What does a positive Antinuclear Antibody (ANA) test result indicate in a patient with moderate Non-Alcoholic Steatohepatitis (NASH) and metabolic comorbidities?

Positive ANA in NASH: Clinical Significance and Management

A positive Antinuclear Antibody (ANA) test in a patient with moderate Non-Alcoholic Steatohepatitis (NASH) and metabolic comorbidities is frequently an epiphenomenon of no clinical consequence and does not necessarily indicate autoimmune hepatitis. 1

Prevalence and Significance of ANA in NASH

• Elevated serum autoantibodies (ANA ≥1:160 or ASMA ≥1:40 or both) are present in approximately 21% of patients with biopsy-proven NAFLD/NASH in the absence of autoimmune hepatitis (AIH) 1
• Studies show that 34-48% of NASH patients may have positive ANA titers 2, 3
• These autoantibodies in NASH patients are generally considered an incidental finding without clinical significance 1

Clinical Evaluation Algorithm for Positive ANA in NASH

Step 1: Assess ANA titer level and pattern

• Low titers (1:40 to 1:80): More likely to be an epiphenomenon
• High titers (≥1:320): May warrant further investigation as they have been associated with more advanced histological grade and stage of NASH 4

Step 2: Evaluate for features suggesting true autoimmune overlap

Look for:

• Hypergammaglobulinemia (elevated IgG)
• Significantly elevated liver enzymes (ALT/AST >200 IU/L)
• Presence of other autoantibodies (ASMA, anti-LKM)
• Female gender (more common in both AIH and ANA-positive NASH) 2, 4

Step 3: Consider histological features

ANA-positive NASH may show:

• Higher degree of portal inflammation
• More pronounced interface activity
• More severe hepatocellular ballooning 4
• However, plasma cell infiltrates (characteristic of AIH) are typically absent or minimal 3

Management Recommendations

1. For typical NASH with positive ANA without other concerning features:

   • No specific treatment for the autoimmune component is needed
   • Focus on managing underlying metabolic conditions and NASH
   • Consider baseline documentation of autoantibody titers for future reference 1

2. For cases with concerning features suggesting possible AIH overlap:

   • Consider liver biopsy if not already performed
   • Look for plasma cell infiltrates and other AIH features
   • Evaluate IgG levels and other autoimmune markers
   • Consider hepatology referral

Important Clinical Pearls

• The finding of positive ANA titers may be confusing and is generally unhelpful for causality assessment of potential drug-induced liver injury in NASH patients 1
• It is recommended to measure autoantibody titers (ANA and ASMA) prior to enrollment in clinical trials to provide a baseline for subsequent comparison 1
• Women with NASH are more likely to be ANA-positive than men 3, 4
• ANA positivity in NASH may be related to advanced age and chronic inflammation rather than true autoimmunity 2
• The presence of both ANA positivity and hypergammaglobulinemia should prompt further evaluation, including consideration of a liver biopsy 1

Differential Diagnosis

When encountering a positive ANA in a NASH patient, consider:

• Incidental finding in NASH (most common)
• True AIH-NASH overlap syndrome
• Drug-induced autoimmunity
• Concurrent autoimmune disease unrelated to liver

The initial evaluation in patients with suspected NAFLD/NASH should include liver biochemistries and exclusion of other liver diseases through appropriate testing, including autoantibodies (ANA, AMA, ASMA) 1, 5.