In a 70‑year‑old man with a serum total protein of 6.0 g/dL and a globulin level of 1.8 g/dL (albumin normal), what is the differential diagnosis for isolated low globulin and what laboratory work‑up is indicated?

Diagnostic Approach to Isolated Low Globulin in a 70-Year-Old Male

This patient with a total protein of 6.0 g/dL and globulin of 1.8 g/dL (calculated albumin ~4.2 g/dL, which is normal) has isolated hypoglobulinemia that requires immediate evaluation for primary or secondary antibody deficiency, protein-losing states, and medication-induced causes. 1, 2

Immediate Differential Diagnosis

Primary Immunodeficiencies

• Common Variable Immunodeficiency (CVID) is the most likely primary immunodeficiency in this age group, characterized by variable reduction in ≥2 immunoglobulin classes with normal or moderately reduced B-cell numbers, often diagnosed after age 4 years but can present in adulthood 2
• Selective IgA Deficiency presents with IgA <7 mg/dL while IgG and IgM remain normal, affecting approximately 1 in 300-700 white individuals 2
• Good syndrome (thymoma-associated immunodeficiency) should be considered in elderly patients, presenting as late-onset combined immunodeficiency similar to CVID but with thymoma present 2

Secondary Causes (More Common in This Age Group)

• Medication-induced hypogammaglobulinemia from rituximab or anti-CD20 therapies causes prolonged hypoglobulinemia in 21% of patients on long-term treatment 2
• Antiepileptic drugs including phenytoin, carbamazepine, valproic acid, and zonisamide cause reversible hypogammaglobulinemia 2
• Protein-losing enteropathy causes gastrointestinal protein loss with chronic diarrhea, though this typically also lowers albumin 3, 2
• Nephrotic syndrome causes urinary protein loss but usually affects albumin more than globulins 3, 2
• Lymphoproliferative disorders including multiple myeloma with immune paresis can present with low globulins despite the presence of a monoclonal protein 4

Essential Laboratory Work-Up

First-Tier Testing (Order Immediately)

• Serum protein electrophoresis with immunofixation to characterize specific protein fractions, detect monoclonal proteins, and identify immune paresis 4, 1, 5
• Quantitative immunoglobulin levels (IgG, IgA, IgM) to determine which immunoglobulin classes are affected 4, 1, 2
• Complete blood count with differential to assess for lymphopenia, anemia, or infection 1, 3
• Comprehensive metabolic panel including liver function tests (ALT, AST, alkaline phosphatase, bilirubin) and renal function (BUN, creatinine) 1, 3
• 24-hour urine protein quantification with urine protein/creatinine ratio to exclude nephrotic syndrome 3, 2

Second-Tier Testing (Based on Initial Results)

• Vaccine response testing to both protein antigens (tetanus, diphtheria) and polysaccharide antigens (pneumococcal) to assess functional antibody production 4
• IgG subclass measurements if IgG is low-normal but clinical suspicion remains high 2
• Flow cytometry for B-cell enumeration to distinguish between different primary immunodeficiencies 4
• Stool alpha-1 antitrypsin clearance if protein-losing enteropathy is suspected based on gastrointestinal symptoms 2
• Chest CT to evaluate for thymoma if Good syndrome is suspected 2

Critical Clinical Context to Obtain

Infection History

• Recurrent respiratory tract infections (sinusitis, pneumonia, bronchitis) are the hallmark of antibody deficiency and indicate need for immunoglobulin replacement regardless of exact IgG level 2
• Infections with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae) suggest severe immunodeficiency requiring urgent intervention 2

Medication Review

• Current and recent immunosuppressive therapies including rituximab, anti-CD20 agents, or antiepileptic drugs, as drug-induced hypogammaglobulinemia is frequently reversible with cessation 2

Associated Symptoms

• Chronic diarrhea, weight loss, or edema suggest protein-losing states 3, 2
• Autoimmune manifestations (arthritis, cytopenias, granulomatous disease) are common in CVID 4
• Lymphadenopathy or hepatosplenomegaly may indicate lymphoproliferative disorder 4

Risk Stratification and Urgency

High-Risk Features Requiring Urgent Intervention

• IgG <400 mg/dL indicates severe risk of life-threatening bacterial infections from encapsulated organisms 2
• History of ≥2 severe recurrent infections by encapsulated bacteria warrants IVIG replacement therapy regardless of exact IgG level 2
• Calculated globulin <18 g/L (1.8 g/dL in this patient) has 89% sensitivity for detecting IgG <6 g/L and 56% sensitivity for IgG <4 g/L 5

Common Pitfalls to Avoid

Critical Diagnostic Errors

• Failing to verify albumin and total protein levels is the most common mistake, as this simple step distinguishes protein loss syndromes from true immunodeficiency 2
• Overlooking medication history misses reversible drug-induced hypogammaglobulinemia 2
• Assuming normal total protein excludes significant pathology when isolated low globulin can indicate serious immunodeficiency 1, 5
• Missing small paraproteins with immune paresis occurs in 1.2% of patients with low calculated globulin when serum electrophoresis and immunofixation are not performed 5

Monitoring Considerations

• Serum immunoglobulin levels alone are inadequate for monitoring treatment efficacy; frequency of infections is a more important indicator 2
• Serial measurements of globulin and immunoglobulin levels should be performed to assess disease progression and treatment response 1

Treatment Implications

When to Initiate IVIG Replacement

• Monthly IVIG treatment is indicated for patients with ≥2 severe recurrent infections by encapsulated bacteria, continuing until immunoglobulin levels reach ≥400 mg/dL 2
• Prophylactic antibiotics may be considered as bridge therapy while awaiting immunology consultation 4

Prognosis

• Hypogammaglobulinemia is associated with decreased overall survival in multiple myeloma patients and increased morbidity across multiple clinical settings 2
• Early detection and treatment with immunoglobulin replacement therapy shortens diagnostic delay and improves outcomes 5