Protective mechanism
Risk factors compromising protective mechanism
Mechanical
Sphincter of Oddi
Sphincterotomy, biliary stents
Tight junction
Increased intrabiliary pressures
Bacteriostatic
Bile flow
Increased intrabiliary pressures
Bile mucus
Bile stasis
Bile salts
–
Immunologic
Kupffer cells
Increased intrabiliary pressures
Immunoglobulin
Increased intrabiliary pressures
Bacterial colonization (bactobilia ) most commonly occurs in an ascending manner from the small bowel and less frequently from hematogenous spread via the portal vein. Foreign bodies, such as stones and stents, in the biliary tree can serve as a nidus for bactobilia (Fig. 9.1). Biliary lithiasis , the most common cause of acute cholangitis in Western countries [6], acts both as a bacterial and an obstructive source [7, 8].
Fig. 9.1
(a) Proximally migrated plastic biliary stents causing biliary obstruction , resulting in cholangitis. (b) Migrated stents removed with a rat-toothed forceps. (c–e) Two plastic stents placed into the left intrahepatic duct beyond hilar stricture (arrow) followed by a fully covered self-expandable metal stent to anchor the plastic stents and prevent recurrent proximal migration. (f) Some distal migration of plastic stents noted at 4 months, although they still functioned well
Biliary stasis alone can lead to bacterial colonization and stone formation. Fibrocystic diseases of the liver, such as choledochal cysts (types I–V), are especially prone to developing biliary stasis (Fig. 9.2). The cyst wall is composed of dense fibrous tissue, with little or no muscle or elastic tissue, and is often without an epithelial lining.
Fig. 9.2
(a) Type 5 choledochal cyst (Caroli’s disease) involving segment 8 of the liver (arrow points to the cystic duct). (b) Multiple intrahepatic black pigment stones removed. Surgical resection of the affected liver segment was performed subsequently with resolution of recurrent bouts of cholangitis
Both benign and malignant strictures can increase the risk of developing acute cholangitis in the right setting. Malignant and benign strictures alone are infrequently the cause of cholangitis. However, these pathologies usually lead to interventions (e.g., contrast injection, stent placement), which can lead to bacterial infections (Fig. 9.3). Other risk factors that increase the susceptibility to cholangitis include advanced age (>70 years) and smoking [9].
Fig. 9.3
Patient with a prior orthotopic liver transplant on immunosuppression presenting with cholangitis after a recent ERCP. (a) Note prior pancreatic stent (small arrow) with purulence emerging from biliary sphincterotomy. (b) Anastomotic stenosis and proximal choledocholithiasis (arrow) at choledocho-choledochostomy. (c and d) Stone removal with extraction basket followed by 10 mm fully covered self-expandable metal stent placement (not shown) to treat the anastomotic stenosis
Bacteria have been isolated from gallstones to study their role in the pathogenesis of acute cholangitis. Organisms grown in culture from brown pigment stones are those commonly seen in cholangitis (enterococci—40 %, Escherichia coli—17 %, Klebsiella species—10 %) [10]. Escherichia coli is a coliform bacterium with external pili that facilitate adherence to foreign bodies, such as stones and stents. It is the most commonly isolated organism (25–50 %). Other coliform organisms include Klebsiella (15–20 %) and Enterobacter species (5–10 %) [10]. Enterococcal species are the most common gram-positive organisms identified (10–20 %). Anaerobic organisms, such as Bacteroides and Clostridia, are rare and usually seen in the setting of a mixed infection. These organisms are also more likely present in the setting of repeated infections and prior biliary surgery and among elderly patients (Table 9.2) [11]. Cultures from bile stones or occluded stents are positive in >90 % and are often polymicrobial relative to blood cultures obtained in patients with acute cholangitis [6, 12].
Table 9.2
Organisms associated with acute bacterial cholangitisa
Microorganism | Percent (%) |
|---|---|
Gram-negative organisms | |
Escherichia Coli | 25–50 |
Klebsiella spp. | 15–20 |
Enterobacter spp. | 5–10 |
Pseudomonas spp. | 0.5–19 |
Gram-positive organisms | |
Enterococcus spp. | 10–20 |
Streptococcus spp. | 2–10 |
Anaerobes | 4–20 |
Fungal | Rare |
Clinical Manifestations
The clinical presentation of acute bacterial cholangitis ranges from mild illness to septic shock. Fever is the most common clinical symptom, followed by right upper quadrant abdominal pain and jaundice (Table 9.3). However, the classic Charcot’s triad occurs in only 50–75 % of patients [6]. It is seen less frequently in the elderly and immunocompromised patients [13]. Hypotension and altered mental status occur in less than 14 % of patients and suggest suppurative cholangitis, which is associated with morbidity and mortality rates as high as 50 % [14]. The addition of hypotension and altered mental status to Charcot’s triad is known as Reynolds’ pentad.
