Hyperglobulinemia Increases in total globulins can result from increases in any or all of the fractions as determined by electrophoresis. Alpha globulins Acute phase reactant response: This usually results in increased alpha (especially alpha-2) globulins. Acute phase reactants are a diverse group of proteins that increase in serum very rapidly (within 12-24 hours) following tissue injury of any cause (inflammation, acute bacterial and viral infections, necrosis, neoplasia, trauma). Raised serum levels are the result of increased hepatic synthesis mediated by cytokines (IL-1, IL-6, TNF). They also tend to remain elevated in chronic inflammatory conditions. Nephrotic syndrome: A dramatic increase in alpha-2 globulins is often seen (due to VLDL and alpha-2 macroglobulin). Drugs: In dogs, corticosteroid administration results in an increase in alpha-2 globulins. Beta Globulins Inflammation (acute and chronic): increased beta globulins often accompanies increases in gamma globulins (response to antigenic stimulation). Active liver disease and suppurative dermatopathies (both of which are associated with elevated IgM). Nephrotic syndrome (associated with an increase in transferrin). Gamma Globulins Increases in this fraction occur most commonly in conditions in which there is an active immune response to antigenic stimulation usually resulting in a polyclonal gammopathy. Neoplasms of immunoglobulin-producing cells (plasma cells, B-lymphocytes) can also be responsible for monoclonal increases in this fraction. Polyclonal gammopathy This is seen as a broad-based peak in the beta and/or gamma region. Some common causes include various chronic inflammatory diseases (infectious, immune-mediated), liver disease, FIP (alpha-2 globulins are often concurrently elevated - see adjacent ELP tracing), occult heartworm disease, and Ehrlichiosis. Beta-gamma bridging occurs in disorders with increased IgA and IgM such as lymphoma, heartworm disease and chronic active hepatitis. Monoclonal gammopathy This is seen as a sharp spike in the beta or gamma region. The peak can be compared to the albumin peak - a monoclonal gammopathy has a peak as narrow as that of albumin. Both neoplastic and non-neoplastic disorders can produce a monoclonal gammopathy. 1) Neoplasia: Multiple myeloma is the most common cause (producing an IgG or IgA monoclonal). Other neoplastic disorders associated with a monoclonal gammopathy include lymphoma (IgM or IgG) and chronic lymphocytic leukemia (usually IgG). Extramedullary plasmacytomas are solid tumors composed of plasma cells that are usually found in the skin of dogs. They have also been reported in the gastrointestinal tract and liver of cats and dogs. They can be associated with a monoclonal gammopathy, or even a biclonal gammopathy (if there are multiple tumors). An increase in IgM is called macroglobulinemia. Waldenstrom's macroglobulinemia is a neoplasm of B-cells (lymphoma) that has a different presentation from multiple myeloma. Patients usually have splenomegaly and/or hepatomegaly and lack osteolytic lesions. In contrast, multiple myeloma is a disorder of plasma cells that have undergone antigenic stimulation in peripheral lymph nodes and then home in on the bone marrow (the marrow produces appropriate growth factors that support growth of myeloma cells). Therefore, myeloma is characterized as a bone marrow disorder, with osteolytic bone lesions (in 50% of canine cases) and Bence-Jones proteinuria. Extramedulllary infiltrates of plasma cells are uncommon but can occur in terminal phases of the disease. 2) Non-neoplastic disorders: Monoclonal gammopathies (usually IgG) have been reported with occult heartworm disease, FIPV (rarely), Ehrlichia canis, lymphoplasmacytic enteritis, lymphoplasmacytic dermatitis and amyloidosis. These causes should be ruled out before a diagnosis of multiple myeloma is made in a patient with an IgG monoclonal gammopathy.

---