What are the primary antibodies associated with primary sclerosing cholangitis (PSC)?

Antibodies in Primary Sclerosing Cholangitis

No autoantibodies are diagnostic of PSC, and routine autoantibody screening is not required to establish the diagnosis. 1

Most Commonly Detected Autoantibodies

While PSC patients frequently produce autoantibodies indicating altered immune responsiveness, these lack diagnostic specificity and are present at low prevalence rates and relatively low titers 1:

Perinuclear Antineutrophil Cytoplasmic Antibody (pANCA)

• Most frequently detected antibody in PSC, present in 26-94% of patients (most studies report 65-80%) 1, 2, 3
• The pANCA pattern in PSC is "atypical" because the putative antigen is located in the nucleus rather than the cytoplasm 1
• Not specific for PSC - also frequently present in ulcerative colitis and autoimmune hepatitis 1
• May draw attention to colon involvement in a cholestatic syndrome but has no role in routine diagnosis 1
• Higher titers (positive at 1:50 dilution) are more common in PSC with IBD (54%) compared to UC alone (25%) 4

Antinuclear Antibodies (ANA)

• Present in 8-77% of PSC patients 1
• Completely non-specific and unrelated to disease activity or prognosis 1
• Clinical significance: When positive with markedly elevated transaminases and high IgG levels, should prompt liver biopsy to evaluate for PSC-autoimmune hepatitis overlap syndrome 1, 5

Smooth Muscle Antibodies (SMA)

• Present in 0-83% of PSC patients 1
• Non-specific, similar to ANA 1
• Clinical significance: Positive SMA combined with elevated transaminases and IgG may indicate PSC-AIH overlap requiring liver biopsy 1, 5

Critical Antibodies to Exclude Alternative Diagnoses

Anti-Mitochondrial Antibodies (AMA)

• Characteristically absent in PSC - AMA is pathognomonic for primary biliary cholangitis, not PSC 5, 6
• If AMA is positive in a patient with cholangiographic findings of PSC, this strongly suggests PSC-PBC overlap syndrome requiring liver biopsy and consideration of ursodeoxycholic acid therapy 5

Essential Testing to Perform

You must measure serum IgG4 levels in every patient with suspected PSC at diagnosis to exclude IgG4-related cholangitis (IgG4-SC), which can mimic PSC on imaging but responds to corticosteroid therapy 1, 5, 6:

• Approximately 9-22% of patients initially diagnosed with PSC have elevated IgG4 levels 1
• Some of these cases may actually represent IgG4-associated cholangitis rather than true PSC 1
• Elevated IgG4 in confirmed PSC cases has been associated with more aggressive disease and faster progression to transplantation in some studies 1

Immunoglobulin Patterns

• IgG is modestly elevated (up to 1.5 times upper limit of normal) in approximately 60% of PSC patients 1
• Markedly elevated IgG (not just modest elevation) combined with positive ANA/SMA should raise suspicion for PSC-AIH overlap 1, 5
• IgM levels are elevated in up to 45% of cases 1

Clinical Bottom Line

Autoantibodies should not be used to diagnose or risk-stratify people with PSC 5. The diagnosis of PSC relies on cholestatic liver biochemistry with typical cholangiographic features (multifocal bile duct strictures on MRCP or ERCP) in the absence of secondary causes of sclerosing cholangitis 1. Autoantibody testing serves primarily to identify overlap syndromes (PSC-AIH if ANA/SMA positive with high IgG and elevated transaminases; PSC-PBC if AMA positive) and to exclude IgG4-related cholangitis 1, 5.