High-Titre ANA Positivity in NAFLD: An Uncommon Presentation of a Common Disease

Mitra, Asis; Ray, Saswati

doi:10.12890/2020_001714

Cited by 3 publications

References 7 publications

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Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights

Klepper

Kung

Vazquez

et al. 2023

Preprint

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While the identification of autoantigens remains a critical challenge in understanding and treating autoimmune diseases, the role of autoantibodies in the pathophysiology of autoimmune hepatitis (AIH) is uncertain. To better characterize the antigenic landscape of AIH, we employed Phage Immunoprecipitation-Sequencing (PhIP-Seq) to identify novel autoantibodies specific to patients. Using these results, a logistic regression classifier was able to predict which patients had AIH, relative to healthy controls indicating the presence of a distinct humoral immune signature. To further investigate the autoantibodies most specific to AIH, significant peptides were identified with >98% specificity relative to a broad array of controls (298 patients with NAFLD, PBV, or healthy controls). Top ranked autoreactive targets included anti-SLA, a well-recognized autoantibody in AIH, and a second hit to disco interacting protein 2 homolog A (DIP2A). The autoreactive fragment of DIP2A shares a nearly identical 8 amino acid stretch with the U27 protein of HHV-6, a virus known to reside in the liver. Finally, peptides derived from the LRRNT domain of the relaxin family peptide receptor 1 (RXFP1) were highly enriched and specific to AIH. The enriched peptides map to a motif adjacent to the receptor binding domain, required for RXFP1 signaling. RXFP1 is a G-protein coupled receptor that binds relaxin-2, an anti-fibrogenic molecule shown to reduce the myofibroblastic phenotype of hepatic stellate cells. Eight of nine patients with antibodies to RXFP1 had evidence of advanced fibrosis (F3 or greater). Furthermore, serum from AIH patients positive for anti-RFXP1 antibody was able to significantly inhibit relaxin-2 signaling in THP1 cells relative to anti-RXFP1 negative control serum, while depletion of IgG abrogated this effect. These data demonstrate that PhIP-Seq is a powerful discovery tool, capable of identifying known and novel autoantibody targets in AIH, lending additional supporting evidence that HHV6 may play a role in the development of AIH, and pointing to a potential pathogenic role for anti-RXFP1 IgG in some patients. Identification of anti-RXFP1 in patient serum may enable risk stratification of AIH patients for fibrosis progression and lead to the development of novel strategies for disease intervention.

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Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights

Klepper

Kung

Vazquez

et al. 2023

Preprint

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Diagnostic value of screening methods for the determination of antinuclear antibodies using indirect immunofluorescence on HEp-2 cells and enzyme immunoassay in autoimmune liver diseases

et al. 2022

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Antinuclear antibodies (ANA) are a heterogeneous group of autoantibodies that react with various components of the cell nucleus and cytoplasm. ANA is the main serological marker for autoimmune liver disease (AILD). The aim of the study was to compare the diagnostic value of two methods of screening for the determination of ANA (indirect immunofluorescence reaction on HEp-2 cells (IIF -HEp-2) and enzyme-linked immunosorbent assay (ELISA) in the sera of AILD patients. The sera of 118 patients with AILD (51 with autoimmune hepatitis - AIH, 19 with primary biliary cholangitis - PBC, 48 with overlapping syndrome - OVERLAP), 30 patients with non-alcoholic fatty liver disease (NAFLD) and 30 healthy donors (HD) were studied. Determination of ANA by the IIF-HEp-2 method was carried out by visual assessment of samples under an AXIOSKOP 40 microscope, by ELISA - on an Alegria automatic analyzer. A weak degree of agreement between the positive and negative results of the ANA screening study using IIF-HEp-2 and ELISA (Cohen’s kappa coefficient æ=0.4) was noted. Screening determination of ANA in patients with AILD by the IIF-HEp-2 method was distinguished by greater diagnostic sensitivity (DS) (68.6%) and a lower frequency of false negative results (31.4%) compared with ELISA (35.6% and 64.4 % respectively, p<0.05). The overall diagnostic specificity (DS) of the ANA study in IIF-HEp-2 was lower than with ELISA (66.7% and 86.7%, respectively, p<0.05). Both screening methods for determining ANA (IIF-HEp-2 and ELISA) were useful for diagnosing AILD (positive likelihood ratio - LR+: 2.1 and 2.6, respectively). In terms of the negative likelihood ratio (LR-), screening for ANA by the IIF-HEp-2 method, in contrast to ELISA, served as a “useful” test to exclude the diagnosis of AILD (0.5 and 0.8, respectively). The determination of ANA using IIF-HEp-2 is the most sensitive and “useful” screening test for the diagnosis of AILD, and ELISA is classified as a less “useful” screening method due to low diagnostic sensitivity and a high false-negative rate.

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A retrospective study of prevalence and pattern of international consensus on ANA patterns among patients with hepatitis C virus infection

Hsiao

Fan

Yen

et al. 2022

PeerJ

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Background A previous study reported a 30% prevalence of various autoantibodies among patients with hepatitis C virus (HCV) infection. The International Consensus on Anti-Nuclear Antibody (ANA) Patterns was recently introduced to classify ANA patterns based on immunoassay on HEp-2 cells. There is no previous report with this newly developed classification to evaluate patients with HCV infection. The study aims to study the prevalence and pattern of ANA patterns among HCV-infected patients. Methods We retrospectively analyzed the medical records of patients with HCV infection from September 2020 to June 2021 at our institution. A positive ANA is defined as a titer of more than 1:320. We compared patient features among the positive and negative groups. Results Overall, 258 patients were enrolled—184 patients with negative ANA and 74 patients (28.7%) with positive ANA. The mean age was 67.3 in ANA positive group and 61.2 ANA negative group. Female was prominent with ANA positive and accounted for 63.5%. The most detected ANA pattern was AC-1(homogeneous) (25.9%), followed by AC-4(fine speckled) (25.2%) and AC-21(anti-mitochondrial antibody) (9.6%). In ANA positive group, we found a trend of lower HCV viral load (5.72 log10 IU/ML vs. 6.02 log10 IU/ML), lower alanine aminotransferase level (39.5 U/L vs. 44 U/L), and higher advanced fibrosis (F3 and F4) (38.5% vs. 26.1%). In addition, higher positive ANA (more than 1:640) is significantly associated with lower estimated glomerular filtration rate (eGFR) (77.76 vs. 87.94 mL/min/1.73 m2, P = 0.044). Conclusions A high prevalence (28.7%) of ANA was found in patients with chronic hepatitis C. The presence of positive ANA is not related to the severity of their hepatic manifestation. However, higher positive ANA was significantly associated with lower eGFR.

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High-Titre ANA Positivity in NAFLD: An Uncommon Presentation of a Common Disease

Cited by 3 publications

References 7 publications

Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights

Novel autoantibody targets identified in patients with autoimmune hepatitis (AIH) by PhIP-Seq reveals pathogenic insights

Diagnostic value of screening methods for the determination of antinuclear antibodies using indirect immunofluorescence on HEp-2 cells and enzyme immunoassay in autoimmune liver diseases

A retrospective study of prevalence and pattern of international consensus on ANA patterns among patients with hepatitis C virus infection

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