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 #Globulin #Protein #Gap #ProteinGap #differential #diagnosis #hematology
