What non-rheumatologic conditions can cause a positive Antinuclear Antibody (ANA) result?

Non-Rheumatologic Conditions That Can Raise ANA

ANA positivity occurs frequently in non-rheumatologic conditions, most notably chronic liver diseases (particularly autoimmune hepatitis, primary biliary cholangitis, chronic hepatitis B and C, and non-alcoholic fatty liver disease), chronic infections (especially tuberculosis, syphilis, scrub typhus, and HIV), and in up to 31.7% of healthy individuals at low titers.

Hepatobiliary Diseases

Autoimmune Hepatitis and Related Liver Conditions

• ANA is detected in 80% of patients with autoimmune hepatitis (AIH) at presentation, with isolated ANA positivity occurring in a significant proportion of these cases 1
• ANA can occur as an isolated serological finding in primary sclerosing cholangitis (29% of cases), chronic hepatitis C (26%), chronic hepatitis B (32%), non-alcoholic fatty liver disease (34%), and chronic alcohol-associated liver disease (21%) 1
• The diagnostic accuracy for AIH improves from approximately 58% to 74% when two autoantibodies (such as ANA plus smooth muscle antibodies) are detected together, rather than ANA alone 1
• Up to 20% of AIH cases are seronegative for ANA, highlighting that the relationship between ANA and liver disease is complex and bidirectional 1

Chronic Viral Hepatitis

• In treatment-naive chronic hepatitis B patients, ANA positivity was found in 17% of cases compared to 0% in healthy controls, a statistically significant difference 2
• Low-titer ANA may be present in chronic viral hepatitis patients even without concurrent autoimmune disease, suggesting that chronic viral infection itself can trigger autoantibody production 2

Infectious Diseases

Bacterial Infections

• Mycobacterium tuberculosis is the most common pathogen associated with ANA positivity among infectious diseases, accounting for 10 of 43 confirmed infectious cases in one study 3
• Treponema pallidum (syphilis) is frequently associated with positive ANA testing 3
• Orientia tsutsugamushi (scrub typhus) and Bartonella henselae are notable intracellular infections that can produce positive ANA results 3
• Escherichia coli and other bacterial infections can trigger ANA production 3

Viral Infections

• Human immunodeficiency virus (HIV) infection is associated with ANA positivity 3
• Epstein-Barr virus-induced infectious mononucleosis can produce positive ANA results 3
• Hepatitis C virus infection is associated with ANA positivity in approximately 26% of cases 1

Key Pattern: Intracellular Infections

• Several patients with positive ANA tests were found to have intracellular infections, including mycobacterial infections, syphilis, and scrub typhus, suggesting a particular association between intracellular pathogens and ANA production 3

Healthy Individuals and Age-Related Factors

Prevalence in Healthy Populations

• 31.7% of healthy individuals test positive for ANA at 1:40 dilution, 13.3% at 1:80, and 5.0% at 1:160 1
• A large proportion (20%) of the general population has a positive ANA test, with very few developing autoimmune disease 4
• The optimal screening dilution of 1:160 represents the 95th percentile of healthy controls, meaning 5% of healthy individuals will still test positive at this threshold 1

Drug-Induced ANA Elevation

Medications Associated with ANA Positivity

• Procainamide, hydralazine, and minocycline are specific medications that can lead to drug-induced ANA elevation 5
• Drug-induced lupus should be considered when ANA positivity occurs in the context of these medications 5

Non-Autoimmune Inflammatory Conditions

Associated Clinical Conditions

• In individuals without autoimmune disease, ANA positivity is associated with increased risk of Raynaud's syndrome (OR ≥ 2.1) and alveolar/perialveolar-related pneumopathies (OR ≥ 1.4) 4
• Interestingly, ANA positivity in non-autoimmune individuals is associated with decreased risk of hepatitis C, tobacco use disorders, mood disorders, convulsions, fever of unknown origin, and substance abuse disorders (OR ≤ 0.8) 4

Critical Clinical Pitfalls

Interpretation Challenges

• When ANA testing is used as an initial screen in patients with non-specific symptoms (fever, joint pain, myalgias, fatigue, rash, or anemia), the likelihood of a positive result due to infection increases substantially, especially in children 6
• The diagnostic value of ANA testing alone is limited in non-rheumatic conditions, and ANA presence must be interpreted in clinical context with consideration of titer, pattern, and specific autoantibody testing 5
• A positive ANA test may reflect a state of immune dysregulation rather than autoimmune disease, particularly at lower titers 4

Risk of Progression

• One patient developed systemic lupus erythematosus after Epstein-Barr virus infection, and another developed adult-onset Still's disease after scrub typhus, indicating that infections can occasionally trigger true autoimmune disease in susceptible individuals 3
• The presence of ANA in infectious or non-rheumatic conditions does not necessarily predict future autoimmune disease development 4

Testing Recommendations

• At screening dilution of 1:40, the high false-positive rate makes clinical correlation essential before pursuing extensive autoimmune workup 1
• For adults, positivity at dilutions of 1/40 is common in healthy individuals, so clinically significant positivity typically starts at 1/160 1
• In pediatric patients (under 18 years), any level of autoantibody reactivity is clinically relevant, as ANA positivity is infrequent in healthy children 1