What is cholangitis, including its definition, types, diagnostic criteria, treatment options, and differential diagnosis?

Cholangitis: Definition, Types, Diagnosis, Treatment and Differential Diagnosis

Definition

Cholangitis is a bacterial infection of the biliary ductal system that results from the combination of bacterial colonization and biliary obstruction, leading to regurgitation of infected bile into the systemic circulation. 1, 2

• The pathogenic mechanism requires two essential components: presence of microorganisms in bile (bactibilia) and increased biliary pressure from obstruction 2, 3
• The infection can range from mild, self-limiting disease to life-threatening septic shock with mortality rates historically between 11-27% in severe cases 4

Types of Cholangitis

Acute Bacterial Cholangitis (Ascending Cholangitis)

Acute bacterial cholangitis is the most common form, typically caused by biliary obstruction from choledocholithiasis, benign strictures, or malignant obstruction. 1, 4

• Common bacterial pathogens include: E. coli, Klebsiella species, Enterococcus, Enterobacter, and Pseudomonas, with anaerobes (including Bacteroides fragilis) recovered in 15-30% of patients 2
• Infections are frequently polymicrobial 3
• Patients with indwelling biliary tubes or prior instrumentation may harbor resistant organisms including Enterobacter, Pseudomonas species, and yeasts 2

Primary Sclerosing Cholangitis (PSC)

• PSC is a chronic immune-mediated cholestatic liver disease characterized by progressive inflammation and fibrosis of intra- and extra-hepatic bile ducts, resulting in multifocal strictures and eventual cirrhosis 5
• Strongly associated with inflammatory bowel disease (up to 80% of patients have concurrent IBD, most often ulcerative colitis) 5, 6
• Bacterial cholangitis is an important complication of PSC, occurring in 13% of patients and usually associated with high-grade biliary strictures 7

IgG4-Associated Cholangitis (IAC)

• A recently characterized form commonly encountered along with autoimmune pancreatitis 6
• Responds favorably to immunosuppressive therapy, particularly corticosteroids 5
• Serum IgG4 measurement is recommended to exclude this diagnosis 5

Secondary Cholangitis

• Results from iatrogenic introduction of bacteria during biliary procedures, most commonly endoscopic retrograde cholangiopancreatography (ERCP) in patients with biliary obstruction 1
• ERCP (especially with stenting) is a major risk factor for bacterial cholangitis 7

Diagnosis

Clinical Presentation

The classic Charcot triad consists of fever, right upper quadrant abdominal pain, and jaundice, though this complete triad is now seen less frequently (especially in patients with indwelling tubes or after biliary manipulation). 8, 2

• Fever and/or chills are the most common presenting symptom 8
• Right upper quadrant or epigastric abdominal pain is a key component 8
• Jaundice indicates biliary obstruction 8
• Reynolds pentad (Charcot triad plus hypotension and altered mental status) indicates severe disease with septic shock 4

Important caveat: In PSC-related cholangitis, signs can be mild and nonspecific, with patients sometimes presenting without significant change in baseline liver biochemistry, as infections may be limited to smaller ducts 7

Diagnostic Criteria

For acute bacterial cholangitis in general populations, use clinical presentation plus laboratory and imaging findings. 8, 4

For PSC-specific cholangitis, recently proposed criteria require either:

• Single criterion: Suppurative cholangitis on ERCP, OR
• At least 1 major criterion (temperature >38°C, leukocyte count >12/nL, or CRP >75 mg/L) PLUS at least 2 minor criteria (positive bile culture, increase in ALP or total bilirubin above 2x ULN, no other focus of infection) 7

Note: In milder PSC cases, response to antibiotics often confirms the clinically suspected diagnosis retrospectively 7

Laboratory Evaluation

Cholestatic biochemical pattern is the hallmark: 8

• Elevated alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (GGT) 8
• Elevated serum bilirubin (direct and indirect) 8
• Elevated AST and ALT (usually 2-3 times upper limit of normal in PSC) 5, 8
• Leukocytosis is common 2
• In critically ill patients, elevated CRP, procalcitonin, and lactate help evaluate severity 8

