In a 39‑year‑old man with total protein 5.9 g/dL, normal albumin, and calculated globulin 1.4 g/dL, what is the differential diagnosis and recommended initial work‑up?

Low Globulin with Normal Albumin in a 39-Year-Old Male

Immediate Clinical Interpretation

A calculated globulin of 1.4 g/dL with normal albumin and total protein 5.9 g/dL represents significant hypoglobulinemia that warrants urgent evaluation for primary or secondary immunodeficiency, as this pattern indicates isolated reduction in immunoglobulins rather than generalized protein loss. 1

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Differential Diagnosis

Primary Immunodeficiencies

• Common Variable Immunodeficiency (CVID) is the most likely diagnosis in an adult presenting with isolated hypoglobulinemia, characterized by reduction in ≥2 immunoglobulin classes with normal or moderately reduced B-cell numbers, typically diagnosed after age 4 years 1

• Selective IgA Deficiency presents with IgA <7 mg/dL but normal IgG and IgM levels in patients older than 4 years, affecting approximately 1 in 300-700 white individuals 1

• IgG subclass deficiency requires measurement of all 4 subclasses simultaneously with confirmation by repeat testing ≥1 month apart 1

Secondary Causes (Drug-Induced or Acquired)

• Rituximab and anti-CD20 therapies cause prolonged hypogammaglobulinemia, with 21% of patients on long-term rituximab developing IgG <5 g/L 1

• Antiepileptic drugs including phenytoin, carbamazepine, valproic acid, and zonisamide cause reversible hypogammaglobulinemia 1

• Good syndrome (thymoma-associated immunodeficiency) presents with late-onset combined immunodeficiency similar to CVID but with thymoma present 1

Protein Loss Syndromes (Less Likely Given Normal Albumin)

• Nephrotic syndrome causes hypogammaglobulinemia through urinary protein loss but would typically show concurrent hypoalbuminemia 1

• Protein-losing enteropathy causes gastrointestinal protein loss with chronic diarrhea but would affect albumin as well 1

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Critical Diagnostic Pitfall

The single most important error is failing to recognize that normal albumin with low globulin distinguishes true immunodeficiency from protein loss syndromes—this simple observation immediately narrows the differential to immunoglobulin production disorders rather than nephrotic syndrome or enteropathy. 1

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Initial Laboratory Work-Up

First-Tier Essential Tests

• Serum protein electrophoresis with immunofixation to characterize protein fractions, detect monoclonal proteins, and identify immune paresis 1

• Quantitative immunoglobulin measurement (IgG, IgA, IgM) to determine which specific immunoglobulin classes are reduced 1

• Complete blood count with differential to assess for lymphopenia or other cytopenias 2

Second-Tier Functional Assessment

• Vaccine response testing using both protein antigens (tetanus/diphtheria) and polysaccharide antigens (pneumococcal) to evaluate functional antibody production 1

• Flow cytometry for B-cell enumeration to distinguish between different primary immunodeficiencies such as CVID versus selective IgA deficiency 1

Additional Screening Based on Clinical Context

• Comprehensive medication history focusing on immunosuppressive agents, antiepileptics, and biologics, as drug-induced hypogammaglobulinemia is frequently reversible with cessation 1

• Chest imaging (CT chest) to evaluate for thymoma if Good syndrome is suspected 1

• 24-hour urine protein and urine protein/creatinine ratio only if concurrent hypoalbuminemia develops or proteinuria is suspected 1

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Clinical Significance and Urgency

Infection Risk Assessment

• Patients with IgG <400 mg/dL face severe risk of life-threatening bacterial infections, particularly from encapsulated organisms like Streptococcus pneumoniae and Haemophilus influenzae 1

• Recurrent respiratory tract infections are the hallmark presentation requiring immediate evaluation for immunoglobulin replacement 1

Screening Utility of Calculated Globulin

• Using calculated globulin with a cut-off <18 g/L (1.8 g/dL), 89% of samples had IgG <6 g/L and 56% had IgG <4 g/L, demonstrating high sensitivity for detecting clinically significant antibody deficiency 3

• This patient's globulin of 1.4 g/dL (14 g/L) falls well below the screening threshold, indicating high probability of significant immunoglobulin deficiency requiring urgent quantitative assessment 3

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Management Considerations

Treatment Indications

• IVIG replacement therapy is indicated for patients with ≥2 severe recurrent infections by encapsulated bacteria, regardless of exact IgG level 1

• Monthly IVIG treatment is recommended until immunoglobulin levels reach ≥400 mg/dL 1

Monitoring Strategy

• Serum levels alone are inadequate for monitoring treatment efficacy—frequency of infections should be monitored as the more important indicator 1

• Serial measurements of immunoglobulin levels should be performed to track disease progression and treatment response 4

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Associated Clinical Features to Assess

• Autoimmune manifestations including arthritis, cytopenias, and granulomatous disease are frequently observed in CVID patients 1

• Lymphadenopathy or hepatosplenomegaly may indicate underlying lymphoproliferative disorder despite low globulin, reflecting immune paresis 1

• History of recurrent sinopulmonary infections, bronchiectasis, or chronic lung disease supports diagnosis of antibody deficiency 1