Laboratory Studies
Alkaline phosphatase
Alkaline phosphatase is a marker of cholestasis (ie, elevation of alkaline phosphatase occurs in more than 90% of patients with cholestasis) and suggests a reduction in bile flow. It also is elevated in infiltrative disorders or fungal infections of the liver, often quite strikingly, with levels above 1000 U/L.
Because isozymes are found in the liver, bone, placenta, leukocytes, and small intestine, an elevated alkaline phosphatase is not specific for the biliary tract. Although the source can be determined by measuring isozyme subtypes, these electrophoretic tests seldom are available clinically. A biliary source is inferred when the alkaline phosphatase is associated with an elevated gamma-glutamyl transpeptidase (GGT), 5'-nucleotidase, or leucine aminopeptidase.
An elevation of the hepatic alkaline phosphatase level involves an enzyme-induced secretory process, ie, it represents enzyme induction and accelerated de novo synthesis of alkaline phosphatase and backup into the circulation, not just a simple mechanical obstruction to flow. For this reason, an elevation of alkaline phosphatase may be delayed in the setting of acute obstruction.
Bilirubin
Bilirubin is a breakdown product of heme, with 80% coming from senescent red blood cells and 20% coming from cytochromes and myoglobin. Unconjugated bilirubin is hydrophobic and transported in the blood reversibly bound to albumen. It is taken up by the hepatocyte, converted to conjugated bilirubin by glucuronyl transferase, and actively secreted into the biliary canaliculi.
Aminotransferases
In addition to the liver, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are found in cardiac and skeletal muscles and renal and cerebral nerve cells. The ALT is found predominantly in the cytosol of the hepatocyte, and an elevated ALT is more likely to suggest liver injury. The AST has both cytosolic and mitochondrial forms. Elevated aminotransferase levels are observed with hepatocellular injury (eg, viral hepatitis), usually sustained over weeks. A rapid rise and fall may be observed in acute posthepatic biliary obstruction or transient hepatic ischemia.
Antimitochondrial antibodies
More than 95% of cases of primary biliary cholangitis are associated with positive test results for antimitochondrial antibodies (AMA). The antigen that reacts with AMA is part of the 2-oxo-acid dehydrogenase multienzyme complex in the mitochondria, especially the E2 subunit of pyruvate dehydrogenase, located on the inner mitochondrial membrane.
Miscellaneous immunologic markers
An emerging role for immune markers in inflammatory bowel disease may have implications in the diagnostic evaluation of cholestatic liver disease. Just as AMA is an immunologic marker of primary biliary cholangitis (PBC), two markers are used in the evaluation of patients with suspected inflammatory bowel disease and primary sclerosing cholangitis (PSC). These are antineutrophil cytoplasmic antibody (ANCA) and anti-Saccharomyces cerevisiae antibody (ASCA). ANCA is strongly associated with ulcerative colitis (79%) and PSC (82%). Although ASCA is associated with Crohn disease, currently, no association with PSC exists. Multispecific ANCA with anti-nuclear antibodies (ANA) and anti-smooth muscle antibody (ASMA) may be potential markers for PSC. [15]
Tumor markers
Findings from a 2018 study indicated detection of a combination of serum tumor markers carcinoembryonic antigen (CEA), cancer antigen (CA)-125, and CA-19-9 had the best clinical diagnostic value in patients with cholangiocarcinoma. [16] Optimal cutoff values were 2.85 U/mL for CEA, 23.85 U/mL for CA-125, and 46.75 U/mL for CA-19-9.
Imaging Studies
Ultrasonography
Ultrasonography uses technology similar to sonar. A two-dimensional image of echoes is created. Fluid appears black, solid organs appear hypoechoic, and structures with high amounts of fat or minimal water are hyperechoic.
Note that although ultrasonography is commonly used for the initial evaluation of patients with primary sclerosing cholangitis (PSC), it is not good at detecting small tumors in the heterogeneous liver. [12] However, contrast-enhanced ultrasonography can be useful for revealing cholangiocarcinoma by demonstrating rapid and marked washout. [12]
Right upper quadrant ultrasound
This is the principal study used to evaluate biliary-type pain and detect gallbladder disease and biliary dilatation. Gallstones appear as a highly echogenic focus with acoustic shadows and move to the dependent portion of the gallbladder. Right upper quadrant ultrasound can detect stones as small as 1-2 mm and has a sensitivity of 95% and a specificity of 97%. The presence of a thickened gallbladder wall, pericholecystic fluid, and a sonographic Murphy sign supports the diagnosis of cholecystitis. Because of interference by bowel gas, ultrasound does not reveal the common bile duct well, and ultrasound may miss 25%-40% of bile duct stones.
