Why does a 64‑year‑old woman with chronic hepatitis C have elevated ferritin and positive anti‑SSA/Ro and anti‑SSB/La antibodies?

Elevated Ferritin and Sjögren's Antibodies in Hepatitis C

In a 64-year-old woman with chronic hepatitis C, elevated ferritin reflects hepatic inflammation and metabolic dysfunction rather than true iron overload, while positive Sjögren's antibodies represent an HCV-driven autoimmune response that mimics but differs from primary Sjögren's syndrome.

Understanding the Ferritin Elevation in Hepatitis C

Primary Mechanism: Hepatic Inflammation, Not Iron Overload

• Ferritin elevation in chronic HCV infection primarily reflects hepatocellular injury, systemic inflammation, and insulin resistance rather than true iron accumulation 1, 2.
• The first critical step is to measure transferrin saturation (TS) alongside ferritin to distinguish true iron overload (TS ≥45%) from secondary hyperferritinemia (TS <45%) 1, 2.
• When TS <45%, iron overload is excluded with >90% probability, and the elevated ferritin represents an acute-phase reactant response to chronic liver disease 2.

Clinical Significance of Ferritin in HCV

• Elevated serum ferritin in HCV patients is independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-based antiviral therapy 3.
• Ferritin ≥ the sex-specific median is one of the strongest predictors of treatment failure in HCV, with an odds ratio comparable to IL28B genotype (OR = 0.35,95% CI = 0.20-0.61, P = 0.0002) 3.
• The ferritin elevation does NOT require phlebotomy or iron reduction therapy unless TS is also elevated ≥45% 1, 2.

Diagnostic Workup for the Ferritin

• Order fasting transferrin saturation, complete metabolic panel (ALT, AST), and inflammatory markers (CRP, ESR) 2.
• If TS <45%, the elevated ferritin confirms secondary hyperferritinemia from chronic HCV infection and does not warrant HFE genetic testing 1, 2.
• Consider abdominal ultrasound to assess for fatty liver, hepatomegaly, or cirrhotic features, as nearly 40% of patients with abnormal liver tests show fatty liver on imaging 1.

Understanding the Sjögren's Antibodies in Hepatitis C

HCV-Related Sicca Syndrome vs. Primary Sjögren's Syndrome

• Sicca symptoms occur in 20-30% of HCV patients, but less than 5% have true primary Sjögren's syndrome 1.
• The presence of anti-SSA/Ro and anti-SSB/La antibodies is uncommon in HCV-related sicca syndrome, distinguishing it from primary Sjögren's syndrome 1.
• When these antibodies are present in HCV patients, they represent an HCV-driven autoimmune response with a distinct immunological pattern 4.

Characteristic Immunological Profile of HCV-Related Sjögren's

• HCV-infected patients with Sjögren's features show a predominant Th2 cytokine pattern with higher circulating levels of IL-6 (73.6 vs 33.0 pg/mL, P=0.045), IL-10 (6.7 vs 3.1 pg/mL, P=0.01), and TNF-α (59.8 vs 31.7 pg/mL, P=0.003) compared to primary SS 5.
• The frequency of anti-La antibodies relative to anti-Ro is abnormally elevated in HCV-SS (17% vs 15%) compared to primary SS (30% vs 43%), representing an inverted ratio 4.
• HCV-SS patients have a threefold higher frequency of cryoglobulin-related markers (cryoglobulins, rheumatoid factor, C4 consumption) compared to primary SS 4.

Additional Immunological Features

• Cryoglobulinemia occurs in 50% of HCV-SS patients versus 12% in primary SS (P=0.003) 5.
• Hypocomplementemia (low C3/C4) is present in 40% of HCV-SS versus 11% in primary SS (P=0.015) 5, 4.
• Anti-mitochondrial antibodies (AMA) are more common in HCV-SS (20% vs 2%, P=0.025) 5.

Clinical Implications and Management

This Patient's Likely Pattern

• The combination of elevated ferritin with positive Sjögren's antibodies in an HCV patient suggests:
  • Active hepatic inflammation driving ferritin elevation 3
  • HCV-mediated autoimmune response producing Sjögren's antibodies 4
  • Possible cryoglobulinemic vasculitis as an extrahepatic manifestation 1, 4

Essential Diagnostic Steps

• Measure transferrin saturation immediately to exclude true iron overload (target: confirm TS <45%) 1, 2.
• Check cryoglobulins, complement levels (C3, C4), and rheumatoid factor to assess for cryoglobulinemic syndrome 5, 4.
• Assess liver disease severity with liver enzymes, platelet count, and consider non-invasive fibrosis scoring (FIB-4 or NAFLD Fibrosis Score) 1.
• Evaluate for sicca symptoms with Schirmer and Saxon tests if not already performed 6.

Management Priorities

• Treat the underlying HCV infection with direct-acting antivirals (DAAs), as viral eradication may improve both ferritin levels and autoimmune manifestations 1.
• Do NOT initiate phlebotomy or iron chelation unless transferrin saturation is ≥45%, which is unlikely in this clinical context 1, 2.
• Manage sicca symptoms with topical treatments (artificial tears, saliva substitutes), as systemic immunosuppression has limited efficacy in HCV-related sicca syndrome 1.
• Monitor for cryoglobulinemic vasculitis if cryoglobulins are present, as this may require specific treatment 1, 4.

Critical Pitfalls to Avoid

• Never diagnose iron overload based on elevated ferritin alone without confirming TS ≥45% 1, 2.
• Do not assume primary Sjögren's syndrome when Sjögren's antibodies are present in an HCV patient; the immunological profile differs significantly 1, 4.
• Avoid unnecessary liver biopsy if ferritin <1000 μg/L with normal liver enzymes, as the negative predictive value for advanced fibrosis is 94% 2.
• Do not overlook cryoglobulinemia screening, as it occurs in 50% of HCV-SS patients and may require specific management 5, 4.