Table 9.3
Clinical presentation of acute cholangitisa
Symptom | Percent | Syndrome |
|---|---|---|
Fever | 90 | Charcot’s triad involves first three |
Abdominal pain | 70 | |
Jaundice | 60 | |
Hypotension | 30 | Reynolds’ pentad involves all five |
Altered mental status | 20 |
Acute renal failure and intrahepatic abscesses are the two most common complications of cholangitis, with abscesses usually occurring later in the course of the disease [15]. The 30-day mortality of ineffectively treated patients with cholangitis approximates 10 % [16]. In a study assessing 449 episodes of cholangitis over 20 years, seven factors were found to independently predict mortality: acute renal failure, female gender, age, cholangitis associated with liver abscess or cirrhosis, and cholangitis secondary to high biliary strictures or after transhepatic cholangiography [17]. Further risk factors predicting complications and overall mortality are addressed below.
Diagnosis
Laboratory Tests
Laboratory results help distinguish a biliary source of sepsis from other causes. Eighty percent of patients will have a serum bilirubin greater than 2.0 mg/dL [18]. However, a normal bilirubin does not rule out acute cholangitis, especially early in the disease process. Eighty percent of patients will have an elevated white blood count (WBC), and, in those with a normal WBC, the peripheral blood smear usually reveals a “left” shift to immature neutrophils. A classic cholestatic pattern with elevations in the serum alkaline phosphatase from biliary origin is seen in the majority of patients. With increasing pressure to the biliary system, concomitant transaminase elevation is also observed. Rarely will the transaminase levels increase to 1000 IU/L as in the case of hepatic ischemia, drug-induced liver injury, or fulminant viral hepatitis. During an episode of acute cholangitis, the hepatic synthetic function is usually preserved, but repeated episodes of obstruction and cholangitis may eventually lead to chronic hepatic failure [19].
Pancreatic enzymes can be elevated in cases of biliary pancreatitis. Other nonspecific markers of inflammation, such as C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR), are also usually elevated.
Imaging
Transabdominal ultrasonography is a rapid, readily available, noninvasive first modality of choice that can quickly assess for biliary ductal dilation and choledocholithiasis. Its limitations include decreased image quality in the setting of large body habitus and decreased sensitivity with small stones and in non-dilated ducts.
Magnetic resonance cholangiopancreatography (MRCP) is more sensitive and specific than ultrasound for biliary dilation and choledocholithiasis and can provide a useful “road map” prior to endoscopic retrograde cholangiopancreatography (ERCP). This is especially important in patients with suspected intrahepatic biliary obstruction (i.e., fibrocystic diseases, primary sclerosing cholangitis (PSC), hilar and intrahepatic cholangiocarcinoma). In addition, MRCP can help evaluate for hepatic abscesses. In a recent meta-analysis, MRCP was shown to have excellent sensitivity and specificity for demonstrating the presence and level of biliary obstruction. It was, however, less sensitive at detecting choledocholithiasis and for differentiating benign from malignant obstruction when compared to endoscopic ultrasound (EUS) and ERCP [20]. In the presence of a dilated common bile duct (CBD), MRCP has 90–95 % concordance with ERCP in diagnosing CBD stones over 1 cm in diameter [21, 22]. In high-risk patients with low to moderate suspicion for cholangitis, MRCP can be very useful prior to proceeding to an ERCP. In the setting of obvious and severe cholangitis, however, a therapeutic ERCP with drainage of the obstruction should not be delayed.
Computerized tomographic (CT) scan of the abdomen does not have the same resolution in defining the anatomy of the biliary tree compared to MRCP, but is more often obtained due to wider availability and lower cost. In addition, a CT scan can evaluate for other diagnoses and associated complications, such as pancreatitis and liver abscesses. CT findings of papillitis and marked early inhomogeneous enhancement of the liver have been found to be associated with acute suppurative cholangitis [22].
EUS is valuable in diagnosing the cause of cholangitis in select cases. Two large meta-analyses have shown high sensitivities (89–94 %) and specificities (94–95 %) for EUS in detecting choledocholithiasis when compared to ERCP and intraoperative cholangiogram as the gold standard [23, 24]. Although EUS is a minimally invasive procedure that requires sedation, it can be performed prior to consideration of an ERCP and in the right clinical context to confirm passage of a CBD stone and, thus, avoid an unnecessary ERCP.
ERCP remains the gold standard for the diagnosis and management of acute cholangitis. With cross-sectional imaging modalities and ultrasound almost universally available, ERCP should be regarded as a therapeutic procedure. However, an ERCP could be the first step in the evaluation and treatment of cholangitis in the right clinical scenario, such as in patients with indwelling stents or established biliary obstruction.
