Elevated Globulin - Protein Gap (Total Protein - Albumin > 4)



Work-up of an Elevated Globulin Gap:

• An elevated globulin gap (>4 g/dL) should always be evaluated.

• (Total protein concentration minus albumin concentration = "gamma gap")

• The first step in evaluation is to determine whether it represents a monoclonal or polyclonal gammopathy.



Causes of Monoclonal Gammopathy Include:

• MGUS

• Multiple myeloma

• Waldenstrom’s macroglobulinemia

• Amyloidosis

• Lymphoma

• Smoldering multiple myeloma

• Plasma cell leukemia

• Solitary plasmacytoma

• Heavy chain disease

• Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS syndrome)

• Solitary plasmacytoma

• Castleman disease

• AL (light chain) amyloidosis



Causes of Polyclonal Gammopathy Include:

• Viral infections (acute HIV, HBV, EBV, VZV, hepatitis C)

• Connective tissue disorders (RA, Temporal arteritis, Sarcoidosis)

• Liver disease: Cirrhosis, ETOH, autoimmune hepatitis, PBC, PSC, Viral hepatitis

• Malignancies: Solid tumors, ovarian tumors, lung cancers, HCC, renal tumors, gastric tumors

• Hematology: Lymphoma, Leukemia, Thalassemia, Sickle cell anemia

• Other causes of persistent inflammation (acute phase reactants will cause an increase in the globulin gap)



Next Step: Etiology of Protein Gap:

• SPEP, immunofixation and free light chain assay

• An abnormal free light chain ratio indicates overproduction of either kappa or lambda light chain

• Normal kappa/Lambda FLC ratio is 0.26 - 1.65



SPEP can:

1. Detect a spike

2. Determine its size (amount)

SPEP cannot:

1. Confirm monoclonality

2. Comment on type (heavy/light chain)

3. Always detect a small spike



Immunofixation:

1. Confirm monoclonality

2. Determine heavy/light chain specificity

3. Detect smaller M spikes



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