TITLE: GALLBLADDER AND BILIARY TRACT DISEASE
AUTHOR: DAVID S. BARNES, MD -- Department of Gastroenterology and Hepatology
PUBLISHED: JULY 9, 2002
    
Gallbladder diseases considered here include gallstones, tumors, and acute acalculous cholecystitis.
GALLSTONE
DEFINITION

Gallbladder stones are a very 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 caused by 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
It is estimated that there are 20.5 million cases of gallbladder disease in the United states, 14.2 million of whom are women.1 More than 600,000 cholecystectomies per year are performed in the United States, the majority of which are for symptomatic gallstone disease.
SIGNS AND SYMPTOMS
The vast majority of patients with gallstones are asymptomatic. Symptomatic gallstones typically present 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 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. 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.

THERAPY

The primary treatment for symptomatic gallstone disease is cholecystectomy. The majority of cholecystectomies in the United States are now 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 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.

OUTCOMES

The majority of 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 prior to surgery.

NATIONAL GUIDELINES
National guidelines for treatment of gallstones and gallbladder disease were released on June 3, 1998 and revised in January 2000. The Society for Surgery of the Alimentary Tract guidelines 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 laproscopic and open, and the expected outcomes. There are also recommendations for treatment of common duct stones. The guidelines are available at www.ssat.com/guidelines/chole7.htm. The guidelines are entitled SSAT Patient Care Guidelines 2000, Treatment of Gallstone and Gallbladder Disease.
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 very uncommon. The most common malignant tumor of the gallbladder is adenocarcinoma although squamous cell carcinoma, cystadenocarcinoma and adenoacanthomas have been reported. Adenomacarcinoma of the gallbladder is associated with chronic cholecystitis; exposure to rubber or petroleum products has also been suggested as an etiology. It occurs more commonly in women and people over 50 years old.

Patients with small gallbladder tumors may present with symptoms suggesting cholecystitis (abdominal pain and fever); whereas larger tumors may present late with jaundice and an abdominal mass. Computerized 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 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 4 types polypoid lesions including cholesterol polyps, adenomas, adenomyomatous hyperplasia, and malignant polyps. Although polyp size (>10 mm) and patient age >60 are more suggestive of malignancy, no radiologic test can distinguish benign from malignant polyps in the absence of metastatic or invasive cancer.2 Although there are no firm guidelines, cholecystectomy for patients with polyps >10 mm seems warranted.2,3 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.2
ACUTE ACACULOUS 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 felt 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 immune deficiency. Clinical manifestations can be similar to those seen with calculus 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 where 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, either 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.4 The outcome of patients with acalculous cholecystitis depends to a large extent on their underlying illness, but mortality can be as high as 30% when perforation of the gallbladder occurs as a complication.5
BILIARY TRACT DISEASES
CHOLEDOCHOLITHIASIS
DEFINITION
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
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.6 It is believed the stones represent either retained stones or stones that have formed de novo after the operation.
PATHOPHYSIOLOGY
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 longstanding presence of stones in the bile duct can lead to secondary biliary cirrhosis. Choledocholithiasis can also lead to gallstone pancreatitis.
SIGNS AND SYMPTOMS

The majority of 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 presentation of choledocholithiasis can also be heralded by an episode of cholangitis. Gallstone pancreatitis presents 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 as it is usually less expensive than abdominal CT scan, does not use ionizing radiation, and is very accurate in detecting gallbladder stones and bile duct dilatation.7 Abdominal CT scanning can also be very helpful in evaluating patients with obstructive jaundice. It is more accurate than ultrasound in detecting common duct stones and may help localize the level of obstruction in the biliary tree. Magnetic resonance cholangiography is also gaining acceptance as a tool for diagnosing choledocholithiasis. Its accuracy in detecting bile duct stones is offset by its expense and lack of availability in some centers.

Once biliary dilatation 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 (ERC) is recommended. ERC provides a means of visualizing the biliary tree and the opportunity for therapy. Percutaneous transhepatic cholangiogram can be a useful alternative when ERC is not successful, although it is sometimes not successful in the absence of dilated bile ducts.

