ERCP with sphincterotomy can provide palliation for what are often slow-growing tumors.

Pancreatic Disorders

Carcinoma of the head of the pancreas can manifest with painless jaundice caused by obstruction of the bile duct as it passes through the head of the pancreas. Weight loss, fatigue, and other constitutional symptoms often accompany the cholestasis. CT scanning or ultrasound typically reveal biliary ductal dilation to the level of the pancreatic head and a pancreatic mass.

Cholestasis can also result from benign pancreatic disorders such as chronic pancreatitis resulting in pancreatic fibrosis leading to common duct narrowing and cholestasis or a pancreatic pseudocyst causing compression of the biliary tree.

Mirizzi's Syndrome

Mirizzi's syndrome is caused by an impacted cystic duct stone, leading to gallbladder distention and subsequent compression of the extrahepatic biliary tree. Occasionally, the gallstone erodes into the common hepatic duct, producing a cholecystocholedochal fistula. The original classification of Mirizzi's syndrome has been expanded to include hepatic duct stenosis caused by a stone at the junction of the cystic and hepatic ducts or as a result of cholecystitis, even in the absence of a obstructing cystic duct stone.28

Patients present with jaundice, right upper quadrant, pain and fever. Ultrasound or CT scanning reveals biliary dilation above the cystic duct. ERCP may reveal the obstructing stone, which can occasionally be removed, but the definitive treatment is usually surgical, consisting of cholecystectomy with surgical repair of the bile duct, if necessary.

AIDS Cholangiopathy

Cholestasis can be seen in AIDS as a result of biliary ductal changes seen on a cholangiogram that resemble primary sclerosing cholangitis. The ductal strictures are believed to be caused by infections, including Cryptosporidium spp, cytomegalovirus, microsporidian, and Cyclospora spp.29

Patients present with right upper quadrant pain and laboratory tests suggesting cholestasis. A wide variety of other hepatobiliary abnormalities may also occur in those with HIV infection, including granulomatous liver disease from mycobacteria, fungi, or drugs, bacterial abscesses, neoplasms such as Kaposi's sarcoma or lymphoma, and drug toxicity. Initial evaluation should include ultrasound and ERCP if the ultrasound is abnormal.30 ERCP should also be carried out despite a normal ultrasound if there is evidence of severe abdominal pain. Endoscopic therapy is useful in certain circumstances. Endoscopic sphincterotomy is useful for those patients with symptoms of papillary stenosis (e.g., abdominal pain, jaundice, cholangitis). Endoscopic stenting of the dominant structure of the biliary may also be helpful.

Parasites

Extrahepatic biliary obstruction has been seen with various parasitic infections, such as Strongyloides and Ascaris spp, and liver flukes, such as Opisthorchis sinensis and Fasciola hepatica.

