Globulins

 
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Globulins can be divided into three fractions based on their electrophoretic mobility. Most of the α and β globulins are synthesized by the liver, whereas γ globulins are produced by lymphocytes and plasma cells in lymphoid tissue. α globulins consist of α-1 and α-2 globulins, and β globulins consist of β-1 and β-2 globulins. A few examples of globulin proteins are found in the table below.  The third fraction known as γ globulins consists of the immunoglobulins: IgM, IgA, and IgG.
Globulins
Protein kDa Functions (partial list) Response in disease
α-1 α-1 antitrypsin 45 Inhibits trypsin, anti-inflammatory ↑ acute infl. disease ↓ hereditary deficiency (humans)
α-1 antichymotrypsin 68 Inhibits chymotrypsin, anti-inflammatory ↑ acute infl. disease
α-1 acid glycoprotein 44 anti-inflammatory andimmunomodulatory functions ↑ acute infl. disease
α-1 lipoprotein (HDL) 180-350 Lipid transport – reverse cholesterol transport ↑ causes of hypercholesterolemia (inherited, nephrotic syndrome, DM, pancreatitis, hypothyroidism, cholestasis) ↓ liver disease
α-2 Antithrombin (AT) 65 Inhibitor of thrombin and other clotting factors ↑ acute phase response (possible in cats) ↓ in DIC, liver disease, protein-losing disorders (renal, GI)
α-2 macroglobulin 820 Protease inhibitor, anti-inflammatory ­­↑ nephrotic syndrome, chronic active liver disease, acute infl. disease
Haptoglobin 80-160 Hb binding, antibacterial effect ↑ acute infl. disease, glucocorticoids in dogs ↓ hemolytic anemia
Ceruloplasmin 151 Copper transport, ferroxidase ↑ acute infl. disease
Protein C 62 inhibitor of activated coagulation factors FVIII and FV ↓ sepsis, portosystemic shunts, liver disease, inherited (human and horse)
α-2 lipoprotein (VLDL) May migrate as early b-1 in some species. 1000 Lipid transport – triglyceride transport ↑ causes of hypertriglyceridemia and hypercholesterolemia (inherited lipoprotein disorders, nephrotic syndrome, DM, hypothyroidism, HAC, pancreatitis, hepatic lipidosis)
β-1 Transferrin 76 Iron transport ± iron def., acute liver necrosis ↓ infl. disease, chronic liver disease, iron overload
Hemopexin 80 Heme scavenger ↓ hemolytic disease, chronic active liver disease
β-2 Fibrinogen 340 Fibrin precursor ↑ acute infl. disease ↓ DIC, severe liver disease
Complement factor 3a 180 Pro-inflammatory, chemotactic substance ↑ acute infl. disease
β-2 lipoprotein (LDL) 2400 Lipid transport – cholesterol transport ↑ causes of hypercholesterolemia (inherited, nephrotic syndrome, DM, pancreatitis, hypothyroidism, HAC, cholestasis)
C-reactive protein 140 On bacteria, promotes the binding of complement ↑ acute infl. disease
IgM 900 Antigen specific binding ↑ infectious or inflammatory dis., liver disease, B cell neoplasia (lymphoma, macroglobulinemia) ↓ deficiency syndromes
IgA 160 Antigen specific binding ↑ infectious or inflammatory dis. (particularly mucosa), liver disease,  plasma cell neoplasia (EMP, MM) ↓ newborns, deficiency syndromes
γ IgG 150 Antigen specific binding ↑ infectious or inflammatory dis., liver disease, B or plasma cell neoplasia (EMP, MM, lymphoma) ↓ newborns, deficiency syndromes
IgM and IgA also migrate here As described above
 

Physiology

The globulins consist of all non-albumin proteins. In contrast to the situation with albumin, which is a single protein, there are hundreds of different proteins included in the globulins. Although knowledge of the total globulin concentration is useful, it gives no information about the distribution of the different types of proteins within that total. Included in the globulins are specific groups of proteins that are produced in response to inflammatory stimuli.  These include the acute phase proteins and the immunoglobulins (Igs).  As such, important information aiding in the diagnosis and monitoring of inflammatory conditions can be obtained by further characterizing the globulin fraction by electrophoresis (ELP) of serum proteins (SPE). While only a few electrophoretic patterns are pathognomic for a specific disease, useful information of a more general nature often can be found.

