What causes elevated Immunoglobulin G (IgG) levels?

Causes of Elevated Immunoglobulin G (IgG)

Elevated IgG levels are most commonly associated with autoimmune conditions, chronic infections, liver diseases, and certain immunodeficiency syndromes, with autoimmune hepatitis being a classic cause requiring specific diagnostic consideration.

Primary Causes of Elevated IgG

1. Autoimmune Conditions

• Autoimmune Hepatitis (AIH)

  • Polyclonal hypergammaglobulinemia is a central diagnostic feature 1
  • IgG levels >1.5 times the upper normal limit is a key diagnostic criterion 1
  • AIH patients have significantly higher serum IgG levels compared to patients with other chronic liver diseases 2
  • Elevated IgG levels correlate with inflammatory activity in AIH 1

• Other Autoimmune Diseases

  • Systemic autoimmune diseases often present with polyclonal gammopathy 3
  • Approximately 13.5% of patients with elevated IgG4 have underlying autoimmune diseases 4

2. Chronic Infections

• Recurrent or persistent infections are the most common cause (25% of cases) of elevated IgG4 levels 4
• Chronic bacterial, viral, fungal, and parasitic infections can lead to persistent immune stimulation

3. Liver Diseases

• Chronic Liver Disease (CLD)
  • Advanced liver cirrhosis commonly presents with hypergammaglobulinemia 2
  • Decompensated cirrhosis patients have significantly higher IgG levels than those with compensated disease 2
  • The mechanism likely involves decreased clearance of immunoglobulins and increased gut permeability leading to immune stimulation

4. Immunodeficiency Syndromes

• Hyper-IgM Syndrome

  • Characterized by normal/high IgM with low IgG, IgA, and IgE 5
  • Results from defects in immunoglobulin class-switching 1
  • Multiple genetic forms exist, including deficiencies in:
    • Activation-induced cytidine deaminase (AID)
    • Uracil nucleoside glycosylase (UNG)
    • CD40 ligand (CD40L)
    • CD40 1

• Other Primary Immunodeficiencies

  • Common Variable Immunodeficiency (CVID) may occasionally present with elevated IgG subclasses despite overall hypogammaglobulinemia 1

5. Malignancies

• IgG4-Related Disease

  • Characterized by elevated serum IgG4 levels (>135 mg/dL) 6
  • Affects multiple organs with lymphoplasmacytic infiltration 4
  • Accounts for approximately 10% of cases with elevated IgG4 4

• Other Malignancies

  • Lymphoproliferative disorders
  • Multiple myeloma (monoclonal gammopathy)
  • Solid tumors can occasionally trigger immune responses 4

6. Other Conditions

• Pancreatic Diseases

  • Autoimmune pancreatitis shows elevated IgG and particularly IgG4 levels 1, 6
  • IgG4 >135 mg/dL has 73.3% sensitivity and 98.7% specificity for autoimmune pancreatitis vs. pancreatic cancer 6

• Atopic Dermatitis

  • Approximately 80% of patients have elevated total IgE and may have associated IgG elevations 1

Clinical Significance

Elevated IgG levels are associated with increased mortality risk:

• Higher IgG concentrations correlate with greater risk of death (HR=5.8,95% CI 3.38-9.95) 7
• Particularly strong association with infectious disease mortality 7

Diagnostic Approach

When elevated IgG is detected:

1. Determine pattern of elevation:

   • Polyclonal vs. monoclonal (protein electrophoresis)
   • Isolated IgG elevation vs. elevation of multiple immunoglobulin classes
   • Specific IgG subclass pattern (IgG1-4)

2. Screen for autoimmune conditions:

   • Autoantibody testing (ANA, SMA, anti-LKM1, etc.)
   • Liver function tests
   • Consider liver biopsy if autoimmune hepatitis is suspected 1

3. Evaluate for chronic infections:

   • Viral hepatitis serologies
   • Tuberculosis testing
   • HIV testing
   • Parasite screening if clinically indicated

4. Assess for liver disease:

   • Comprehensive liver function tests
   • Imaging studies (ultrasound, CT, or MRI)
   • Consider liver biopsy if indicated

5. Consider specialized testing:

   • IgG subclass analysis
   • Flow cytometry for lymphocyte subsets
   • Genetic testing if immunodeficiency suspected

Important Caveats

• IgG elevation alone is not diagnostic of any specific condition and must be interpreted in clinical context
• In AIH, approximately 15% of patients may have normal IgG levels, particularly in acute-onset disease 1
• IgG4 elevation >1.35 g/L is not specific to IgG4-related disease and can be seen in multiple conditions 4
• The range for normal IgG is wide, and some patients may have relative increases while still within the statistical normal range 1
• Serial monitoring of IgG levels can be useful for assessing treatment response in conditions like AIH 1