Case Report: A Rare Manifestation of <scp>IgG4</scp> ‐Related Disease: Isolated Hepatocellular Injury

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated condition characterized by elevated serum IgG4 levels and the infiltration of IgG4-positive plasma cells in affected tissues [1]. When it affects the liver, IgG4-RD typically presents as obstructive jaundice and cholestatic liver injury, often associated with type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis [2]. However, isolated hepatocellular injury due to IgG4-RD is extremely rare and has been poorly documented in the literature. We present a case of IgG4-related hepatitis in a 34-year-old male who experienced recurrent liver enzyme elevations over 9 years, ultimately achieving remission with glucocorticoids and azathioprine (Figure 1A). In March 2015, during a routine physical examination, his ALT levels peaked at 2000 U/L. The patient had a 10-year history of diabetes and a 3-year history of hypertension. He reported occasional alcohol consumption but denied any other significant medical issues. Initially, he was treated with hepatoprotective agents, including reduced glutathione and compound ammonium glycyrrhetate injections, which led to a gradual normalization of his ALT levels. However, in November 2018, he experienced a recurrence, with ALT levels rising to 1100 U/L, prompting further evaluation. After seeking medical attention, he was prescribed additional hepatoprotective medications. By January 2019, laboratory tests revealed elevated ALT (209 U/L) and AST (80 U/L) levels, along with significantly increased serum IgG (16.2 g/L) and IgG4 (5.48 g/L). Comprehensive serologic tests for other liver conditions returned negative results (Table 1). Additionally, to aid in the differential diagnosis, the patient underwent abdominal MRI, chest and abdominal CT scans, renal and prostate ultrasounds and a thyroid ultrasound. No abnormalities were observed in the pancreas, bile ducts, lungs, kidneys, retroperitoneal tissues or thyroid. A liver biopsy subsequently confirmed significant lymphocytic infiltration and the presence of IgG4-positive plasma cells, with histopathological analysis indicating fibrous connective tissue proliferation (Figure 1B). Immunohistochemical analysis revealed more than 10 IgG4-positive plasma cells per high-power field, with an IgG4-positive to IgG ratio exceeding 40% (Figure 1C,D). Initially, the patient was prescribed prednisone at a daily dose of 30 mg, resulting in a rapid normalization of liver function. He was discharged with a plan to taper the prednisone dose gradually to 5 mg for maintenance. In November 2019, prednisone was discontinued. However, 5 months later, the patient experienced a recurrence, with ALT levels rising to 907 U/L. In May 2020, a new treatment regimen was initiated, combining corticosteroids and immunosuppressants. Methylprednisolone was introduced at a starting dose of 32 mg daily and gradually tapered to 4 mg for maintenance, alongside azathioprine at 50 mg daily. Regular monthly follow-ups showed sustained normalization of liver function tests. After 4 months of treatment, methylprednisolone was discontinued, and the patient was maintained on azathioprine alone, remaining asymptomatic with normal liver function tests. By June 2023, after 3 years of treatment, azathioprine was also discontinued. To date, we continue to monitor this patient, and there has been no recurrence of IgG4-related hepatitis in the past 4 years. IgG4-RD is a complex immune-mediated condition, with approximately 60% of patients experiencing varying degrees of organ damage due to delayed diagnosis and associated fibrosis [3]. Clinicians often underestimate the impact of IgG4-RD on the liver, as evidenced by our patient, who presented with recurrent symptoms of liver failure. This case exemplifies IgG4-RD characterized by isolated primary hepatocellular injury, a manifestation that, to our knowledge, has not been reported previously. Previous reports of IgG4-related autoimmune hepatitis can exhibit similar hepatic features (Table S1), such as lobular hepatitis and portal inflammation [4]. To differentiate between these conditions, we utilized the autoimmune hepatitis (AIH) scoring system developed by the International Autoimmune Hepatitis Group in 1999 [5], allowing us to exclude the diagnosis of IgG4-AIH. Early diagnosis and timely intervention are crucial for preventing irreversible inflammatory damage and fibrosis in IgG4-RD. Currently, corticosteroids are the cornerstone of initial treatment and have shown favorable effects in most cases with organ involvement [3]. Following this assessment, we promptly initiated glucocorticoid therapy as the first-line treatment for IgG4-RD. After the patient experienced a relapse upon discontinuation of medication, suggesting that glucocorticoid monotherapy may be insufficient for long-term disease control, we quickly implemented combination therapy with glucocorticoids and azathioprine, resulting in favorable outcomes. This finding aligns with the research by Dina Omar et al. [6], indicating that patients receiving a combination of glucocorticoids and immunosuppressants have higher remission rates compared to those treated with glucocorticoids alone. Emerging treatments, including rituximab, inebilizumab, and other biologic therapies, offer promising alternatives for refractory or relapsing IgG4-RD [7-9]. However, in this case, the patient responded favorably to corticosteroid therapy combined with immunosuppressants, so these novel options were not pursued. This experience suggests that combining corticosteroids with immunosuppressants may offer an effective treatment pathway for IgG4-related hepatitis, underscoring the importance of adjusting treatment promptly in response to relapse. For patients with varying disease types or severities, optimizing treatment strategies and exploring individualized approaches remain critical areas for future research. The etiology and pathogenesis of IgG4-RD remain unclear. Studies suggest that chronic antigen-induced immune activation plays a central role. Circulating plasma cells and B cells present self-antigens to CD4+ cytotoxic T cells (CD4+ CTLs), which then activate CTLs in local tissues. These cells release cytotoxic molecules, such as perforin and granzyme, leading to tissue damage through apoptosis of target cells. CD4+ CTLs also promote fibrosis by secreting factors like TGF-β, IL-1β, and IFN-γ [10, 11]. Furthermore, IL-10 and IL-4 from follicular helper T cells may drive IgG4 class switching and B cell responses, causing elevated serum IgG4, IgG4+ plasma cell infiltration, and tissue fibrosis [12, 13]. The mechanism of IgG4-related hepatitis likely involves similar immune responses, but further research is needed due to the liver's unique immune tolerance environment. In conclusion, this case highlights the importance for clinicians to carefully consider that isolated hepatocellular injury may be the sole manifestation of IgG4-related disease. Timely initiation of appropriate treatment is essential to prevent liver failure, cirrhosis, and potentially more severe outcomes. Xinmei Yan: conceptualization, data collection, analysis, manuscript drafting, and literature review; contributed to the design and interpretation of the case report. Junxing Li and Huyu Jiao: data collection, methodology, and analysis; provided clinical insights, edited the manuscript, and validated the data. Zhengang Zhang: supervision, project administration, and manuscript review; oversaw case study interpretation and validation; approved the final manuscript submission. This study was approved by the Ethics Committees of Tongji Hospital, Wuhan, China (TJ-IRB202410016). The participant provided written informed consent for the use of their medical records for the purpose of research. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.