What diseases can IgG4 help differentiate from IgG4‑related disease?

What IgG4 Helps Differentiate from IgG4-Related Disease

IgG4 testing primarily helps differentiate IgG4-related disease from primary sclerosing cholangitis (PSC), cholangiocarcinoma (CCA), and other inflammatory conditions, though elevated IgG4 alone is insufficient for diagnosis as it occurs in numerous non-IgG4-RD conditions.

Key Differential Diagnoses

Primary Sclerosing Cholangitis (PSC)

• PSC is the most critical differential diagnosis for IgG4-related sclerosing cholangitis (IgG4-SC), particularly when biliary disease is present 1
• Elevated serum IgG4 occurs in 9-15% of PSC patients, making distinction challenging based on IgG4 levels alone 1, 2
• An IgG4/IgG1 ratio >0.24 improves specificity for distinguishing IgG4-SC from PSC 1, 3, 2
• Serum IgG4 >4× upper limit of normal is highly specific for IgG4-SC compared to PSC 1, 3, 2
• Inflammatory bowel disease (IBD) is a key discriminating feature: present in approximately 70% of PSC patients but only 5.6% of IgG4-SC patients 3, 4, 2
• IgG4-RD shows rapid and dramatic response to corticosteroids within 2-4 weeks in 62-100% of cases, whereas PSC does not respond to steroids 3, 4, 2

Cholangiocarcinoma (CCA)

• CCA is a critical malignant differential, with pathological features of IgG4-SC found in up to 8% of patients undergoing surgery for presumed hilar CCA 1
• Tissue diagnosis should be pursued whenever possible to distinguish IgG4-RD from malignancy, requiring >10 IgG4-positive plasma cells per high-power field and IgG4+/IgG+ ratio >40% 3, 4, 2
• Blood IgG4/IgG RNA ratio >5% by quantitative PCR has excellent sensitivity (94%) and specificity (99%) for distinguishing IgG4-RD from CCA 1, 3

Other Conditions with Elevated IgG4

Elevated serum IgG4 is not specific to IgG4-RD and occurs in multiple conditions:

• Chronic diseases of various organs (21.7% of elevated IgG4 cases) 5
• Rheumatic immune diseases (19.4%), including SLE, RA, and EGPA 5, 6
• Respiratory diseases, particularly COPD and asthma 6
• Bacterial infections (11.5%) 5
• Malignant tumors (5.2%), predominantly lung and hematologic cancers 5, 6
• Eosinophilia, which manifests similarly high IgG4 levels as IgG4-RD 5
• Only 3.2-5.1% of patients with elevated serum IgG4 actually have IgG4-RD 7, 6

Diagnostic Algorithm for Differentiation

Step 1: Serum IgG4 Measurement

• Serum IgG4 is elevated in 50-80% of IgG4-RD patients but cannot be relied upon for definitive diagnosis 1, 3, 2
• A cutoff of 1.4 g/L provides 82.8% sensitivity and 84.7% specificity 7
• Increasing the cutoff to 2.8 g/L improves specificity to 96.2% and negative predictive value to 97.7%, though sensitivity drops to 56.9% 7
• IgG4/IgG ratio >0.295 provides 80% sensitivity and 88.8% specificity 5

Step 2: Clinical Features Assessment

• Look for multi-organ involvement: extrapancreatic manifestations occur in 85% of IgG4-RD cases, including salivary glands, kidneys, retroperitoneum, and biliary tree 3, 2
• Assess for pancreatic involvement: present in >80% of IgG4-SC cases 2
• Check for IBD: its presence strongly favors PSC over IgG4-SC 3, 4, 2

Step 3: Imaging Evaluation

• MRCP is the cornerstone non-invasive evaluation with 90% sensitivity 3, 2
• IgG4-SC shows long biliary strictures with pre-stenotic dilatation, while PSC shows short, band-like strictures 2
• Absence of peripheral duct pruning and biliary pseudodiverticula supports IgG4-SC over PSC 2
• PET scanning may identify fluorodeoxyglucose uptake at distant sites characteristic of multisystem IgG4-RD 1, 3

Step 4: Histopathological Confirmation

• Tissue diagnosis is essential to exclude malignancy and confirm IgG4-RD 3, 4, 8
• Diagnostic criteria require >10 IgG4-positive plasma cells per high-power field 3, 4, 2
• IgG4+/IgG+ plasma cell ratio >40% provides additional diagnostic evidence 3, 4, 2, 8
• Look for the histologic triumvirate: dense lymphoplasmacytic infiltrate, storiform-type fibrosis, and obliterative phlebitis 8

Step 5: Therapeutic Trial

• Consider a corticosteroid trial when diagnosis remains uncertain after above workup 3, 4
• Dramatic clinical and radiographic response within 2-4 weeks strongly supports IgG4-RD over PSC or malignancy 3, 4, 2

Critical Pitfalls to Avoid

• Never diagnose IgG4-RD based on elevated serum IgG4 alone, as less than one-quarter of patients with elevated IgG4 meet IgG4-RD diagnostic criteria 7
• Do not exclude IgG4-RD if serum IgG4 is normal, as 20-50% of IgG4-RD patients have normal levels 1, 3, 2
• Always pursue tissue diagnosis when feasible to avoid missing malignancy, particularly cholangiocarcinoma 1, 3, 4
• Recognize that imaging alone has high inter-observer variation and must be interpreted with clinical, serologic, and histopathologic findings 2
• Be aware that IgG4-positive plasma cells occur in various inflammatory and neoplastic diseases, requiring the full histologic context 8