Blood cultures should be obtained before antibiotic administration whenever feasible, but do not delay antibiotics 8

Imaging Studies

Abdominal ultrasound should be the initial imaging modality to assess for biliary obstruction, looking for bile duct dilation >6 mm, gallstones, and gallbladder abnormalities. 8

• Ultrasound has high diagnostic accuracy for demonstrating biliary dilatation, though sensitivity for CBD stone detection is only 25-63% 7
• Abdominal triphasic CT is recommended as first-line diagnostic imaging in acute settings to detect intra-abdominal fluid collections and ductal dilation 8
• Contrast-enhanced MRCP provides exact visualization, localization, and classification of biliary obstruction with >90% accuracy for CBD stones 7, 8
• Endoscopic ultrasound (EUS) has aggregated sensitivity of 93% and specificity of 96% for CBD stone detection, superior to MRCP (sensitivity 85%, specificity 93%) 7
• For PSC diagnosis, MRCP or direct cholangiography (ERCP) is recommended to visualize characteristic multifocal strictures 5

Severity Assessment

Grade III (Severe): Presence of organ dysfunction (hypotension despite fluids, altered mental status, acute kidney injury, coagulopathy) 7, 8

Grade II (Moderate): Risk of increased severity without early biliary drainage 7

Grade I (Mild): Responds to medical management alone 7

Treatment

Antibiotic Therapy

Broad-spectrum antibiotic therapy should be initiated within 1 hour for septic patients and within 6 hours for less severe cases. 8

For non-critically ill, immunocompetent patients:

• Amoxicillin/Clavulanate 2g/0.2g every 8 hours 8

For beta-lactam allergy:

• Eravacycline 1 mg/kg every 12 hours OR Tigecycline 100 mg loading dose then 50 mg every 12 hours 8

For critically ill or immunocompromised patients:

• Piperacillin/tazobactam 6g/0.75g loading dose then 4g/0.5g every 6 hours or 16g/2g by continuous infusion 8

Duration of antibiotic therapy:

• With successful biliary drainage, 3 days of antibiotics is equivalent to 5 days 7
• In the presence of residual stones or ongoing obstruction, extend antimicrobial treatment until anatomical resolution 7

For PSC-related cholangitis:

• Antibiotics should be used routinely during ERCP procedures 7

Biliary Drainage

Endoscopic transpapillary biliary drainage (ERCP) is the first-line procedure for biliary decompression, as it is safer and more effective than percutaneous or surgical approaches. 8

• Early biliary drainage within 24 hours is necessary for moderate cholangitis 8
• Urgent biliary decompression is required for severe cholangitis 8
• Percutaneous transhepatic biliary drainage should be reserved for cases where endoscopic approaches fail or are not feasible 8
• Only 5-10% of patients with toxic cholangitis require emergency biliary decompression 2

For PSC with dominant strictures:

• Biliary decompression via ERCP is indicated if an underlying relevant stricture is present 7
• An episode of acute bacterial cholangitis should prompt imaging/MRCP studies to assess for flow-limiting biliary strictures 7

Supportive Care

Initial management includes: 2

• Bowel rest
• Intravenous fluid resuscitation
• Correction of electrolyte abnormalities (particularly hypokalemia, which increases arrhythmia risk) 8

For septic shock:

• Give at least 20 mL/kg crystalloid immediately (≈1.4L for 70kg adult), repeat as needed, targeting systolic BP >90 mmHg 8
• If hypotension persists after cumulative 30 mL/kg fluid challenge, start norepinephrine to maintain mean arterial pressure ≥65 mmHg 8

Definitive Treatment

After resolution of sepsis, definitive treatment depends on the underlying cause: 8

