What causes low Immunoglobulin G (IgG) levels?

Causes of Low IgG Levels

Low IgG levels result from either primary immunodeficiencies (genetic defects affecting B-cell development or antibody production) or secondary causes (medications, protein loss, malignancies, or infections that deplete immunoglobulins). 1

Primary Immunodeficiency Causes

Severe B-Cell Defects

• X-linked agammaglobulinemia (Bruton disease) accounts for 85% of agammaglobulinemia cases and presents with absent or extremely low B cells and profoundly low IgG levels 1
• Autosomal recessive agammaglobulinemia causes similar severe IgG deficiency with absent B cells 1
• These conditions typically manifest with recurrent bacterial infections of the upper and lower respiratory tract 1

Common Variable Immunodeficiency (CVID)

• CVID should be suspected in patients over 4 years old with IgG below 450-500 mg/dL, low IgA levels, and impaired antibody responses 1
• This affects approximately 1 in 30,000 persons and presents with recurrent sinopulmonary infections from encapsulated bacteria like H. influenzae and S. pneumoniae 1
• CVID requires exclusion of secondary causes including medications, protein loss through gastrointestinal/renal routes, B-cell lymphomas, and bone marrow failure 1

IgG Subclass Deficiencies

• Isolated IgG subclass deficiencies can occur with normal total IgG levels, particularly affecting IgG2 (often with IgG4 deficiency) and frequently associated with IgA deficiency 2
• IgG1 deficiency typically occurs with disturbances of other immunoglobulin isotypes and may represent a form of CVID 2
• IgG3 deficiency has been reported with lung dysfunction and viral diseases 2
• The clinical significance depends on specific antibody production capacity rather than absolute subclass levels alone 3

Syndromic Immunodeficiencies with Low IgG

Ataxia-Telangiectasia (AT):

• Presents with low or increased immunoglobulin levels, with up to 40% displaying oligogammaglobulinemia 1
• Low IgA levels, IgG subclass abnormalities, and impaired pneumococcal polysaccharide responses are common 1

Wiskott-Aldrich Syndrome:

• Associated with variable immunoglobulin abnormalities including low IgG levels 1

ICF Syndrome (Immunodeficiency, Centromeric Instability, Facial Anomalies):

• Hypogammaglobulinemia occurs in most patients (39/44 in one series) 1
• Presents from 3 months to 4 years with frequent bacterial respiratory infections 1

Bloom Syndrome:

• Characterized by low IgG and IgA levels with leukopenia 1

Transient Hypogammaglobulinemia of Infancy

• IgG levels spontaneously correct to normal at a mean age of 27 months, with all patients reaching normal levels by 59 months 4
• More common in males (60% of cases) 4
• Should be considered in children under 4 years with low IgG but preserved specific antibody responses 4

Secondary Causes of Low IgG

Medication-Induced

• Antiepileptic drugs, gold, penicillamine, hydroxychloroquine, and NSAIDs can cause secondary IgG subclass deficiency 5
• Rituximab causes hypogammaglobulinemia (IgG or IgM below normal) in a significant proportion of treated patients, with prolonged hypogammaglobulinemia (lasting ≥4 months) observed in 72% of pediatric GPA/MPA patients 6
• At 6 months post-rituximab, 58% of patients with normal baseline IgG developed low IgG levels 6

Protein Loss Syndromes

• Gastrointestinal protein loss (protein-losing enteropathy) 1
• Renal protein loss (nephrotic syndrome) 1
• Lymphatic protein loss 1
• These conditions present with low serum total protein and/or albumin levels alongside low IgG 1

Malignancies

• B-cell lymphomas can cause secondary hypogammaglobulinemia 1
• IgE deficiency with non-CVID humoral immunodeficiency has been associated with increased malignancy risk 7

Other Secondary Causes

• HIV infection causes secondary immunodeficiency with variable IgG abnormalities 5
• Post-hematopoietic stem cell transplantation (HSCT) 5
• Bone marrow failure 1

Critical Diagnostic Considerations

Age-Specific Interpretation

• Normal IgG for a 4-year-old should be above 450-500 mg/dL 4
• IgG levels gradually increase with age, reaching adult-like levels by 59 months 4
• Low IgG in children under 4 years may represent normal developmental variation or transient hypogammaglobulinemia 4

Essential Functional Assessment

• Measuring specific antibody responses to protein and polysaccharide vaccines is essential, as IgG levels alone do not predict antibody production capacity 1, 3
• Completely asymptomatic individuals who totally lack certain IgG subclasses due to gene deletions can produce antibodies normally 3
• Healthy children with low IgG2 but normal polysaccharide responses have been described 3

Important Pitfalls to Avoid

• Do not diagnose IgG subclass deficiency based solely on laboratory values without clinical correlation 5
• Laboratory error can lead to misdiagnosis; confirm abnormal results with repeat testing 4
• Normal total IgG does not exclude subclass deficiency, but isolated low subclass levels may not be clinically significant 5
• Approximately 2.5% of healthy individuals naturally have IgG subclass levels below 2 standard deviations of the mean 5
• Some patients with IgG subclass deficiency may evolve into CVID over time, requiring long-term monitoring 5