Endoscopic ultrasonography (EUS)
By placing a higher-frequency transducer into the gut adjacent to the hepatobiliary tract, endoscopic ultrasound provides more detailed images than a transcutaneous approach. Although no major advantage to examining the gallbladder exists, EUS can be used to detect intraductal stones with a sensitivity of 88%-97% and specificity of 97%. It also can be used to assess adjacent structures, such as porta hepatis nodes; malignancy is suggested by the presence of large (>1 cm), round, sharply demarcated hypoechoic nodes. By better defining the local anatomy of the ampullary tumors in relation to neighboring structures, information obtained with EUS can help guide the physician's selection of an appropriate intervention.
Abdominal computed tomography (CT) scanning
This imaging study usually is not very helpful in evaluating the biliary system. It may demonstrate dilated bile ducts and reveal the cause of a biliary obstruction. Relatively recent technologic advances, such as thin-section helical CT scanning, have increased the sensitivity for detection of bile duct stones from 60% to 90%.
Cholangiography
Both endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) provide images of the biliary ductal system, which has an appearance similar to a deciduous tree in the wintertime. ERCP is an invasive endoscopic procedure in which radiopaque contrast is injected into the biliary ductal system under fluoroscopic guidance. MRCP is a noninvasive procedure that relies on heavily T2-weighted images to create an image of the fluid within the biliary and pancreatic ductal system. MRCP combined with magnetic resonance imaging (MRI) is able to demonstrate focal biliary anomalies and subtle liver lesions. [12]
Choledocholithiasis
On a cholangiogram, stones within the bile ducts appear as filling defects within the trunk or branches of the biliary tree. Depending on the type of stone and duration of the illness, they may be single or multiple, round or faceted, free-floating or adherent.
Primary sclerosing cholangitis
In PSC, the bile ducts are characterized by strictures and ectatic areas in an irregular, diffuse pattern. In some cases, the duct may resemble a string of beads due to alternating annular bandlike strictures separating areas of cholangiectasia. Diverticular outpouchings occur in 10% of cases and are observed exclusively in PSC, not cholangiocarcinoma. Specific radiologic patterns (ie, diffuse involvement versus intrahepatic versus extrahepatic) are not associated with differences in median survival.
Hepatobiliary scintigraphy
This test should be ordered when acute cholecystitis is suspected. Nonvisualization of the gallbladder supports the diagnosis of acute calculous cholecystitis with a sensitivity of 92%-98% and a specificity of 95%-98%. It also is used to confirm the presence of a biliary leak.
Although controversial, hepatobiliary scintigraphy occasionally is helpful in diagnosing chronic cholecystitis or gallbladder dyskinesia in patients with biliary-type pain and normal findings on right upper quadrant ultrasound. The test employs a 45-minute infusion of cholecystokinin (CCK) octapeptide to measure the gallbladder ejection fraction; values lower than 35% are considered abnormal. In some patients, an abnormal gallbladder ejection fraction may be associated with sphincter of Oddi dysfunction.
Staging
Hepatobiliary histology has emerged as an objective reference for staging primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In both, 4 stages are identified.
Primary sclerosing cholangitis
In PSC, stage 1 is characterized by portal tracts that are enlarged by edema, increased connective tissue, and proliferation of interlobular bile ducts. Periductal inflammation and fibrosis characterize stage 2. Connective tissue begins to encroach into the periportal parenchyma, and a fibrous-obliterative cholangitis is present. Stage 3 is defined by a discernible loss of interlobular bile ducts, and stage 4 is reached when cirrhosis is present.
