Conditions Associated with Positive ANA and Positive Mitochondrial Antibody
The combination of positive ANA and positive mitochondrial antibody most commonly indicates autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome, though isolated mitochondrial antibody positivity can occur in 8-12% of autoimmune hepatitis patients without true overlap syndrome. 1
Primary Hepatobiliary Conditions
AIH-PBC Overlap Syndrome
- AIH-PBC overlap syndrome is the most clinically significant diagnosis when both ANA and antimitochondrial antibody (AMA) are positive, occurring in 8-10% of AIH patients and 7.4-11.7% in Korean studies. 1
- This overlap can be diagnosed simultaneously or sequentially—in one cohort, 7.8% were diagnosed with AIH and PBC simultaneously, 1.8% were diagnosed with AIH first, and 4.3% were diagnosed with PBC first. 1
- Critical pitfall: AMA positivity alone should NOT be diagnostic for AIH-PBC overlap syndrome—8-12% of patients with AIH may be AMA-positive despite no histologic findings of bile duct damage or loss, and these patients respond well to glucocorticoid therapy alone. 1
AMA-Negative Primary Biliary Cholangitis
- Conversely, antinuclear antibodies are frequently found in AMA-negative PBC patients, where ANA and antismooth muscle antibodies appear in the absence of histologic autoimmune hepatitis features. 2
- AMA and ANA can fluctuate independently during the disease course—patients may transition between AMA-positive/ANA-negative, AMA-negative/ANA-negative, AMA-negative/ANA-positive, and AMA-positive/ANA-positive phases of the same disease. 3
Systemic Autoimmune Diseases
Systemic Lupus Erythematosus (SLE)
- SLE is the second most common concurrent autoimmune disease in AIH patients (2.2% prevalence), and AMA can be detected in patients with systemic lupus erythematosus as part of the broader autoimmune disease spectrum. 1, 4
- Approximately 2.8-3% of patients with AIH are accompanied by SLE, and conversely, 2.7-4.7% of patients with SLE have concurrent AIH. 1
Sjögren's Syndrome
- Sjögren's syndrome is associated with both positive ANA (typically nuclear speckled pattern with anti-SSA/Ro and anti-SSB/La antibodies) and can have concurrent AMA positivity. 5, 4
- The association between AMA and Sjögren's syndrome is well established in the literature. 4
Systemic Sclerosis
- Systemic sclerosis shows association with both ANA positivity (fine speckled pattern with anti-Topoisomerase-1) and can demonstrate concurrent AMA. 5, 4
- This represents one of the established autoimmune disease associations with AMA beyond PBC. 4
Other Autoimmune Conditions Concurrent with AIH
The following conditions are associated with AIH (which commonly presents with positive ANA) and may theoretically co-occur with AMA positivity:
- Autoimmune thyroid disease is the most common concurrent condition (10.5% of AIH cases), including Hashimoto's thyroiditis (10.2-14.1%) and Graves' disease (3-6%). 1
- Rheumatoid arthritis occurs in 0.4% of AIH patients. 1
- Mixed connective tissue disease, polymyositis, and other rheumatologic conditions are documented concurrent diagnoses. 1
Non-Autoimmune Liver Diseases
Viral Hepatitis and Other Liver Conditions
- AMA can occur as an isolated serological finding in chronic hepatitis C (26% of cases), chronic hepatitis B (32%), non-alcoholic fatty liver disease (34%), and chronic alcohol-associated liver disease (21%). 6
- Hepatitis C virus infection is associated with ANA positivity in approximately 26% of cases. 6
- In unselected AMA-positive patient populations, only 38% have established PBC at a given time point, with medium and low anti-M2 titers present across various disease groups. 7
Important Clinical Considerations
Diagnostic Approach
- The presence of both antibodies requires histologic evaluation to distinguish true AIH-PBC overlap syndrome from isolated AIH with incidental AMA positivity—this distinction is critical because treatment differs. 1
- Very high and high anti-M2 values are present mainly in patients with PBC and some patients with other liver diseases, while medium and low values occur across different disease groups. 7
Monitoring and Prognosis
- In the sub-cohort without established autoimmune disease, ANA positivity is associated with increased risk of Raynaud's syndrome and alveolar/perialveolar-related pneumopathies. 8
- Approximately 10% of AMA-positive patients have a diagnosis of systemic autoimmune disease, and 3% have other organ-specific autoimmune diseases. 7