What is IgG4 SC (IgG4 serum concentration)?

IgG4-SC: IgG4-Related Sclerosing Cholangitis

IgG4-SC (IgG4-related sclerosing cholangitis) is a biliary tract manifestation of IgG4-related disease characterized by progressive bile duct stenosis, elevated serum IgG4 levels (in 50-80% of cases), lymphoplasmacytic infiltration with IgG4-positive plasma cells, and dramatic response to corticosteroid therapy. 1

Disease Definition and Classification

IgG4-SC represents the biliary manifestation of IgG4-related disease (IgG4-RD), a systemic immune-mediated fibro-inflammatory condition. 1, 2 The disease has been classified into four distinct anatomical patterns: 1

• Type 1: Stenosis confined to the intrapancreatic bile duct, typically associated with IgG4-related pancreatitis
• Type 2a: Intrahepatic stenosis with prestenotic dilatation
• Type 2b: Intrahepatic stenosis with peripheral bile duct pruning
• Type 3: Combined hilar and lower common bile duct stenosis
• Type 4: Isolated hilar stenosis

Clinical Presentation

The majority of patients (77%) present with obstructive jaundice, with 91% having concurrent IgG4-related pancreatitis. 1 Key clinical features include:

• Symptomatic biliary obstruction is the predominant presentation 1
• IgG4-SC develops in 24-39% of patients previously diagnosed with IgG4-related pancreatitis 1
• In patients with systemic IgG4-RD, 59% have biliary involvement 1
• Up to 8% of patients undergoing surgery for presumed cholangiocarcinoma are found to have IgG4-SC instead 1

Diagnostic Approach

Serum IgG4 Measurement

Elevated serum IgG4 supports the diagnosis but cannot be relied upon alone for definitive diagnosis or to distinguish IgG4-SC from PSC (STRONG recommendation, MODERATE quality evidence). 1

Critical diagnostic thresholds: 1, 3

• Serum IgG4 is elevated in 50-80% of IgG4-SC patients
• Serum IgG4 >4× upper limit of normal is highly specific for IgG4-SC compared to PSC
• IgG4/IgG1 ratio >0.24 improves specificity for distinguishing IgG4-SC from PSC
• Blood IgG4/IgG RNA ratio >5% by quantitative PCR demonstrates 94% sensitivity and 99% specificity 1, 4

Important caveat: 9-15% of PSC patients also have elevated serum IgG4, making distinction challenging. 1 Only 1% of primary biliary cholangitis patients have elevated IgG4. 1

Imaging Requirements

Non-invasive imaging with MRI/MRCP is the cornerstone of evaluation, defining the pancreaticobiliary ductal system and identifying multiorgan involvement. 1, 4

• Cholangiography (preferentially MRCP) is central to investigating all suspected cases 1
• Cross-sectional imaging (CT, MRI/MRCP) allows assessment of the pancreas and other organs potentially involved in IgG4-RD 1, 4
• PET scanning may identify fluorodeoxyglucose uptake at distant sites (salivary glands, lacrimal glands, kidneys) characteristic of multisystem disease 1, 4

Histopathological Confirmation

Tissue diagnosis should be pursued whenever possible to exclude malignancy and confirm IgG4-RD. 4 Diagnostic histological criteria include: 4, 3

• >10 IgG4-positive plasma cells per high-power field in biopsy specimens
• IgG4+/IgG+ plasma cell ratio >40% provides additional diagnostic evidence
• Dense lymphoplasmacytic infiltration with extensive fibrosis in the bile duct wall 3

Critical Differential Diagnoses

The most important conditions to exclude are: 1

1. Primary sclerosing cholangitis (PSC):

   • PSC does not respond to steroids in a sustained manner 5
   • 70% of PSC patients have inflammatory bowel disease vs. only 5.6% in IgG4-SC 5, 6
   • Elevated IgG4 occurs in 9-15% of PSC patients 1, 5

2. Cholangiocarcinoma: Up to 8% of presumed hilar cholangiocarcinoma cases are actually IgG4-SC 1

3. Pancreatic cancer: Requires exclusion through imaging and tissue diagnosis 6

Disease Course and Prognosis

The natural history of IgG4-SC remains incompletely defined: 1

• Recent studies suggest an indolent course in many patients
• Progression to cirrhosis occurs in 7.7-9% of patients
• Liver transplantation may be required in advanced cases
• Increased morbidity, malignancy, and mortality compared to age-matched controls has been reported 1

Treatment Response

A characteristic feature distinguishing IgG4-SC from PSC is the dramatic response to corticosteroid therapy, occurring in 62-100% of cases. 4, 2, 3 This excellent steroid responsiveness is both a diagnostic feature and therapeutic approach. 2, 3

Key Clinical Pitfalls

• Never rely on serum IgG4 alone for diagnosis, as it lacks sufficient sensitivity and specificity 1, 6
• Always pursue tissue diagnosis when feasible to avoid misdiagnosis of malignancy 4, 6
• Do not continue empiric immunosuppression without tissue confirmation, as this delays appropriate cancer treatment if malignancy is present 6
• Lack of steroid response is a red flag suggesting an alternative diagnosis such as PSC or malignancy 6