What is the recommended workup for a patient suspected of having IgG4 (Immunoglobulin G4)-related disease?

IgG4-Related Disease Workup

The workup for suspected IgG4-related disease requires a systematic approach combining serum IgG4 measurement, cross-sectional imaging to assess multi-organ involvement, and most importantly, histopathological confirmation with tissue biopsy showing >10 IgG4-positive plasma cells per high-power field with an IgG4/IgG ratio >40%. 1

Initial Laboratory Assessment

Serum IgG4 Level

• Measure serum IgG4 concentration as the initial screening test, which is elevated in 50-80% of IgG4-RD patients 1
• Critical caveat: Elevated serum IgG4 alone cannot establish the diagnosis or distinguish IgG4-RD from mimickers like primary sclerosing cholangitis 1
• An IgG4/IgG1 ratio >0.24 improves diagnostic specificity when distinguishing from PSC 1, 2
• Serum IgG4 >4× upper limit of normal is highly specific for IgG4-related sclerosing cholangitis 1, 2

Additional Laboratory Tests

• Peripheral eosinophilia (commonly present) 3
• Hypergammaglobulinemia and elevated serum IgE levels 3
• Hypocomplementemia 3

Imaging Studies

Cross-Sectional Imaging (CT/MRI/MRCP)

• Obtain CT or MRI with MRCP to define the pancreaticobiliary ductal system and identify other organ involvement 1
• Look specifically for: pancreatic enlargement or masses, biliary strictures, retroperitoneal fibrosis, kidney involvement, and salivary/lacrimal gland enlargement 1
• MRCP patterns in IgG4-SC include: lower CBD stenosis (type 1), intrahepatic stenosis with prestenotic dilatation (type 2a), intrahepatic stenosis with peripheral pruning (type 2b), hilar and lower CBD stenosis (type 3), or isolated hilar stenosis (type 4) 1

PET Scanning (Optional)

• Consider PET scan to identify fluorodeoxyglucose uptake at distant sites characteristic of multisystem IgG4-RD (salivary glands, lacrimal glands, lymph nodes) 1
• Pitfall: PET positivity localized only to one site cannot distinguish IgG4-RD from malignancy 1

Histopathological Confirmation

Tissue Biopsy - Essential Step

• Pursue histological diagnosis in all suspected cases to distinguish from malignancy and other mimickers 1
• Target the most accessible affected organ for biopsy 1

Key Histopathological Features

• Dense lymphoplasmacytic infiltrate with >10 IgG4-positive plasma cells per high-power field 1, 2
• IgG4+/IgG+ plasma cell ratio >40% 2, 4
• Storiform fibrosis (except in bone marrow and lymph nodes) 5, 4
• Obliterative phlebitis (except in bone marrow and lymph nodes) 5, 4

Biopsy Site Selection

• Endoscopic ampullary biopsy (positive in 52-72% of IgG4-SC cases) 1
• Core biopsy of affected organs provides more definitive pathological evidence 1
• Avoid bone marrow and lymph node biopsies as primary diagnostic sites - they lack storiform fibrosis and obliterative phlebitis, making them suboptimal for confirmation 4

Assessment of Multi-Organ Involvement

Systematically evaluate for involvement of:

• Pancreas (present in >80% of IgG4-SC cases) 1, 2
• Biliary tree 1
• Kidneys (tubulointerstitial nephritis) 4
• Retroperitoneum (retroperitoneal fibrosis) 4
• Salivary and lacrimal glands 4
• Lungs 1

This multi-organ assessment is critical for distinguishing IgG4-RD from organ-specific diseases like isolated PSC 1

Differential Diagnosis Considerations

Key Distinguishing Features from PSC

• Inflammatory bowel disease present in 70% of PSC vs. 5.6% of IgG4-SC 1, 2
• Pancreatic involvement much more common in IgG4-RD 1
• Therapeutic trial consideration: IgG4-RD shows prompt clinical and radiographic response to corticosteroids, unlike PSC 1, 2, 5

Exclude Malignancy

• Up to 8% of presumed hilar cholangiocarcinoma cases are actually IgG4-SC 1
• Histopathological confirmation is essential before initiating treatment 5, 3

Application of Diagnostic Criteria

Follow international consensus guidelines for final diagnosis 1

• Diagnosis requires integration of clinical presentation, elevated serum IgG4, characteristic imaging findings, histopathology, multi-organ involvement assessment, and response to steroids 5
• No single finding is pathognomonic - diagnosis requires careful interpretation of all findings together 6, 3

Special Considerations

ANCA Testing

• Consider ANCA testing if vasculitis is in the differential diagnosis 7
• Important caveat: ANCA positivity does not exclude IgG4-RD, as some patients have concomitant ANCA-associated vasculitis 7

Complex Cases

• Refer patients with complex presentations or suspected malignancy to a specialist multidisciplinary team 1