What are the possible causes and appropriate work‑up for a patient with a total serum protein of about 4.9 g/dL, immunoglobulin G of roughly 270 mg/dL, and reduced gamma‑globulin and beta‑1 globulin fractions?

Diagnostic Approach to Low Total Protein, Low IgG, and Reduced Globulin Fractions

The combination of low total protein (4.9 g/dL), severely reduced IgG (270 mg/dL), and decreased gamma and beta-1 globulin fractions requires immediate distinction between protein-loss syndromes and primary immunodeficiency by checking serum albumin levels. 1, 2

Critical First Step: Albumin Measurement

• If albumin is also low (concurrent with low total protein), this strongly indicates secondary hypogammaglobulinemia from protein loss through the gastrointestinal tract, lymphatics, or kidneys rather than primary immunodeficiency. 1, 2

• If albumin is normal despite low total protein and low immunoglobulins, this pattern is consistent with primary immunodeficiency such as Common Variable Immunodeficiency (CVID) or agammaglobulinemia, where only immunoglobulin production is impaired. 1, 2

Immediate Evaluation for Secondary Causes (If Albumin is Low)

Nephrotic Syndrome Workup

• Obtain 24-hour urine protein collection, spot urine protein-to-creatinine ratio, and urinalysis to assess for significant proteinuria (>3.5 g/day). 1, 2

Protein-Losing Enteropathy Assessment

• Evaluate for chronic diarrhea history and measure stool alpha-1 antitrypsin clearance; consider intestinal imaging if clinical suspicion is high. 1, 2

Lymphatic Disorder Consideration

• Assess for disrupted lymphatic drainage, which can cause protein loss, particularly if there is history of lymphedema or prior lymphatic surgery. 1

Primary Immunodeficiency Workup (If Albumin is Normal)

Distinguish CVID from Agammaglobulinemia

• Perform B-cell enumeration by flow cytometry immediately: normal or moderately reduced B cells suggest CVID, while absent or severely reduced B cells indicate agammaglobulinemia. 1, 2

• CVID is most likely if the patient is ≥4 years old with a history of recurrent bacterial respiratory infections and normal/moderately reduced B-cell counts. 3, 1

• Agammaglobulinemia typically presents in the first 2 years of life with more severe infections and absent B cells. 1

Functional Antibody Assessment

• Test specific antibody responses to both protein antigens (tetanus/diphtheria) and polysaccharide antigens (pneumococcal vaccine) to document functional antibody deficiency, which is more predictive of infection risk than immunoglobulin levels alone. 1, 2

Complete Immunologic Evaluation

• Measure all immunoglobulin classes quantitatively (IgG, IgA, IgM) to determine which are reduced; CVID requires IgG <450-500 mg/dL plus IgA or IgM below the 5th percentile. 1, 2

• Perform lymphocyte subset analysis including CD4, CD8, CD19, and memory B-cell counts to identify potential combined immunodeficiency. 2

• Obtain serum protein electrophoresis with immunofixation to detect any monoclonal proteins and characterize immune paresis, as lymphoproliferative disorders like multiple myeloma can cause isolated low globulin despite monoclonal protein presence. 1

Medication and Secondary Cause Review

• Review medication history for drugs causing reversible hypogammaglobulinemia: antiepileptics (phenytoin, carbamazepine, valproic acid), rituximab/anti-CD20 therapies, sulfasalazine, gold, penicillamine, and hydroxychloroquine. 1, 2

• Exclude hematologic malignancies (B-cell lymphomas, multiple myeloma) and thymoma-associated Good syndrome through appropriate imaging and bone marrow evaluation if clinically indicated. 1, 2

Urgent Clinical Management Considerations

Infection Risk Assessment

• With IgG at 270 mg/dL (well below 400 mg/dL threshold), this patient faces severe risk of life-threatening bacterial infections from encapsulated organisms like Streptococcus pneumoniae and Haemophilus influenzae. 1

• Consider urgent immunoglobulin replacement therapy for patients with IgG <300 mg/dL to reduce infection risk, regardless of current symptom severity. 2

Antibiotic Prophylaxis

• Initiate antibiotic prophylaxis while awaiting definitive diagnosis and treatment, as this is a mainstay of management alongside potential immunoglobulin replacement. 2

Common Pitfalls to Avoid

• Failing to check albumin and total protein together is the most critical error, as this simple step distinguishes protein-loss syndromes from true immunodeficiency. 1

• Overlooking medication history is common, yet drug-induced hypogammaglobulinemia is frequently reversible with cessation of the offending agent. 1

• Relying solely on serum immunoglobulin levels without testing functional antibody responses underestimates true infection risk. 1, 2

• Delaying immunoglobulin replacement in symptomatic patients with very low IgG (<300 mg/dL) places them at unacceptable risk for severe bacterial infections. 2