What is the workup for a patient with elevated globulin (proteins) levels?

Workup for Elevated Globulin Levels

Begin with serum protein electrophoresis (SPEP) and immunofixation to identify monoclonal proteins, followed by quantitative immunoglobulin levels (IgG, IgA, IgM) to characterize the pattern of elevation. 1

Initial Laboratory Testing

The first-tier workup should include:

• Serum protein electrophoresis (SPEP) with immunofixation to detect monoclonal proteins (M-proteins) that may indicate plasma cell disorders, lymphoproliferative diseases, or monoclonal gammopathy 1
• Quantitative immunoglobulin levels (IgG, IgA, IgM, IgE) to determine which immunoglobulin class is elevated and whether the pattern is polyclonal or monoclonal 1, 2
• Serum free light chain analysis to evaluate for plasma cell disorders, particularly important when suspecting multiple myeloma or light chain disease 1, 2
• Complete blood count with differential to assess for cytopenias, lymphocytosis, or other hematologic abnormalities 1, 2

Pattern-Specific Evaluation

For Polyclonal Hypergammaglobulinemia (IgG >1.5x Upper Normal Limit)

When IgG is predominantly elevated with polyclonal pattern:

• Autoimmune hepatitis workup: Check antinuclear antibodies (ANA), smooth muscle antibodies (SMA), anti-liver-kidney microsomal antibodies (anti-LKM1), anti-soluble liver antigen (anti-SLA/LP), with titers ≥1:40 in adults 1
• Liver function tests: AST, ALT, bilirubin, alkaline phosphatase to assess for hepatitic pattern 1
• Viral hepatitis serologies: Rule out hepatitis A, B, and C infection 1
• Liver biopsy: Essential for definitive diagnosis if autoimmune hepatitis is suspected, looking for interface hepatitis and lymphoplasmacytic infiltrates 1
• Alpha-1 antitrypsin phenotype, ceruloplasmin, iron studies, and ferritin to exclude other causes of liver disease 1

For IgM Predominance

When IgM is the primary elevated immunoglobulin:

• Assess for hyperviscosity symptoms: Visual changes, bleeding, neurologic symptoms, headache 1
• Serum viscosity measurement if symptomatic 1
• Hepatitis C serology as Waldenström's macroglobulinemia is associated with HCV 1
• Bone marrow aspirate and biopsy to confirm excess lymphoplasmacytoid cells 1
• CT scans of chest, abdomen, and pelvis to assess for organomegaly and lymphadenopathy 1, 2
• Cold agglutinins and cryocrit if clinically indicated 1

For Monoclonal Protein Detection

When SPEP/immunofixation reveals an M-protein:

• Hematology consultation for evaluation of plasma cell disorders 1
• Bone marrow aspiration and biopsy with cytogenetic analysis to evaluate for multiple myeloma, MGRS (monoclonal gammopathy of renal significance), or other plasma cell dyscrasias 1, 2
• 24-hour urine protein electrophoresis with immunofixation to detect Bence Jones proteins 1
• Skeletal survey or whole-body low-dose CT if multiple myeloma is suspected 1
• Serum calcium, creatinine, and BUN to assess for end-organ damage 1

Evaluation for Secondary Causes

Infectious Etiologies

• Bacterial infections: Blood cultures if febrile, evaluation for chronic infections (endocarditis, osteomyelitis, abscess) 1
• Viral infections: HIV, EBV, CMV serologies as clinically indicated 1
• Parasitic infections: Consider based on travel history and exposure 1

Inflammatory/Autoimmune Conditions

• Inflammatory markers: ESR and CRP 1
• Autoimmune serologies: ANA, rheumatoid factor, ANCA, complement levels (C3, C4) based on clinical presentation 1
• Cryoglobulin analysis if vasculitis or cold-related symptoms present 1, 2

Chronic Liver Disease

• Comprehensive liver function tests: AST, ALT, alkaline phosphatase, GGT, bilirubin 1
• Indocyanine green (ICG) retention test if available, as hyperglobulinemia correlates with ICG clearance in severe chronic liver disease 3
• Imaging: Ultrasound or CT to assess for cirrhosis, portal hypertension 1

Critical Pitfalls to Avoid

• Do not dismiss "normal" IgG levels in the upper range of normal when clinical suspicion for autoimmune hepatitis exists, as many patients have relative elevations that fall during treatment 1
• Do not overlook immune-paresis (low uninvolved immunoglobulins) when a monoclonal protein is present, as this indicates more significant disease 1, 4
• Do not delay bone marrow evaluation when monoclonal restriction is identified on immunofixation, even with small M-proteins 1, 2
• Always evaluate for hyperviscosity clinically before assuming elevated IgM is benign, as plasmapheresis may be urgently needed 1

Special Clinical Contexts

In Patients on Immune Checkpoint Inhibitors

If elevated globulins develop during immunotherapy:

• Autoimmune serology panel including direct antiglobulin test (Coombs) 1
• Protein electrophoresis and cryoglobulin analysis 1
• Evaluation for autoimmune hemolytic anemia: LDH, haptoglobin, bilirubin, reticulocyte count, peripheral smear 1

In Patients with Renal Disease

When elevated globulins occur with kidney dysfunction:

• Evaluate for immune complex-mediated glomerulonephritis: Check for monoclonal restriction with immunofluorescence-specific stains 1
• Complement studies: C3, C4, CH50 to assess for complement-mediated disease 1
• Consider kidney biopsy with immunofluorescence to distinguish immune complex-mediated from complement-dominant patterns 1