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Evolving liver inflammation in biochemically normal individuals with anti-mitochondria antibodies
Danielle Cristiane Baldo1,2, Alessandra Dellavance2, Maria Lucia Gomes Ferraz3
11Rheumatology Division, Universidade Federal de São Paulo, UNIFESP, Rua Botucatu 740, São Paulo, SP 04023-900 Brazil.
Background:
Anti-mitochondria autoantibodies (AMA) occur in > 95% primary biliary cholangitis (PBC) patients. Biochemically normal AMA-positive (BN/AMA+) individuals, occasionally noticed by indirect immunofluorescence (IIF) on HEp-2 cells and confirmed in AMA-specific assays, may represent early stages of PBC. The Enhanced Liver Fibrosis (ELF) score is a surrogate marker for liver fibrosis. This prospective study investigated the ELF score in BN/AMA+ individuals and PBC patients, considering autoantibody avidity and serum levels along the years.
Methods:
327 samples from 35 PBC and 59 BN/AMA+ were prospectively obtained in average 3.83 (range 0.50-7.40) years apart. Samples were tested by IIF on rat-kidney (IIF-AMA), western-blot for AMA (WB-AMA), and ELISA for antibodies against pyruvate-dehydrogenase (PDC-E2), gp210, sp100 and CENP-A/B. Anti-PDC-E2 avidity was determined by 6 M urea-elution ELISA. Alkaline phosphatase (ALP), gamma glutamyl transferase (ɣGT) and ELF score were measured by automated methods.
Results:
Along the follow-up period BN/AMA+ subjects and PBC patients presented significant increase in serum anti-PDC-E2 (mean 10.45% and 8.86% per year; respectively), anti-PDC-E2 avidity (3.02% and 4.94%/year) and ELF score (3.24% and 2.71%/year). IIF-AMA and ɣGT increased in BN/AMA+ (6.59% and 2.36%) and decreased in PBC (- 4.89%/year and - 3.88%/year). In BN/AMA+ individuals there was positive correlation of ELF with IIF-AMA titer (r = 0.465; p < 0.001) and with anti-PDC-E2 levels (r = 0.239; p < 0.001). Expansion of autoantibody targets along time occurred in 39% BN/AMA+ and 49% PBC patients. The frequency of BN/AMA+ with high probability of having established PBC increased from 7 to 14%.
Conclusions:
BN/AMA+ individuals present an orchestrated increase in ELF score and humoral autoimmune response over time, indicating an opportunity for early therapeutic intervention and prevention in autoimmunity.
Insights
Biochemically normal anti-mitochondria autoantibody-positive (BN/AMA+) individuals show increasing liver fibrosis markers and autoimmune responses over time. This suggests potential for early intervention in primary biliary cholangitis (PBC) development.
Area of Science:
- Autoimmune liver diseases
- Biomarker research
- Immunology
Background:
- Anti-mitochondria autoantibodies (AMA) are present in over 95% of primary biliary cholangitis (PBC) patients.
- Biochemically normal AMA-positive (BN/AMA+) individuals may represent an early stage of PBC.
- The Enhanced Liver Fibrosis (ELF) score is a validated marker for liver fibrosis.
Purpose of the Study:
- To prospectively investigate the changes in the ELF score in BN/AMA+ individuals and PBC patients.
- To analyze autoantibody avidity and serum levels over time in these groups.
- To explore the relationship between ELF score, autoantibodies, and disease progression.
Main Methods:
- Prospective collection of 327 samples from 35 PBC and 59 BN/AMA+ individuals over an average of 3.83 years.
- Testing for AMA by indirect immunofluorescence (IIF) and western blot (WB).
- Quantification of antibodies against pyruvate dehydrogenase (PDC-E2), gp210, sp100, and CENP-A/B using ELISA, with anti-PDC-E2 avidity determined by urea-elution ELISA. ELF scores and liver enzymes (ALP, ɣGT) were measured.
Main Results:
- Both BN/AMA+ individuals and PBC patients showed significant increases in anti-PDC-E2, anti-PDC-E2 avidity, and ELF score over time.
- BN/AMA+ individuals exhibited increasing IIF-AMA titers and ɣGT, while PBC patients showed decreases.
- A positive correlation was found between ELF score and IIF-AMA titer/anti-PDC-E2 levels in BN/AMA+ individuals. The probability of BN/AMA+ individuals having established PBC increased from 7% to 14%.
Conclusions:
- BN/AMA+ individuals demonstrate a coordinated progression in ELF score and autoimmune humoral response.
- These findings highlight an opportunity for early therapeutic intervention and prevention strategies in autoimmunity, potentially before overt PBC diagnosis.
- Monitoring ELF score and autoantibody profiles can identify individuals at risk for developing PBC.
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