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 α (especially α-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, TNFα ). They also tend to remain elevated in chronic inflammatory conditions.
  • Nephrotic syndrome: A dramatic increase in α-2 globulins is often seen (due to VLDL and α-2 macroglobulin).
  • Drugs: Corticosteroids in dogs will cause a sharp almost monoclonal-like peak in the α-2 region due to increases in haptoglobin.
Beta Globulins
  • Inflammation (acute and chronic): increased β globulins often accompanies increases in γ 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 and lipoproteins).
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. For more information, see the electrophoresis page.

Polyclonal gammopathypolyclonal ELP
This is seen as a broad-based peak in the β and/or γ region (arrow on image to the right). Some common causes include various chronic inflammatory diseases (infectious, immune-mediated), liver disease, FIPV (α-2 globulins are often concurrently elevated), occult heartworm disease, and Ehrlichiosis.

Monoclonal gammopathy
This is seen as a sharp spike in the β or γ region. The peak can be compared to the albumin peak - a monoclonal gammopathy has a peak as narrow as that of albumin (see image below to the right). The usual cause of monoclonal gammopathies is neoplasia of B cells or plasma cells, although cases of non-neoplastic monoclonal gammopathy have been reported (see below for more information).

  • 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). monoclonal ELP
    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 systemic versus localized neoplastic 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). Thus, the bone marrow is often used for diagnosis of multiple myeloma, although since the tumor is systemic, plasma cell infiltrates are frequently found in other organs (liver, spleen), particularly in cats. Monoclonal light chain may also be present in the urine in affected animals, but is not a consistent feature (see Bence-Jones proteinuria).
  • 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. However, these previous reports possibly mis-interpreted a "restricted oligoclonal" gammopathy as a true monoclonal gammopathy (see the electrophoresis page for more information) and a true IgG monoclonal gammopathy is likely only seen with B lymphoid (B-CLL, B cell lymphoma) or plasma cell neoplasia (extramedullary plasmacytoma or multiple myeloma) rather than these reactive causes.

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