Normal IgG4 Percentage of Total IgG Pool
In healthy individuals, IgG4 should comprise less than 10% of the total IgG pool, with most sources indicating it represents approximately 3-6% under normal circumstances. 1
Normal Distribution of IgG Subclasses
The four IgG subclasses follow a predictable distribution pattern in healthy adults:
- IgG1: Comprises approximately 60-70% of total circulating IgG 1
- IgG2: Constitutes 20-25% of total circulating IgG 1
- IgG3: Represents less than 10% of total IgG 1
- IgG4: Represents less than 10% of total IgG, typically 3-6% 1
Research on intravenous immunoglobulin preparations from normal donor pools confirms that IgG4 content ranges from 0.5-3%, with preparations containing below 0.5% IgG4 considered at or below the lower limit of normal adult values 2. This provides additional context that the normal range spans a relatively narrow window.
Clinical Significance of IgG4 Percentage
The IgG4/IgG ratio becomes diagnostically important when evaluating for IgG4-related disease (IgG4-RD):
- An IgG4/IgG ratio >0.24 may improve specificity for distinguishing IgG4-related sclerosing cholangitis from primary sclerosing cholangitis 3
- For diagnosing IgG4-RD among patients with elevated serum IgG4, optimal cut-off values are approximately 0.114-0.295 for the IgG4/IgG ratio, depending on the clinical context 4, 5
- In one study, an IgG4/IgG ratio >0.114 demonstrated 96.2% sensitivity and 92.1% specificity for IgG4-RD diagnosis 5
Important Clinical Caveats
Approximately 2.5% of healthy individuals naturally have IgG subclass levels below 2 standard deviations of the mean for at least one subclass 6. This means isolated low IgG4 levels may not be clinically significant in asymptomatic individuals.
Conversely, elevated IgG4 levels (and thus elevated IgG4/IgG ratios) are not specific to IgG4-RD and can occur in multiple conditions 3:
- Elevated serum IgG4 is found in 9-15% of patients with primary sclerosing cholangitis 3
- Only 1% of patients with primary biliary cholangitis have elevated IgG4 3
- Chronic diseases of various organs, rheumatic immune diseases, bacterial infections, and malignancies can all present with elevated IgG4 4
The key principle: IgG4 percentage should be interpreted in clinical context, not as an isolated laboratory value 6. Normal total IgG does not exclude clinically significant IgG4 abnormalities, and abnormal IgG4 percentages require confirmation with repeat testing at least one month apart before making clinical decisions 6, 7.