What is the approach to a patient with suspected false negatives for Immunoglobulin G4 (IgG4)?

Approach to Patients with Suspected False Negatives for IgG4

In patients with suspected false negative IgG4 tests, a comprehensive diagnostic approach should include histological confirmation, evaluation of organ involvement patterns, and advanced testing such as IgG4/IgG RNA ratio analysis, which has shown excellent sensitivity (94%) and specificity (99%) for IgG4-related disease.

Understanding IgG4 False Negatives

Serum IgG4 testing has significant limitations that can lead to false negative results:

• Serum IgG4 may be elevated in only 50-80% of patients with IgG4-related disease (IgG4-RD) 1
• Relying solely on serum IgG4 levels is insufficient for diagnosis 1
• False negatives are common enough that the British Society of Gastroenterology strongly recommends against using serum IgG4 as the sole diagnostic test 1

Diagnostic Algorithm for Suspected False Negative IgG4

Step 1: Advanced Serological Testing

• Measure total IgG and calculate IgG4/IgG1 ratio (>0.24 improves diagnostic accuracy) 1
• Consider IgG4/IgG RNA ratio testing by quantitative PCR (>5% has 94% sensitivity and 99% specificity) 1, 2
• Look for other laboratory clues:
  • Peripheral eosinophilia
  • Hypergammaglobulinemia
  • Elevated serum IgE levels
  • Hypocomplementemia 3

Step 2: Histopathological Confirmation

• Tissue biopsy is essential and should be pursued in all cases of suspected IgG4-RD 1, 2
• Look for characteristic features:

  • 10 IgG4-positive plasma cells per high power field

  • IgG4+/IgG+ plasma cell ratio >40%
  • Storiform fibrosis
  • Obliterative phlebitis
  • Lymphoplasmacytic infiltrate 1, 3

Step 3: Targeted Biopsy Approaches

• For biliary involvement:
  • Endoscopic ampullary biopsies (positive in 53-80% of cases) 1
  • Fluoroscopically guided endobiliary biopsy
  • Visually directed cholangioscopic biopsies 1
• For pancreatic involvement:
  • EUS-guided core biopsy (preferred over FNA) 1, 2
• For other organs:
  • Target the most accessible involved organ
  • Note that lymph nodes and bone marrow are suboptimal sites for diagnosis 4

Step 4: Cross-sectional Imaging

• MRI/MRCP for biliary and pancreatic involvement 1, 2
• CT for assessment of other organ involvement 1
• PET scanning to identify multisystem involvement 1
• Look for characteristic patterns:
  • Biliary: Four types of stenosis patterns 1
  • Pancreatic: Long pancreatic duct stricture, multifocal stricturing 1
  • Involvement of salivary/lacrimal glands, kidneys, retroperitoneum 1, 2

Clinical Pearls and Pitfalls

Key Differentiating Features

• IgG4-SC vs. PSC differentiation:
  • IgG4-SC: Often associated with pancreatic involvement (>80% of cases) 1
  • IgG4-SC: Less commonly associated with IBD (5.6%) compared to PSC (70%) 1
  • IgG4-SC: More likely to have other organ involvement 1

Common Pitfalls

• Relying solely on serum IgG4 levels for diagnosis 1
• Failing to obtain histological confirmation 1, 2
• Misinterpreting cholangiographic findings (high interobserver variation) 1
• Overlooking other organ involvement that could aid diagnosis 1
• Mistaking IgG4-RD for malignancy or vice versa 1, 2

Advanced Diagnostic Considerations

• Consider a therapeutic trial of corticosteroids (prednisolone 40mg daily for 2-4 weeks) with assessment of objective improvement at 4-8 weeks 2
• Lack of response suggests either incorrect diagnosis or fibrotic phase of disease 2
• For complex cases, refer to a specialist multidisciplinary team 1, 2

By following this structured approach, clinicians can effectively address suspected false negative IgG4 results and establish an accurate diagnosis of IgG4-related disease, leading to appropriate treatment and improved patient outcomes.