High IgA levels linked to increased risk of liver complications

A research group centered around Lecturer Takefumi Kimura and Clinical Assistant Professor Shun-ichi Wakabayashi at the Second Department of Internal Medicine, and Professor Naoki Tanaka at the Department of Global Medical Research Promotion, Shinshu University School of Medicine, through joint research with the Department of Laboratory Medicine at Shinshu University Hospital, Ogaki Municipal Hospital, Gifu Kyoritsu University, Oita University, and others, identified a new high-risk disease type characterized by high serum IgA levels in metabolic dysfunction-associated steatotic liver disease (MASLD: Metabolic dysfunction-associated steatotic liver disease).

In this type of disease, liver-related events such as liver cancer, varices requiring treatment, ascites requiring hospitalization, and hepatic encephalopathy are prone to occur in the future. By adding serum IgA, which can be measured in general medical practice, to conventional fibrosis evaluation, there is a possibility that risk evaluation for MASLD patients can be made more precise. The findings were published in the Journal of Hepatology.

MASLD is a disease where fat accumulates in the liver against a background of metabolic abnormalities such as obesity, type 2 diabetes, and dyslipidemia, serving as a major cause of chronic liver disease. While the degree of liver fibrosis was considered the most important indicator predicting future liver-related events, patients whose courses differ exist even at the same fibrosis stage. It is necessary to capture diversity of pathological conditions including immune, metabolic, and gut-derived factors other than fibrosis.

Targeting 349 cases diagnosed with MASLD via liver biopsy at Shinshu University Hospital, unsupervised clustering using a variational Bayesian Gaussian mixture model was conducted using 51 items such as age, sex, comorbidities, liver function, metabolic indicators, and immunoglobulins. Without including liver histology findings or information on liver-related events in classification, 4 groups were extracted solely from data characteristics.

Among the 4 groups, the group with high serum IgA and hyaluronic acid and low platelets (72 cases) was a disease type often accompanied by diabetes and hypertension, also possessing a high proportion of advanced liver fibrosis. During a median follow-up period of 6.8 years, 20 liver-related events occurred, and the 5-year cumulative incidence rate in this group was 24.0%. Even in analyses adjusted for advanced liver fibrosis and other factors, this group was a strong risk factor.

When the optimal cutoff value for serum IgA was set to 318 milligrams per deciliter (mg/dL), sensitivity to liver-related events was 60.0%, specificity was 80.4%, and the area under the ROC curve was 0.73. Even in multivariate analysis simultaneously including advanced liver fibrosis, high IgA was an independent predictive factor (hazard ratio 3.17). Furthermore, in patients possessing both high IgA and advanced liver fibrosis, the 10-year cumulative incidence rate reached 48%, whereas it was less than 5% in other patients.

In a separate cohort of 287 cases at Shinshu University evaluated via VCTE (vibration-controlled transient elastography) without performing liver biopsy, serum IgA in patients who developed liver-related events was significantly higher. In addition, in an external multicenter cohort of 272 cases from Ogaki Municipal Hospital and Oita University Hospital, the high-risk group characterized by high IgA was reproduced, confirming that liver-related events are frequent in patients with IgA of 318 mg/dL or higher.

Hepatic tissue IGHA1 (gene encoding IgA1) expression increased along with the progression of fibrosis, also correlating with serum IgA values. In spatial transcriptomics, IGHA1 expression increased in severely fibrotic livers, localizing mainly in portal areas. In single-cell RNA analysis, IGHA1 was strongly expressed in B-cell lineage cells including plasma cells. In IGHA1 high-expression regions, B-cell receptor signaling, extracellular matrix remodeling, TGF-β response, and vascular remodeling-related pathways were activated.

In MASLD patients with advanced liver fibrosis, IgA-positive cells in the colonic mucosa and submucosa increased compared to the control group. In addition, EndoCAB IgG, reflecting exposure to gut-derived antigens, showed a positive correlation with serum IgA and intrahepatic IGHA1 expression. These results support the possibility that antigen stimulation accompanying enhanced intestinal permeability leads to systemic and intrahepatic IgA-related immune activation.

Journal Information
Publication: Journal of Hepatology
Title: IgA-enriched phenotype predicts liver-related events in MASLD
DOI: 10.1016/j.jhep.2026.06.044