THERAPY

The goals of therapy for choledocholithiasis are to remove the stone from the biliary tree and to urgently decompress the biliary tree if bacterial cholangitis is present. Stone extraction can be accomplished with ERC often preceded by an endoscopic sphincterotomy. In the presence of bacterial cholangitis when a stone cannot be removed for technical reasons due to, for example, its large size, an endoscopically placed biliary stent can be useful for decompressing the biliary tree. An alternative to ERC for 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 in performing an ERC with stone extraction where ERC previously failed technically.

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

There are 2,000 to 3,000 new cases of cholangiocarcinoma per year in the United States, accounting for 10% to 15% of all primary hepatobiliary malignancies.8 It is most common in middle-aged men.
PATHOPHYSIOLOGY

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.9 This study might underestimate the true incidence of PSC-associated cholangiocarcinoma. Other diseases associated with the development of cholangiocarcinoma include choledochal cysts and infection with liver flukes including Clonorchis sinensis, Opisthorchis felineus, and Opisthorchis viverrini.

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. Ultrasound examination or CT scanning may reveal areas of focal biliary dilatation. Direct cholangiography with ERC or percutaneous transhepatic 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%.10

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 CEA.11,12 Neither method is highly sensitive or specific but can help confirm suspected cholangiocarcinoma.
THERAPY
Surgical resection of cholangiocarcinoma has resulted in a 5-year survival rate of 16% to 44%.13,14 Liver transplantation for cholangiocarcinoma is not offered by most transplant centers because of 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.15 Palliative therapy includes percutaneously or endoscopically placed biliary stenting. Photodynamic therapy has also been used with some success.16
MISCELLANEOUS CONDITIONS CAUSING BILIARY TRACT OBSTRUCTION
BENIGN TUMORS
Although the majority of bile duct tumors are malignant, some benign biliary lesions result in biliary obstruction and cholestasis. These include papillomas, adenomas and cystadenomas.17
AMPULLARY TUMORS

Tumors of the ampulla of Vater can be both benign (adenomas) and 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 due to bile duct obstruction distal to the cystic duct. Laboratory findings typically show an elevation of alkaline phosphatase and bilirubin. Imaging studies of the biliary tree will often show dilatation 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.18,19 Whipple's procedure is the treatment of choice for people with resectable ampullary carcinoma. The 5-year survival is as high as 60% in patients with tumor-free surgical margins.20 For patients who are not surgical candidates, ERC with sphincterotomy can provide palliation for what are often slow-growing tumors.
PANCREATIC DISORDERS

Carcinoma of the head of the pancreas can present 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 scan or ultrasound typically reveal biliary ductal dilatation to the level of the pancreatic head and a pancreatic mass.

Cholestasis can also result from benign pancreatic disorders such as 1) chronic pancreatitis resulting in pancreatic fibrosis leading to common duct narrowing and cholestasis; or 2) 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.21

Patients present with jaundice, right upper quadrant pain and fever. Ultrasound or CT scan reveals biliary dilatation above the cystic duct. ERC 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 cholangiogram resembling primary sclerosing cholangitis. The ductal strictures are thought to be caused by infections including cryptosporidia, cytomegalovirus, microsporidium and Cyclospora.22

Patients present with right upper quadrant pain and laboratory tests suggesting cholestasis. A wide variety of other hepatobiliary abnormalities may also occur in HIV including granulomatous liver disease from mycobacteria, fungi or drugs; bacterial abscesses; neoplasm such as Kaposi's sarcoma or lymphoma and drug toxicity. Initial evaluation should include ultrasound and ERC of the ultrasound is abnormal.23 ERC 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 in those patients with symptoms of papillary stenosis (abdominal pain, jaundice or cholangitis). Endoscopic stenting of dominant structure of the biliary may also be helpful.
PARASITES
Extrahepatic biliary obstruction has been seen with various parasitic infections such as Strongyloides, Ascaris, and liver flukes such as Clonorchis sinensis and Fasciola hepatica.
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