Primary biliary cholangitis
In PBC, stage 1 is characterized by dramatic evidence of asymmetric destruction of septal and interlobular bile ducts by a mononuclear infiltrate (the typical appearance is referred to as a florid duct lesion). Occasionally, hepatic granulomas are observed. Diffuse periportal inflammation characterizes stage 2 and is accompanied by portal fibrosis, periportal liver cell necrosis, patchy ductopenia, and ductular proliferation. Stage 3 is defined by the presence of bridging fibrosis, and stage 4 is reached when cirrhosis is present.
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A normal postcholecystectomy cholangiogram.
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Biliary disease. In a patient with persistent elevation of liver-associated enzymes, the contrast medium entering the biliary ductal system preferentially enters the cystic duct.
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Biliary disease. Even when the catheter is advanced to the proximal common hepatic duct, contrast dye preferentially fills the cystic duct and gallbladder rather than allowing visualization of the intrahepatic ductal system (same patient as in previous image).
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Biliary disease. In this image, the common bile duct is occluded with a balloon-tipped catheter. Contrast material fills the intrahepatic ductal system to reveal diffuse intrahepatic sclerosing cholangitis.
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Biliary disease. Common bile duct stones are among the most frequent problems occurring in the biliary system. In this cholangiogram, the stones line up like peas in a pod.
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Biliary disease. After a biliary sphincterotomy, a balloon-tipped catheter is used to remove the stones one by one.
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Biliary disease. This clearing cholangiogram shows a common bile duct free of filling defects and good flow into the duodenum. The stones are visible as filling defects in the duodenal bulb.
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Biliary disease. A patient with pancreatic cancer developed jaundice during his treatment. The cholangiogram shows a stricture in the distal common bile duct.
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Biliary disease. A patient with pancreatic cancer developed jaundice during his treatment (same patient as in previous image). To palliate the jaundice, the biliary stricture is dilated and stented with a 10F plastic stent. Note the contrast dye flowing down the stent.
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Biliary disease. This computed tomography scan of the abdomen shows a large tumor mass in the head of the pancreas. The brightly colored object within the mass is the biliary stent placed by endoscopic retrograde cholangiopancreatography.
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Biliary disease. This abdominal computed tomography scan shows mild intrahepatic biliary ductal dilatation.
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Biliary disease. Abdominal computed tomography scanning in a patient with jaundice revealed polycystic liver disease.
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Biliary disease. Findings on this endoscopic retrograde cholangiopancreatogram exclude extrahepatic biliary obstruction but demonstrate that the intrahepatic biliary ductal system is splayed by multiple hepatic cysts.
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Biliary disease. This cholangiogram shows a choledochal cyst. Fusiform dilatation of the entire extrahepatic bile duct is present.
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A 92-year-old woman had recurrent abdominal pain and jaundice. A right upper quadrant ultrasonogram showed a dilated biliary duct with no stones. She had a previous Roux-en-Y surgery that made endoscopic retrograde cholangiopancreatography impossible. Critical aortic stenosis increased the risk of most interventions. This percutaneous cholangiogram, performed under conscious sedation in the operating room, revealed a large stone missed by the ultrasonogram. It was removed successfully with percutaneous choledochoscopy and electrohydraulic lithotripsy.
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Biliary disease. This cholangiogram shows a stone too large to deliver through a standard biliary sphincterotomy.
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Biliary disease. Here, a mechanical lithotripter is used to grab a stone too large to deliver through a standard biliary sphincterotomy and crush it into small pieces (same patient as in previous image). The smaller pieces then are removed with a balloon-tipped catheter.
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Biliary disease. A patient had malignant strictures of the biliary system palliated with metal mesh stents. Unfortunately, the tumor grew through the metal mesh to reobstruct the biliary system.
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Biliary disease. A patient had malignant strictures of the biliary system that were palliated with metal mesh stents, but the tumor grew through the metal mesh to reobstruct the biliary system (same patient as in previous image). In this image, after a wire was passed through the lumen, a balloon-dilating catheter was passed into the metal mesh stents and inflated to enlarge the lumen.
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Biliary disease. A patient had malignant strictures of the biliary system that were palliated with metal mesh stents, but the tumor grew through the metal mesh to reobstruct the biliary system (same patient as in previous image). After a wire was passed through the lumen, a balloon-dilating catheter was passed into the metal mesh stents and inflated to enlarge the lumen. In this image, two plastic stents were passed into the intrahepatic ductal system to again palliate the obstruction.
