From the Guidelines
No, a serum IgG4 level above 135 mg/dL is not required for the diagnosis of IgG4-Related Disease (IgG4-RD). While elevated serum IgG4 levels can support the diagnosis, approximately 30-40% of patients with histologically confirmed IgG4-RD have normal serum IgG4 concentrations 1. The diagnosis primarily relies on characteristic histopathological findings, including dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and immunohistochemical demonstration of increased IgG4-positive plasma cells in affected tissues. The ratio of IgG4 to total IgG-positive plasma cells (>40%) in tissue is more diagnostically valuable than serum levels. Clinical presentation with involvement of typical organs (pancreas, biliary tract, salivary glands, orbital tissues, lymph nodes, retroperitoneum) also contributes significantly to diagnosis. Serum IgG4 elevation, when present, provides supportive evidence but lacks sufficient sensitivity and specificity to be a standalone diagnostic criterion.
Some key points to consider in the diagnosis of IgG4-RD include:
- Elevated serum IgG4 levels support the diagnosis but cannot be relied on for making a definite diagnosis 1
- A pathological diagnosis should be pursued in cases of suspected IgG4-SC, as this may allow distinction from disease mimics (including PSC and CCA) 1
- Other organ involvement (in particular, pancreatic manifestations of IgG4-RD) may provide important information to distinguish IgG4-SC from PSC 1
- The international consensus guidelines recommend that IgG4-SC should be diagnosed according to their recommendations 1
Treatment decisions should be based on comprehensive clinical, radiological, and histopathological assessment rather than serum IgG4 levels alone. The most recent and highest quality study 1 suggests that elevated serum IgG4 levels support the diagnosis of clinically suspected IgG4-RD but cannot be relied on for making a definite diagnosis.
From the Research
Diagnosis of IgG4-Related Disease (IgG4-RD)
- The diagnosis of IgG4-RD is based on a combination of clinical, radiological, and histopathological findings, as well as elevated serum IgG4 levels 2, 3.
- Elevated serum IgG4 levels are a key diagnostic criterion for IgG4-RD, with a concentration of >135 mg/dL considered indicative of the disease 3, 4.
Serum IgG4 Levels in IgG4-RD
- Serum IgG4 levels are used to support the diagnosis of IgG4-RD, with levels >135 mg/dL suggesting a more active form of the disease 4.
- Elevated serum IgG4 levels are associated with increased concentrations of inflammatory serum biomarkers, hypocomplementemia, and more extensive organ involvement 4.
- However, it is noted that an elevated serum IgG4 level can also be encountered in other diseases, and only a small minority of patients with elevated serum IgG4 levels have IgG4-RD 5.
Diagnostic Criteria for IgG4-RD
- The comprehensive diagnostic criteria for IgG4-RD include:
- Serum IgG4 concentration >135 mg/dL
40% of IgG+ plasma cells being IgG4+ and >10 cells/high powered field of biopsy sample 3
- These criteria are intended for the practical use of general physicians and nonspecialists, and are considered adequately sensitive for the diagnosis of IgG4-related Mikulicz's disease and kidney disease 3.