What are the causes of low globulin levels?

Causes of Low 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 Initial Distinction

The pattern of protein abnormalities immediately narrows the differential diagnosis:

• Concurrent low total protein AND low albumin strongly indicates secondary hypogammaglobulinemia from protein loss (nephrotic syndrome, protein-losing enteropathy, or lymphatic disorders), as both albumin and globulins are lost together 1
• Normal albumin and total protein with isolated low globulin suggests primary immunodeficiency, where only immunoglobulin production is impaired 1

Primary Causes (Immunodeficiency Disorders)

Congenital/Genetic Immunodeficiencies

• Agammaglobulinemia: Very low or undetectable immunoglobulins with absent or severely reduced B cells, typically presenting in the first 2 years of life with recurrent bacterial respiratory infections 2
• Common Variable Immunodeficiency (CVID): Variable reduction in ≥2 immunoglobulin classes (IgG <450-500 mg/dL plus low IgA or IgM), with normal or moderately reduced B-cell numbers, often diagnosed after age 4 years 3, 1
• Selective IgA Deficiency (SIGAD): IgA <7 mg/dL with normal IgG and IgM levels in patients older than 4 years, affecting approximately 1 in 300-700 white individuals 2, 4
• IgG Subclass Deficiency: Subnormal levels of one or more IgG subclasses, noted in about 25% of patients with recurrent respiratory infections 5
• Dyskeratosis Congenita: Telomere biology disorder presenting with hypogammaglobulinemia, lymphopenia, and impaired antibody responses alongside characteristic skin findings 2
• Immunodeficiency with Multiple Intestinal Atresia: SCID-like phenotype with variable immune defects including hypogammaglobulinemia and markedly decreased B- and T-cell counts 2

Transient Conditions

• Transient Hypogammaglobulinemia of Infancy: Temporarily low immunoglobulin levels that typically resolve spontaneously, requiring monitoring of IgG, IgA, and IgM levels over time 3

Secondary Causes

Hematologic Malignancies

• Multiple myeloma (particularly light chain and non-secretory types) with associated immunoparesis accounts for approximately 2.2% of cases with low calculated globulin 6
• B-cell lymphomas and chronic lymphocytic leukemia cause secondary hypogammaglobulinemia through disrupted B-cell function 7
• Hematologic malignancies represented approximately 47% of patients with low globulin in one cohort study 6

Iatrogenic/Medication-Induced

• Rituximab and anti-CD20 therapies: 21% of patients on long-term rituximab develop IgG <5 g/L with prolonged hypogammaglobulinemia 8, 7
• Antiepileptic drugs: Phenytoin, carbamazepine, valproic acid, and zonisamide can cause reversible SIGAD and hypogammaglobulinemia 2
• Immunosuppressive medications: Various agents used for autoimmune conditions, transplantation, and neurologic disorders 7
• Other medications: Sulfasalazine, gold, penicillamine, hydroxychloroquine, and NSAIDs 2
• Iatrogenic causes accounted for 20% of secondary immune deficiency cases in one study 6

Protein Loss Syndromes

• Nephrotic syndrome: Urinary protein loss leading to hypogammaglobulinemia, diagnosed by 24-hour urine protein, urine protein/creatinine ratio, and urinalysis 1, 7
• Protein-losing enteropathy: Gastrointestinal protein loss with chronic diarrhea, assessed by stool alpha-1 antitrypsin clearance and intestinal imaging 1, 7
• Lymphatic disorders: Disrupted lymphatic drainage causing protein loss 1

Other Secondary Causes

• Good syndrome: Thymoma-associated immunodeficiency with late-onset combined immunodeficiency phenotype, similar to CVID but with thymoma present 2
• Post-transplant immunosuppression: Chronic immunosuppressive therapy following solid organ or hematopoietic stem cell transplantation 7
• Autoimmune conditions: Various autoimmune diseases can be associated with secondary hypogammaglobulinemia 7

Clinical Pitfalls and Diagnostic Considerations

A critical pitfall is failing to check albumin and total protein levels, as this simple step distinguishes protein loss syndromes from true immunodeficiency 1. In protein loss syndromes, both albumin and globulin are low, whereas primary immunodeficiencies show isolated low globulin with normal albumin 1.

Medication history is essential and often overlooked, as drug-induced hypogammaglobulinemia is frequently reversible with cessation of the offending agent 2. Always review antiepileptics, immunosuppressants, and disease-modifying antirheumatic drugs 2, 7.

Screening at calculated globulin <18 g/L (using bromocresol green) or <23 g/L (using bromocresol purple) detects 89% and 74% of patients with IgG <6 g/L, respectively 9. This widely available, inexpensive test is significantly under-utilized for detecting both primary and secondary antibody deficiency 9.

Approximately 23% of patients with low globulin have multiple comorbidities with unexpected hypogammaglobulinemia, requiring further investigation and increased clinician awareness 6. These patients may benefit from optimized treatment and watchful clinical assessment 6.