• Choledocholithiasis: Stone extraction via ERCP
• Benign strictures: Balloon dilatation, stenting
• Malignant obstruction: Palliative stenting or surgical bypass
• PSC with dominant strictures: Endoscopic dilatation ± short-term stenting

For IgG4-associated cholangitis specifically, immunosuppressive therapy with corticosteroids is the treatment of choice 5, 6

Differential Diagnosis

Hepatobiliary Conditions

Acute cholecystitis:

• Fever, right upper quadrant pain, but typically without jaundice unless Mirizzi syndrome present
• Ultrasound shows gallbladder wall thickening, pericholecystic fluid, positive sonographic Murphy sign 8

Hepatic abscess:

• Fever, right upper quadrant pain, elevated inflammatory markers
• CT or ultrasound shows focal hepatic lesion with rim enhancement
• May complicate severe cholangitis 8

Acute hepatitis:

• Jaundice with predominantly elevated transaminases (often >10x ULN)
• ALP elevation is less prominent than in cholangitis
• Viral serologies, autoimmune markers, drug history help differentiate

Biliary Obstruction Without Infection

Choledocholithiasis without cholangitis:

• Biliary colic, jaundice, elevated bilirubin and ALP
• Absence of fever, normal white blood cell count
• Still requires biliary drainage but less urgency

Malignant biliary obstruction:

• Progressive painless jaundice (classically)
• Weight loss, cachexia
• Imaging shows mass lesion
• In PSC, approximately 10-15% develop cholangiocarcinoma, most often presenting as perihilar stenotic lesion 5

Pancreatic Conditions

Acute pancreatitis:

• Epigastric pain radiating to back
• Elevated lipase and amylase (>3x ULN)
• May have mild cholestatic pattern if gallstone pancreatitis
• CT shows pancreatic inflammation

IgG4-related disease:

• Can present with cholangitis-like picture
• Measure serum IgG4 levels to exclude this diagnosis 5
• Commonly associated with autoimmune pancreatitis 6

Infectious Conditions

Liver abscess (pyogenic or amebic):

• Fever, right upper quadrant pain
• Imaging shows focal hepatic collection
• May have similar laboratory findings but distinct imaging

Parasitic cholangitis:

• Endemic areas: Ascaris lumbricoides, Clonorchis sinensis, Opisthorchis species, Fasciola hepatica 3
• Parasites cause obstruction, introduce bacteria, induce stone formation 3
• Eosinophilia may be present
• Imaging or ERCP may visualize parasites

Sepsis from other source:

• Fever, leukocytosis, hypotension
• Absence of cholestatic biochemical pattern
• Imaging does not show biliary pathology

Chronic Cholestatic Conditions

Primary biliary cholangitis (PBC):

• Chronic cholestatic disease predominantly affecting small intrahepatic bile ducts
• Positive anti-mitochondrial antibodies (95%)
• Gradual onset, predominantly middle-aged women
• MRCP shows normal large bile ducts

Primary sclerosing cholangitis (PSC) without acute cholangitis:

• Chronic progressive cholestasis
• Multifocal strictures on MRCP
• May be asymptomatic or have pruritus, fatigue
• Absence of acute fever, sepsis

Important Pitfalls to Avoid

Do not delay antibiotics waiting for imaging or cultures - initiate empiric therapy immediately in suspected cholangitis 8

Do not assume complete Charcot triad is required - many patients (especially with indwelling tubes or PSC) present with incomplete or atypical features 7, 2

Do not overlook drug-induced reactions in critically ill patients - lip and cheek excoriations may represent Stevens-Johnson syndrome/toxic epidermal necrolysis; obtain drug exposure history 8

Do not forget to assess for PSC in patients with inflammatory bowel disease presenting with cholangitis - up to 80% of PSC patients have concurrent IBD 5

Do not use standard Tokyo criteria rigidly in PSC patients - PSC-related cholangitis may present with milder, more nonspecific signs 7

Monitor for complications after treatment: hepatic abscess, recurrent cholangitis, pancreatitis, and acute kidney injury 8