What is serum IgG4 (Immunoglobulin G4)?

Serum IgG4: Diagnostic Marker for IgG4-Related Disease

Serum IgG4 is a subclass of immunoglobulin G that serves as a key diagnostic marker for IgG4-related disease (IgG4-RD), though elevated levels alone are insufficient for definitive diagnosis. 1

Definition and Clinical Significance

Serum IgG4 is one of four subclasses of IgG antibodies that can be measured in blood. Its primary clinical utility is in the diagnosis and monitoring of IgG4-related disease (IgG4-RD), a systemic fibro-inflammatory condition that can affect multiple organs.

Key characteristics of serum IgG4:

• Normal range: Generally <1.4 g/L
• Diagnostic value: Elevated in 50-80% of patients with IgG4-RD 1
• Specificity limitations: Can be elevated in other inflammatory and malignant conditions 2

Diagnostic Performance

Serum IgG4 has variable diagnostic performance depending on the cutoff value used:

• Standard cutoff (≥1.4 g/L):

  • Sensitivity: 82.8%
  • Specificity: 84.7% 2

• Higher cutoff (≥2.8 g/L):

  • Sensitivity: 56.9%
  • Specificity: 96.2%
  • Negative predictive value: 97.7% 2

Improved Diagnostic Accuracy

To improve diagnostic accuracy, additional measurements can be considered:

• IgG4/IgG1 ratio >0.24: Enhances specificity for distinguishing IgG4-SC from PSC 1
• Blood IgG4/IgG RNA ratio >5%: Offers excellent sensitivity (94%) and specificity (99%) for IgG4-RD, though not widely available 1, 3

Clinical Applications

Serum IgG4 testing is valuable in several clinical scenarios:

1. Diagnostic workup: When IgG4-RD is suspected based on clinical presentation
2. Disease monitoring: Levels typically decrease with corticosteroid therapy 2
3. Prognostic indicator: Levels ≥2.8 g/L at diagnosis are associated with:
   • Multi-organ involvement
   • Higher risk of disease relapse 2

Limitations and Pitfalls

Important limitations to consider when interpreting serum IgG4 results:

• Low specificity: Elevated in multiple non-IgG4-RD conditions 2
• False negatives: Normal in approximately 20% of IgG4-RD patients 1, 2
• Diagnostic confusion: Elevated in 9-15% of PSC patients, complicating differentiation 1
• Insufficient alone: Cannot be relied upon for definitive diagnosis without supporting clinical and histopathological evidence 1

Role in Specific Diseases

Serum IgG4 is particularly relevant in diagnosing:

• IgG4-related sclerosing cholangitis (IgG4-SC): Found in 59% of IgG4-RD patients 3
• IgG4-related pancreatitis: Often presents with obstructive jaundice 3
• Multi-organ IgG4-RD: Affecting salivary glands, lacrimal glands, orbits, thyroid, lungs, and kidneys 4

Diagnostic Algorithm

When elevated serum IgG4 is detected:

1. Confirm with histopathology: Look for characteristic features:

   • Dense lymphoplasmacytic infiltrate with IgG4+ plasma cells
   • IgG4+/IgG+ plasma cell ratio >40%
   • Storiform fibrosis
   • Obliterative phlebitis 3, 5

2. Rule out mimickers:

   • Multicentric Castleman disease
   • Lymphoma
   • Plasma cell neoplasms
   • Hypereosinophilic syndromes 5

3. Assess organ involvement with appropriate imaging:

   • MRI/MRCP for pancreaticobiliary evaluation
   • CT for other organ involvement
   • PET scan for multisystem disease 3

Conclusion

While serum IgG4 is a valuable biomarker for IgG4-RD, it must be interpreted in the context of clinical presentation, imaging findings, and histopathology. A comprehensive diagnostic approach is essential, as less than one-quarter of patients with elevated IgG4 actually meet IgG4-RD diagnostic criteria 2.