IgG4-related hepatobiliary disease represents the manifestation of IgG4-related disease (a systemic condition involving multiple organs or tissues) in the liver and biliary system. This chronic progressive inflammatory disease is characterized by lymphoplasmacytic infiltration and tissue fibrosis, accompanied by elevated serum and tissue IgG4 levels.
Etiology and Pathogenesis
IgG4 is an antibody produced by plasma cells, primarily regulated by Treg cells. Due to its unique structure, IgG4 differs from the main immunoglobulin component IgG1, as it does not activate the complement pathway or crosslink antigens, thereby losing the ability to form immune complexes with antigens. It can form auto-immune complexes through light chain–light chain or light chain–heavy chain interactions. Genetic studies have confirmed an association between this disease and specific genetic backgrounds, such as HLA-DRB10405 and HLA-DQβ157. Under certain genetic predispositions, both autoimmune and infectious factors can lead to Th2 cell activation and self-proliferation, resulting in Treg cell aggregation and stimulation of plasma cells to produce large amounts of IgG4.
Clinical Manifestations
This condition is more common in males, with a male-to-female ratio of approximately 2–4:1.
IgG4-Related Sclerosing Cholangitis (IgG4-SC)
Clinical features include elevated conjugated bilirubin, pruritus, abdominal pain, loss of appetite, and weight loss. Approximately 80% of IgG4-SC cases are associated with type 1 autoimmune pancreatitis.
IgG4-Related Autoimmune Hepatitis (IgG4-AIH)
The onset is often insidious, with mild cases being asymptomatic. During active disease, symptoms such as fatigue, abdominal distension, loss of appetite, and jaundice may occur, potentially progressing to cirrhosis.
Laboratory and Auxiliary Examinations
Serum Biochemistry
In IgG4-SC, early liver function abnormalities are primarily characterized by significant elevations in ALP and γ-GT. As the disease progresses, conjugated bilirubin and total bile acid concentrations may increase markedly. In contrast, IgG4-AIH primarily presents with recurrent elevations in ALT and AST, often accompanied by elevated ALP levels, indicating liver function impairment.
Immunological Tests
A marked increase in serum IgG4 levels is a common feature of IgG4-related hepatobiliary disease. Some patients also exhibit elevated IgE levels and total IgG, while IgA and IgM levels are reduced. In IgG4-AIH, ANA and/or SMA autoantibodies may also be positive.
Histopathology
Histological findings reveal significant lymphocyte and plasma cell infiltration. Immunohistochemistry shows abundant IgG4-positive plasma cells in the lesions. Storiform fibrosis and obliterative phlebitis are shared pathological features of this condition.
Imaging Studies
In IgG4-SC, imaging often reveals significant narrowing of the distal common bile duct or segmental strictures of the hilar bile ducts, with marked thickening of the bile duct walls at the affected sites. In IgG4-AIH, hepatosplenomegaly may be observed.
Diagnosis and Differential Diagnosis
IgG4-SC
Diagnostic criteria include serum IgG4 levels >1,350 mg/L, liver function changes characterized by significant elevations in ALP and γ-GT, imaging findings of distal common bile duct or hilar bile duct strictures with circumferential thickening of the bile duct walls, and histological evidence of significant lymphocyte and plasma cell infiltration. IgG4-positive plasma cells should exceed 10 cells per high-power field or account for >40% of plasma cells. Storiform fibrosis and obliterative phlebitis may also be observed in the bile duct walls. IgG4-SC should be differentiated from autoimmune liver diseases such as PSC and PBC.
IgG4-AIH
Diagnosis is based on meeting the established scoring criteria for AIH, along with serum IgG4 positivity (>1,350 mg/L). Histological findings include IgG4-positive plasma cell infiltration (>10 cells per high-power field or >40% of plasma cells), with prominent involvement in the portal areas. Clinically, differentiation from isolated AIH is necessary.
Treatment
For all active, newly diagnosed cases of IgG4-related hepatobiliary disease, glucocorticoids are the first-line therapy for inducing remission, unless contraindicated. The initial dose of prednisone is 30–40 mg/day (or 0.6 mg/kg/day). After maintaining this dose for 2–4 weeks, a gradual tapering is initiated, reducing the dose by 5 mg every 1–2 weeks based on the patient's symptoms, serological markers, and imaging findings. To prevent relapse, a maintenance dose of prednisone at 2.5–5.0 mg/day is recommended. There is ongoing debate regarding the optimal maintenance therapy. Researchers often advocate for maintenance treatment with prednisone at 2.5–5.0 mg/day for 1–3 years. In cases of relapse, remission can usually be achieved by returning to the initial treatment dose of glucocorticoids.
For patients whose disease cannot be controlled with glucocorticoid monotherapy or who experience significant side effects from long-term glucocorticoid use, a combination of glucocorticoids and immunosuppressants (such as azathioprine or tacrolimus) may be considered. For patients who relapse or cannot tolerate glucocorticoid therapy, B-cell-depleting biologics (such as rituximab) may be an option. In patients with IgG4-SC, additional treatment with ursodeoxycholic acid (UDCA) or fibrates may be beneficial. For IgG4-AIH patients, hepatoprotective agents such as antioxidants may be used. In severe cases of IgG4-SC, ERCP-guided stent placement or surgical intervention may be necessary.
Prognosis
The short-term efficacy of glucocorticoid therapy in IgG4-related hepatobiliary disease is highly favorable, with most patients achieving good outcomes. However, the long-term prognosis remains uncertain. Higher IgG4 levels and elevated eosinophil counts are associated with an increased likelihood of multi-organ involvement. In some cases, disease progression may lead to the development of malignancies.