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References

  1. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999, 117: 632-639.
  2. Dahan P, Andant C, Levy P, et al: Prospective evaluation of endoscopic ultrasonography and microscopic examination of duodenal bile in the diagnosis of cholecystolithiasis in 45 patients with normal conventional ultrasonography. Gut. 1996, 38: 277-281.
  3. Ransohoff DF, Gracie WA. Prophylactic cholecystectomy or expectant management for silent gallstones. Ann Intern Med. 1983, 99: 199-204.
  4. Terzi C, Sokmen S, Seckin S, et al: Polypoid lesions of the gallbladder: Report of 100 cases with special reference to operative indications. Surgery. 2000, 127: 622-627.
  5. Kubota K, Bandai Y, Noie T, et al: How should polypoid lesions of the gallbladder be treated in the era of laparoscopic cholecystectomy?. Surgery. 1995, 117: 481-487.
  6. Huibregtse K, van Amerongen R, van Deventer SJ. Drainage of the gallbladder in patients with acute acalculous cholecystitis by transpapillary endoscopic cholecystoxeransis. Gastrointest Endosc. 1994, 40: 523.
  7. Barie PS, Fischer E. Acute acalculous cholecystitis. J Am Coll Surg. 1995, 180: 232-244.
  8. Hermann RE. The spectrum of biliary stone disease. Am J Surg. 1989, 158: 171-173.
  9. Balfe DM, Ralls PW, Bree RL, et al: Imaging strategies in the initial evaluation of the jaundiced patient. American College of Radiology. ACR Appropriateness Criteria. Radiology. 2000, 215: (Suppl): 125-133.
  10. Varghese JC, Liddell RP, Farrell MD, et al: Diagnostic accuracy of magnetic resonance cholangiopancreatography and ultrasound compared with direct cholangiography in the detection of choledocholithiasis. Clin Radiol. 2000, 55: 25-35.
  11. Torok N, Gores GJ. Cholangiocarcinoma. Semin Gastrointest Dis. 2001, 12: 125-132.
  12. Broome U, Olsson R, Loof L. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996, 38: 610-615.
  13. de Groen PC, Gores GJ, LaRusso NF, et al: Biliary tract cancers. N Engl J Med. 1999, 341: 1368-1378.
  14. Khan SA, Davidson BR, Goldin R, et al: Guidelines for the diagnosis and treatment of cholangiocarcinoma: Consensus document. Gut. 2002, 51: 7-9.
  15. Ryan ME, Baldauf MC. Comparison of flow cytometry for DNA content and brush cytology for detection of malignancy in pancreaticobiliary strictures. Gastrointest Endosc. 1994, 40: 133-139.
  16. Ramage JK, Donaghy A, Farrant JM, et al: Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology. 1995, 108: 865-869.
  17. Chalasani N, Baluyut A, Ismail A, et al: Cholangiocarcinoma in patients with primary sclerosing cholangitis: A multicenter case-control study. Hepatology. 2000, 31: 7-11.
  18. Levy C, Lymp J, Angulo P, et al: The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci. 2005, 50: 1734-1740.
  19. Nagorney DM, Donohue JH, Farnell MB, et al: Outcomes after curative resections of cholangiocarcinoma. Arch Surg. 1993, 128: 871-879.
  20. Washburn WK, Lewis WD, Jenkins RL. Aggressive surgical resection for cholangiocarcinoma. Arch Surg. 1995, 130: 270-276.
  21. De Vreede I, Steers JL, Burch PA, et al: Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl. 2000, 6: 309-316.
  22. Heimbach JK, Gores GJ, Haddock MG, et al: Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis. 2004, 24: 201-207.
  23. Ortner MA, Liebetruth J, Schreiber S, et al: Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroenterology. 1998, 114: 536-542.
  24. Anthony PP. Tumors of the hepatobiliary system. Fletcher CDM(ed:) . Diagnostic Histopathology of Tumors. London: Churchill Livingstone, 2000, pp 411-460.
  25. Iwama T, Tomita H, Kawachi Y, et al: Indications for local excision of ampullary lesions associated with familial adenomatous polyposis. J. Am Coll Surg. 1994, 179: 462-464.
  26. Chung RS, Church JM, Van Stolk R. Pancreas-sparing duodenectomy: Indications, surgical technique, and results. Surgery. 1995, 117: 254-259.
  27. Allema JH, Reinders ME, van Gulik TM, et al: Results of pancreaticoduodenectomy for ampullary carcinoma and analysis of prognostic factors for survival. Surgery. 1995, 117: 247-253.
  28. Nagakawa T, Ohta T, Kayahara M, et al: A new classification of Mirizzi syndrome from diagnostic and therapeutic viewpoints. Hepatogastroenterology. 1997, 44: 63-67.
  29. Lefkowitch JH. The liver in AIDS. Semin Liver Dis. 1997, 17: 335-344.
  30. Daly CA, Padley SPG. Sonographic prediction of a normal or abnormal ERCP in suspected AIDS related sclerosing cholangitis. Clin Radiol. 1996, 51: 618-621.

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Suggested Readings

  • Anthony PP. Tumors of the hepatobiliary system. Fletcher CDM(ed:) . Diagnostic Histopathology of Tumors. London: Churchill Livingstone, 2000, pp 411-460.
  • Balfe DM, Ralls PW, Bree RL, et al: Imaging strategies in the initial evaluation of the jaundiced patient. American College of Radiology. ACR Appropriateness Criteria. Radiology. 2000, 215: (Suppl): 125-133.
  • Broomé U, Olsson R, Lööf L, et al: Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996, 38: 610-615.
  • de Groen PC, Gores GJ, LaRusso NF, et al: Biliary tract cancers. N Engl J Med. 1999, 341: 1368-1378.
  • Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999, 117: 632-639.
  • Heimbach JK, Gores GJ, Haddock MG, et al: Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis. 2004, 24: 201-207.
  • Hermann RE. The spectrum of biliary stone disease. Am J Surg. 1989, 158: 171-173.
  • Khan SA, Davidson BR, Goldin R, et al: Guidelines for the diagnosis and treatment of cholangiocarcinoma: Consensus document. Gut. 2002, 51: 7-9.
  • Ransohoff DF, Gracie WA. Prophylactic cholecystectomy or expectant management for silent gallstones. Ann Intern Med. 1983, 99: 199-204.
  • Torok N, Gores GJ. Cholangiocarcinoma. Semin Gastrointest Dis. 2001, 12: 125-132.