Anabolic steroids, estrogens
Amoxicillin–clavulanic acid
Azathioprine
Cetirizine
Chlorpromazine
Cyclosporin
Dapsone
Diltiazem
Erythromycin
Fenofibrate
Floxuridine
Gold salts
Infliximab
Itraconazole
Metolazone
Nitrofurantoin
Oral contraceptives
Phenytoin
Rifampicin
Trimethoprim–sulfamethoxazole
5-Fluorouracil or floxuridine
A history of fever, especially when accompanied by rigors or right upper quadrant abdominal pain, may be suggestive of cholangitis. Cholangitis may develop in patients with obstructive processes such as choledocholithiasis or biliary tract strictures. These symptoms may be seen in alcoholic disease and rarely in the setting of viral hepatitis as well [1]. Recent surgery in the region of the biliary system may have resulted in an inadvertent injury to a bile duct and should also be considered as a possible cause. This type of trauma may lead to the development of secondary sclerosing cholangitis.
The differential diagnosis beyond medicines includes the most common cause of extrahepatic cholestasis which is choledocholithiasis [7, 8]. In the setting of cholelithiasis, it is estimated that up to 20 % of patients will develop choledocholithiasis [9]. Other causes to consider include extra-biliary tumors, cysts, parasites, and lymphoma (Table 1.2). Once cholestasis is confirmed, imaging is useful at defining the source of obstruction.
Table 1.2
Causes of extrahepatic biliary obstruction
Intraductal obstruction |
Choledocholithiasis |
Benign bile duct tumors (rare) |
Bile duct strictures including those from IgG4 related disease cholangiocarcinoma |
Cysts |
AIDS cholangiopathy |
Parasites |
Extrinsic compression |
Extra-biliary tumors |
Lymphoma |
Acute and chronic pancreatitis |
Imaging
Ultrasound
Abdominal ultrasound (US) is often the initial imaging performed when evaluating cholestasis. Advantages of US include relatively low cost, wide availability, noninvasive nature, and the absence of radiation. Ultrasound can effectively evaluate for intrahepatic and extrahepatic bile duct dilation and the presence of mass lesions; however, operator variability can be an issue. Ultrasound is highly dependent on the skill of the sonographer and the experience of the interpreter. In addition, technical limitations include the inability to penetrate bone, as well as the risk of excess abdominal adipose tissue or bowel gas obstructing the view. Ultrasound can differentiate between intrahepatic and extrahepatic causes of biliary tract disease, however, and can readily identify gallbladder pathology particularly when the patient is fasting [10, 11]. In cases of obstructive jaundice, the sensitivity and specificity of US may exceed 80 % [12]. US may not be reliable, however, at detecting choledocholithiasis [13]. Use of US as an initial evaluation is reasonable although additional diagnostics may be necessary.
Computed Tomography
Computed tomography (CT) is less operator dependent than US, more effective when imaging obese patients, and is less susceptible to bowel gas when evaluating the distal bile ducts. Computed tomography is more accurate than US at identifying the level (88–97 % vs. 23–95 %) as well as the cause (70–94 % vs. 38–94 %) of biliary obstruction if present [14]. It is not as able to identify choledocholithiasis, however, and exposes the patient to radiation [15]. Computed tomography is therefore reserved for equivocal US findings rather than for first-line imaging.
Magnetic Resonance Imaging/Cholangiopancreatography
MRI is useful in the diagnosis of chronic versus acute etiologies of cholestasis. Use of magnetic resonance cholangiopancreatogram (MRCP) is considered a safe, noninvasive tool for evaluating the biliary tree and hepatic parenchyma. Advantages include the lack of ionizing radiation and sharp contrast resolution between normal and abnormal tissues. The accuracy of MRCP in evaluating the bile ducts is comparable to endoscopic cholangiography. In fact, a review of 67 studies found MRCP sensitivity and specificity to diagnose biliary obstruction to be 95 % and 97 % respectively [16, 17]. As the bile ducts are visualized in their normal physiologic state, MRCP may be a better indicator than endoscopic cholangiogram when assessing true caliber of the bile ducts. The sensitivity for biliary strictures is, however, lower [17]. In addition, MRCP has limited specificity for the diagnosis of malignant strictures [18]. Although stenosis may be identified, direct visualization of the bile duct narrowing is not possible by MRCP. Further disadvantages include the relatively high cost, inability to perform on patients with implanted metallic devices, and the potential for suboptimal images due to motion-related artifacts.
CT Cholangiography
For patients who are unable to undergo MRI, CT cholangiography may be an option. Multidetector helical CT imaging allows for evaluation of the biliary tree more rapidly than MRCP. The study requires use of oral or intravenous contrast. Early studies suggest the accuracy is similar to MRCP [8].
Endoscopic and Percutaneous Assessment
Extrahepatic causes of chronic cholestatic liver disease should be excluded early as they are potentially reversible and failure to do so may result in complications such as recurrent cholangitis or secondary biliary cirrhosis. When suspicion is high or signs on cross-sectional imaging point to mechanical obstruction, direct cholangiography either endoscopically or percutaneously may be necessary. The primary advantage of direct cholangiography, as with endoscopic retrograde cholangiography (ERC) or PTC, is the ability to diagnose and intervene therapeutically when indicated.