Differential Diagnosis
The differential diagnosis includes liver abscess, cholecystitis, hepatolithiasis, biliary leaks, Mirizzi’s syndrome (which can cause cholangitis as well), severe pancreatitis, hepatitis, and right lower lobe pneumonia/empyema. Laboratory testing and imaging studies are helpful in sorting out these diagnoses from cholangitis. Cholecystitis can coexist with cholangitis and should be considered in patients who are not responding to definitive treatment of cholangitis.
Management
The management of cholangitis is based on two tenants: antibiotics and decompression of the biliary tree. In addition to antimicrobial therapy and biliary decompression, supportive measures in the form of fluid resuscitation, correction of coagulopathy, and close monitoring for evidence of sepsis are essential.
Classification of the Severity of Acute Cholangitis
The Tokyo Guidelines consist of a three-stage classification system to categorize patients with suspected acute cholangitis and determine management strategies (Table 9.4).
Table 9.4
Severity of acute cholangitis
Grade 1 (mild) | Grade 2 (moderate) | Grade 3 (severe) |
|---|---|---|
Any two of the following | Any organ dysfunction below | |
Does not meet any of | 1. WBC >12,000 or <4000 | 1. Cardiovascular dysfunction |
Grade 2 or grade 3 criteria | 2. Fever: T >39 °C | 2. Neurologic dysfunction |
3. Age >75 years | 3. Respiratory dysfunction | |
4. Total bilirubin >5 mg/dL | 4. Renal dysfunction | |
5. Albumin <2.8 g/dL | 5. Hepatic dysfunction | |
6. Hematological dysfunction |
Grade 1—mild acute cholangitis : a stable patient who is clinically diagnosed with acute cholangitis and does not meet criteria for grade 2 or 3.
Grade 2—moderate acute cholangitis : any two of the following criteria need to be fulfilled: WBC >12,000 or <4000, total bilirubin >5 mg/dL, albumin <2.8 g/dL, higher fevers (>39 °C), and older age (>75 years).
Grade 3—severe acute cholangitis : this involves end-organ dysfunction, such as cardiovascular dysfunction (e.g., hypotension), neurologic dysfunction (e.g., altered mental status), respiratory dysfunction (e.g., decreased oxygen saturation), renal dysfunction (e.g., elevated creatinine >2.0 mg/dL), and hepatic dysfunction (e.g., INR >1.5) [25, 26].
Antibiotics
Biliary and Blood Cultures
In suspected cholangitis, blood cultures are obtained, and empiric antibiotics are started prior to any biliary intervention. Cultures should also be obtained from bile and/or stents removed at ERCP since the yield for positive cultures is higher [26]. Biliary and blood culture results tailor the antibiotic regimen [11]. However, the clinical benefit of blood cultures has been questioned. In 2010, the Surgical Infection Society and the Infectious Diseases Society of America [27] have recommended against routine collection of blood cultures based on a large retrospective study showing only a 5 % true positivity for blood cultures, with most patients not requiring any change in antibiotic therapy despite the culture results. On the other hand, positive blood culture results would be useful in patients who are responding poorly to the initial choice of antibiotics. In our practice, we recommend the collection of blood cultures prior to the initiation of antibiotics and make every effort to obtain bile cultures as well. In patients who are responding to the initial antimicrobial regimen, there usually is no need to alter the antibiotics. However, in patients who fail to respond appropriately despite adequate biliary drainage, the culture results can help tailor the antibiotic regimen.
Antibiotic Regimens
There is no established consensus on the initial choice of antibiotics due to lack of prospective data [11, 12, 28]. Based on the known bacterial profile of cholangitis, the initial regimen selected should have adequate gram-negative coverage and biliary penetration. Intravenous antibiotics should be used initially in patients presenting with sepsis and/or severe cholangitis.
The choice of initial antimicrobial therapy should be based on local epidemiology and bacterial sensitivities. Beta-lactam-based monotherapies appear to be as effective as and less toxic than the combination of a beta-lactam antibiotic (ampicillin) and an aminoglycoside (gentamicin) [29]. Fluoroquinolones have excellent biliary penetration [12], and in a prospective randomized study, ciprofloxacin monotherapy was as effective as triple therapy with ceftazidime, ampicillin, and metronidazole [30]. Moxifloxacin has been shown to be safe and non-inferior to ceftriaxone plus metronidazole [31] as well as piperacillin/tazobactam followed by amoxicillin/clavulanic acid [32]. Other initial options include a fluoroquinolone with metronidazole, a beta-lactam/beta-lactamase inhibitor, a third-generation cephalosporin with or without metronidazole, and monotherapy with a carbapenem (Table 9.5). For patients with bilio-enteric anastomoses, elderly patients, and those with recurrent infections, one should consider anaerobic coverage upfront. In our practice, we initially start with a fluoroquinolone alone (levofloxacin 500 mg daily).
Table 9.5
Antimicrobial selection for acute cholangitis
