What are the causes of low serum globulin levels?

Causes of Low Serum Globulin Levels

Low globulin levels result from either decreased immunoglobulin production (primary or secondary immunodeficiency) or increased protein loss through the kidneys, gastrointestinal tract, or lymphatic system. 1

Critical First Step: Distinguish Production Defects from Protein Loss

Measure albumin and total protein simultaneously—this single step distinguishes protein-losing conditions from true immunodeficiency. 1, 2, 3

• Primary immunodeficiencies have normal albumin and total protein because only immunoglobulin production is affected 1, 2, 3
• Concurrent low total protein and albumin strongly suggest secondary hypogammaglobulinemia from protein loss 2

Primary Causes: Immunodeficiency Disorders

Agammaglobulinemia

• Very low or undetectable immunoglobulins with absent or severely reduced B cells (<2% of lymphocytes) 1, 3
• Presents in the first 2 years of life with recurrent bacterial respiratory infections 1, 3
• X-linked form (Bruton's disease) accounts for 85% of cases 3

Common Variable Immunodeficiency (CVID)

• IgG <450-500 mg/dL plus IgA or IgM below 5th percentile, with impaired specific antibody production 1, 2, 3
• Normal or moderately reduced B-cell numbers (approximately 13% have <3% B cells) 1, 3
• Should not be diagnosed before age 4 years 1, 3
• Often presents with recurrent bacterial respiratory infections, fatigue, and B-cell abnormalities 4, 1

Selective IgA Deficiency

• IgA <7 mg/dL with normal IgG and IgM in patients older than 4 years 1, 3
• Most common primary immunodeficiency, affecting approximately 1 in 300-700 white individuals 1, 3

Other Primary Immunodeficiencies

• Dyskeratosis congenita: telomere biology disorder with hypogammaglobulinemia, lymphopenia, and impaired antibody responses 1
• Immunodeficiency with multiple intestinal atresia: SCID-like phenotype with markedly decreased B- and T-cell counts 1

Secondary Causes: Acquired Hypogammaglobulinemia

Medication-Induced (Often Reversible)

• Rituximab and anti-CD20 therapies: 21% of patients on long-term rituximab develop IgG <5 g/L 1
• Antiepileptic drugs (phenytoin, carbamazepine, valproic acid, zonisamide) cause reversible hypogammaglobulinemia 1, 2
• Other medications: sulfasalazine, gold, penicillamine, hydroxychloroquine, NSAIDs 2

Protein Loss Syndromes (Low Albumin + Low Total Protein)

• Nephrotic syndrome: urinary protein loss diagnosed by 24-hour urine protein, urine protein/creatinine ratio, and urinalysis 1, 2
• Protein-losing enteropathy: gastrointestinal protein loss with chronic diarrhea, assessed by stool alpha-1 antitrypsin clearance 1, 2
• Lymphatic disorders: disrupted lymphatic drainage leading to protein loss 1

Hematologic Malignancies

• Multiple myeloma with immune paresis: 47% of patients with low globulin in one cohort had secondary antibody deficiency from hematological malignancy 5
• Good syndrome: thymoma-associated immunodeficiency with late-onset combined immunodeficiency phenotype 1
• B-cell lymphomas can cause secondary hypogammaglobulinemia 2

Severe Liver Disease

• Acute liver failure: Gc-globulin levels reduced to 21% of normal, with 7-fold increased production rate unable to compensate for accelerated clearance 6, 7
• Chronic liver disease: Gc-globulin reduced to 43% of normal levels 6
• Hepatic encephalopathy associated with reduced globulin levels 6, 7

Essential Diagnostic Workup

Initial Laboratory Testing

• Quantitative measurement of serum immunoglobulins (IgG, IgA, IgM) to determine which classes are reduced 1, 3
• Serum protein electrophoresis with immunofixation to characterize protein fractions and detect monoclonal proteins 1, 3
• Total protein and albumin to distinguish protein loss from production defects 1, 2, 3

Functional and Cellular Testing

• B-cell enumeration by flow cytometry to distinguish CVID (normal/reduced B cells) from agammaglobulinemia (absent B cells) 1, 2, 3
• Vaccine response testing to protein antigens (tetanus/diphtheria) and polysaccharide antigens (pneumococcal) to evaluate functional antibody production 4, 1, 3
• T-cell evaluation including lymphocyte subset analysis to identify combined immunodeficiency 2

Screening Value of Calculated Globulin

• Calculated globulin ≤20 g/L has 82.5% positive predictive value for hypogammaglobulinemia (IgG ≤5.7 g/L) 8
• Screening at globulin <16-18 g/L detects 89% of patients with IgG <6 g/L 9
• Identifies both primary and secondary antibody deficiency, reducing diagnostic delay 5, 9, 8

Critical Clinical Pitfalls to Avoid

• Failing to check albumin and total protein leads to misdiagnosis of protein-losing syndromes as primary immunodeficiency 1, 3
• Inadequate medication history misses reversible drug-induced hypogammaglobulinemia 1, 3
• Diagnosing CVID before age 4 years leads to misdiagnosis 1, 3
• Relying on serum levels alone without functional antibody testing underestimates infection risk 2, 3

Urgent Clinical Implications

• Patients with IgG <300-400 mg/dL face severe risk of life-threatening bacterial infections from encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae) 1, 2, 3
• Recurrent respiratory tract infections are the hallmark presentation 1, 3
• Consider urgent immunoglobulin replacement therapy for IgG <300 mg/dL to reduce infection risk 2, 3
• Antibiotic prophylaxis should be considered while awaiting definitive diagnosis 2