What are the guidelines for diagnosing and treating IgG4 (Immunoglobulin G4) disease?

Guidelines for IgG4-Related Disease Diagnosis

IgG4-related disease should be diagnosed using a combination of elevated serum IgG4 levels (which support but cannot definitively diagnose the condition), histopathological confirmation showing >10 IgG4-positive plasma cells per high-power field with an IgG4+/IgG+ ratio >40%, cross-sectional imaging to identify organ involvement, and assessment for multi-organ disease according to international consensus guidelines. 1, 2

Diagnostic Algorithm

Step 1: Serum IgG4 Testing

• Measure serum IgG4 levels in all suspected cases, but recognize this alone cannot make or exclude the diagnosis 1
• Serum IgG4 is elevated in only 50-80% of IgG4-RD patients, meaning normal levels do not rule out disease 2
• A serum IgG4 >4× upper limit of normal is highly specific for IgG4-RD and strongly supports the diagnosis 1, 2, 3
• A cutoff of ≥2.8 g/L provides 96.2% specificity and 97.7% negative predictive value, though sensitivity drops to 56.9% 4
• An IgG4/IgG1 ratio >0.24 improves diagnostic specificity when distinguishing from mimickers like PSC 2, 3
• Blood IgG4/IgG RNA ratio >5% by quantitative PCR has excellent sensitivity (94%) and specificity (99%), though not widely available 1, 2

Critical pitfall: 9-15% of patients with other conditions (including PSC, malignancy, and inflammatory diseases) also have elevated IgG4 levels, so this marker must never be used in isolation 2, 4

Step 2: Histopathological Confirmation

Pursue tissue diagnosis whenever possible to distinguish IgG4-RD from malignancy and other inflammatory conditions 1, 2

The British Society of Gastroenterology and American Gastroenterological Association recommend obtaining biopsy specimens with specific quantitative criteria:

• >10 IgG4-positive plasma cells per high-power field in affected tissue 1, 2
• IgG4+/IgG+ plasma cell ratio >40% provides additional diagnostic evidence 1, 2, 3
• Look for characteristic features: lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis 1, 5

Tissue sampling options based on organ involvement:

• Biliary disease: Fluoroscopically guided endobiliary biopsy, cholangioscopic biopsies, or major papilla biopsies (53-80% positive in IgG4-related pancreatitis) 1
• Pancreatic disease: EUS-guided core biopsy (fine-needle aspiration alone rarely provides definitive diagnosis) 1
• Other organs: Direct biopsy of accessible affected tissues 1, 2

Step 3: Cross-Sectional Imaging

Non-invasive imaging with CT or MRI/MRCP is the cornerstone of evaluation 1, 2

Key imaging objectives:

• Define extent of organ involvement (pancreas, bile ducts, kidneys, retroperitoneum, salivary/lacrimal glands) 1, 2
• Identify characteristic patterns in IgG4-related sclerosing cholangitis (four defined types of biliary involvement) 1
• PET scanning may identify fluorodeoxyglucose uptake at distant sites characteristic of multisystem disease, reinforcing diagnostic suspicion 1, 2
• CT and MR imaging typically show organ enlargement, decreased attenuation on CT, and relatively low T2 signal intensity due to increased cellularity and fibrosis 6

Step 4: Multi-Organ Assessment

Actively search for other organ involvement, particularly pancreatic manifestations, as this provides important diagnostic information 1

• Multi-organ involvement is common and may occur synchronously or metachronously 7
• A serum IgG4 ≥2.8 g/L at diagnosis is associated with multi-organ involvement 4
• Organs commonly affected include: pancreas, bile ducts, salivary glands, lacrimal glands, orbits, kidneys, retroperitoneum, lungs, and lymph nodes 6, 8

Step 5: Apply International Consensus Criteria

The British Society of Gastroenterology strongly recommends diagnosing IgG4-RD according to international consensus guidelines 1

The comprehensive diagnostic criteria established by Japanese investigators require:

1. Serum IgG4 concentration >135 mg/dL 7

2. 40% of IgG+ plasma cells being IgG4+ AND >10 cells/high-powered field in biopsy samples 7

Combine comprehensive criteria with organ-specific criteria to achieve 100% diagnostic sensitivity for conditions like Mikulicz disease, kidney disease, and autoimmune pancreatitis 7

Step 6: Multidisciplinary Review for Complex Cases

Refer patients with complex IgG4-RD and those with suspected malignancy to a specialist multidisciplinary team for review 1

This is particularly critical because:

• IgG4-RD can mimic malignancy on imaging 1, 6
• Definitive differentiation from cholangiocarcinoma, PSC, and other conditions often requires expert interpretation 1
• Treatment decisions may require input from multiple specialties 1

Common Diagnostic Pitfalls

Avoid these critical errors:

• Never diagnose IgG4-RD based solely on elevated serum IgG4, as specificity is insufficient 1, 4
• Do not rely on fine-needle aspiration alone for pancreatic lesions; core biopsy provides more definitive pathological evidence 1
• Remember that normal serum IgG4 does not exclude IgG4-RD, as 18-50% of patients have normal levels 2, 4
• Recognize that brush cytology cannot make a definitive diagnosis of IgG4-related sclerosing cholangitis 1