Endoscopic Retrograde Cholangiography
ERC is the “gold standard” for diagnosing PSC. The procedure involves cannulation of the ampulla of Vater (the opening where the common bile duct and pancreatic duct meet the duodenum) followed by the injection of contrast to opacify the biliary tree. The combination of endoscopy and fluoroscopy allows the clinician to evaluate for the presence of stones or blockage of the bile duct. Many patients will undergo sphincterotomy by cutting the Sphincter of Oddi, the muscular ring at the ampulla, during the first ERC. When indicated, this may allow for improved access for stone extraction in the setting of choledocholithiasis or treatment of a biliary stricture with balloon dilation or an expandable stent. In patients with obstructive jaundice, ERC can effectively identify the location in 92–99 % and may identify the cause in 75–87 % of cases [19].
Percutaneous Transhepatic Cholangiography
PTC allows for radiographic assessment of the biliary tree and for interventions such as bile duct dilation, intraductal biopsy, and stone removal. The procedure involves transhepatic insertion of a needle into a bile duct after which X-rays are obtained. The test should be reserved for patients in whom ERC is precluded for anatomic reasons and when need for therapeutic intervention is evident. When the intrahepatic bile ducts are dilated, this technique tends to work well. The complication rate increases in patients with small, non-dilated ducts due to the frequent need for multiple attempts at cannulation of the bile ducts [22]. Bacteremia is also a concern, although the risk is low [23].
Endoscopic Ultrasound
EUS is a highly reliable method of detecting extrahepatic sources of bile duct obstruction. The procedure is performed by passing the endoscope with the transducer into the first or second part of the duodenum. From this position, evaluation of the biliary tree, pancreas, and surrounding structures can be performed. If concerning, fine needle aspiration may be performed at the time of the procedure. The ultrasound probe can be used to assess for stones within the common bile duct.
Use of EUS in one study demonstrated 98 % sensitivity and 99 % specificity in the setting of choledocholithiasis. In this study, 46 % of the patients were able to avoid more invasive testing as a result of undergoing EUS [24]. In another study of patients with suspected choledocholithiasis, 67.1 % of patients were able to avoid ERC after EUS revealed no evidence of stones [25]. A benefit of EUS is avoidance of sphincterotomy and more invasive procedures if indeed choledocholithiasis is suspected but ultimately not identified [26]. Limitations include the inability to intervene therapeutically if indicated.
Many of the conditions in the differential diagnosis may be excluded by history, laboratory tests, and imaging studies. A liver biopsy may be useful when suspecting unusual conditions such as autoimmune cholangitis, overlap syndromes, or in patients with suspected sarcoidosis.
Intrahepatic Causes of Cholestasis
The most common diseases that cause intrahepatic cholestasis include immune-mediated diseases such as PBC, PSC, and sarcoidosis (Table 1.3). Hepatocellular diseases which may cause intrahepatic cholestatic liver disease include viral hepatitis B and C. Hepatitis C has been associated with chronic cholestasis although the usual biochemical abnormalities reflect hepatocellular damage. Alcoholic hepatitis may present with clinical and biochemical features of cholestatic liver disease. This type of hepatocellular disease may also coexist with other liver diseases, so a detailed history is imperative.
Table 1.3
Causes of intrahepatic cholestasis
Immune mediated disease |
Primary biliary cirrhosis |
Primary sclerosing cholangitis |
Sarcoidosis |
Hepatocellular disease |
Alcoholic hepatitis |
Autoimmune hepatitis |
Hepatitis B |
Hepatitis C |
Other causes |
Drug induced cholestasis |
Idiopathic adult ductopenia |
Benign recurrent intrahepatic cholestasis |
Cystic fibrosis |
Sepsis |
Sickle cell disease |
Total parenteral nutrition |
The most common cause of chronic intrahepatic cholestatic liver disease in adults is PBC [27]. PBC is a chronic, inflammatory autoimmune liver disease that affects the cholangiocytes of the interlobular bile ducts. It is estimated that in the USA the prevalence of PBC is about 150–400 cases per million individuals. PBC may have a very long natural history. The presence of antimitochondrial antibodies is noted in over 95 % of PBC patients and is helpful in making the diagnosis. Presence of a positive antimitochondrial antibody (AMA) in a woman with cholestasis is essentially diagnostic of PBC. The specificity of AMA for PBC is 95 % [28]. Over 80 % of patients with PBC are female. The terms autoimmune cholangitis and “AMA negative PBC” have been used for patients who have clinical and histologic features of PBC but are AMA negative. These patients are generally positive for antinuclear or anti-smooth muscle antibodies. Autoimmune cholangitis and PBC appear to be part of a disease spectrum with very similar clinical and histologic features and a similar response to therapy. Liver biopsy is helpful in confirmation of this disease, but in patients who have prominent cholestatic liver biochemistries and a strongly positive AMA, the diagnosis of PBC is highly likely and liver biopsy is usually unnecessary.
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