What blood work is recommended for diagnosing and managing autoimmune liver diseases, such as autoimmune hepatitis, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC)?

Blood Work for Autoimmune Liver Diseases

For suspected autoimmune liver disease, obtain a comprehensive panel including: liver biochemistry (AST, ALT, ALP, GGT, bilirubin, albumin, INR, platelets), immunoglobulins (total IgG and IgG4), and autoantibodies (ANA, SMA, anti-LKM1, anti-LC1, AMA, and atypical pANCA), with additional testing for HIV and viral hepatitis to exclude alternative diagnoses. 1

Initial Liver Biochemistry Panel

Standard liver function tests are essential for all suspected autoimmune liver diseases and provide diagnostic and prognostic information:

• AST and ALT: Elevated in autoimmune hepatitis (AIH), often mildly elevated in primary sclerosing cholangitis (PSC); an AST>ALT ratio suggests cirrhosis and poor prognosis 1
• Alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT): Characteristically elevated in cholestatic diseases (PSC and primary biliary cholangitis); ALP is abnormal in approximately 75% of PSC patients 1
• Bilirubin: Elevated in 28-40% of PSC patients and serves as a marker of poor prognosis 1
• ALP:AST ratio: A ratio <1.5 supports AIH diagnosis, while >3 argues against AIH 1, 2

Synthetic function and portal hypertension markers assess disease severity:

• INR/prothrombin time, albumin, and platelet count: Indicators of cirrhosis or portal hypertension 1

Immunoglobulin Testing

Serum immunoglobulin levels differentiate between autoimmune liver diseases:

• Total IgG or gamma-globulin: Characteristically elevated in AIH (though normal in 10% of European patients and 25-39% of acute presentations); essential for AIH diagnostic scoring 1, 2
• IgG4 levels: Must be measured in all patients with suspected PSC to exclude IgG4-associated sclerosing cholangitis, which responds to corticosteroids; elevated IgG4 may indicate more aggressive PSC or misdiagnosis 1, 3

Autoantibody Panel

For Autoimmune Hepatitis

Type 1 AIH markers (present in 96% of North American adults):

• Antinuclear antibodies (ANA): Detected in 80% of white North American adults with AIH at presentation 1, 2
• Smooth muscle antibodies (SMA): Present in 63% of AIH patients; diagnostic accuracy improves from 58% to 74% when both ANA and SMA are detected 1, 2

Type 2 AIH markers (more common in European patients and children):

• Anti-liver kidney microsome type 1 (anti-LKM1): Present in 3% of North American adults but more frequent in Europeans; characterizes type 2 AIH 1, 2
• Anti-liver cytosol type 1 (anti-LC1): Present in 30% of type 2 AIH cases 1, 2

Additional AIH markers when conventional antibodies are negative:

• Anti-soluble liver antigen (anti-SLA): 99% specificity for AIH; present in 7-22% of type 1 AIH and can be the sole marker in 14-20% of cases 2
• Atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA/pANNA): Present in 50-92% of type 1 AIH patients; can be the only serological marker when conventional antibodies are negative 2

For Primary Biliary Cholangitis

• Antimitochondrial antibodies (AMA): Virtually pathognomonic for PBC, particularly those reacting with E2 components of pyruvate dehydrogenase complex 1
• Disease-specific ANA: Reacting with nuclear pore gp210 and nuclear body sp100 4

For Primary Sclerosing Cholangitis

• No autoantibodies are diagnostic of PSC 1
• Perinuclear antineutrophil cytoplasmic antibody (pANCA): Positive in 33-88% of PSC patients but not specific and not related to disease activity or prognosis 1

Testing to Exclude Alternative Diagnoses

Mandatory exclusion testing before confirming autoimmune liver disease:

• Viral hepatitis serologies: Hepatitis B surface antigen, anti-HBc, hepatitis C antibody, hepatitis E (particularly important as anti-LKM1 can occur in 5-10% of chronic hepatitis C patients) 1, 2
• HIV antibodies: To exclude secondary sclerosing cholangitis 1
• Serum angiotensin converting enzyme: To exclude sarcoidosis 1

Practical Testing Algorithm

For adults with suspected autoimmune liver disease:

1. First-line panel: AST, ALT, ALP, GGT, bilirubin, albumin, INR, platelets, total IgG, ANA, SMA 1, 2
2. If ANA and SMA are negative: Add anti-LKM1, anti-LC1, and anti-SLA 1, 2
3. If cholestatic pattern (elevated ALP/GGT): Add AMA and IgG4 1, 3
4. Always exclude: Viral hepatitis (HBV, HCV, HEV), HIV 1, 2

For children with suspected autoimmune liver disease:

• Test ANA, SMA, and anti-LKM1 simultaneously (do not wait for negative ANA/SMA results) 2

Important Caveats

Common pitfalls to avoid:

• Anti-LKM1 can be confused with AMA if rodent kidney is the sole substrate used in testing 2
• Elevated aminotransferases in PSC do not necessarily indicate overlap with AIH; mild elevations are common 1
• Normal IgG does not exclude AIH, particularly in acute presentations 1, 2
• Positive autoantibodies alone are insufficient for diagnosis; liver biopsy is essential for AIH diagnosis except in highly typical acute presentations 1, 2