Methodology

The globulin value on the chemistry panel is not measured, but is calculated by the equation:

Globulins = Total protein - Albumin

The principal behind this method of quantification is the fact that all serum proteins, except albumin, are considered to be globulins. The certainty of the globulin concentration is limited by the accuracy of calculated total protein and albumin concentrations. To circumvent this issue globulins can also be measured quantitively and qualitatively with electrophoresis. Radial immunodiffusion is used for accurate quantification of immunoglobulins and has also replaced immunoelectophoresis for determining the immunoglobulin comprising a monoclonal gammopathy.

Units of measurement (link to conversion calculator)

The concentration of globulins is measured in g/dL (conventional units) and g/L (SI units). The conversion equation is shown below:

mg/dL x 10 = g/L

Sample considerations

Sample type

Serum and plasma

Anticoagulant

Stability

Interferences

  • Lipemia, hemolysis, and icterus: The interferences of measurement depends on that of total protein and albumin.
  • Drugs: Corticosteroids in dogs will cause a sharp almost monoclonal-like peak in the α-2 region due to increases in haptoglobin.

Test interpretation

Increased globulin concentration (hyperglobulinemia)

Increases in total globulins can result from increases in any or all of the fractions as determined by electrophoresis.
  • Artifact
  • Physiologic
  • Pathophysologic
    • α-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).
    • β-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.
    • γ-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 total protein electrophoresis.
      • Polyclonal gammopathy: 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). An increase in IgM is called macroglobulinemia. Waldenström'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.

Decreased globulin concentration (hypoglobulinemia)

Decreases in alpha and beta globulins are not significant. Decreased gamma globulins are seen when there is a deficiency of immunoglobulins (dependent on class of immunoglobulin involved and severity of the decrease). Radial immunodiffusion (RID) is the best method for pursuing these diagnoses. Decreases in globulins of all fractions may be seen in protein-losing enteropathies, exudative dermatopathies, and hemorrhage. Concomitant loss of albumin in these conditions tends to maintain a normal A:G ratio with a low total protein.
  • Pathophysiologic
    • Inherited hypogammaglobulinemia: A variety of inherited immunodeficient syndromes have been reported. Although some involve cell-mediated immunity (e.g. PSCID), they often have concurrent gamma globulin deficiencies due to impaired helper T cell function.
      • Primary severe combined immunodeficiency: This has been reported in Bassett hounds, Cardigan Welsh Corgis, Dachshunds and Arabians (full and crosses). It is characterized by a lymphopenia, decreased IgM in a presuckle foal, absent IgM and IgA post-suckling. IgM, IgG and IgA are all low after 3 months of age as maternally-derived antibodies are degraded. Animals have thymic and lymph node atrophy and die at a young age (usually when maternal antibodies disappear) of opportunistic infections, e.g. Pneumocystis carinii, adenovirus, cryptosporidiosis.
      • Agammaglobulinemia: This has been reported in foals. They have no B cells and lack Igs by 3 months of age. T cell function is normal as are lymphocyte counts. They die of repeated infections, with a poor response to therapy, by 12-18 months of age.
      • IgM deficiency: Selective IgM deficiency has been reported in horses (Arabians, Paso Fino, quarterhorses and thoroughbreds) and Dobermans. Horses usually die of fatal pneumonia, arthritis and enteritis. Dogs usually have no clinical signs as long as IgG and IgA levels are normal.
      • IgA deficiency: This has been reported in various dog breeds, including Sharpeis, Beagles, Airedale terriers, and German Shepherd Dogs. They suffer from recurrent infections involving the urinary tract, respiratory tract, and skin.
      • Transient hypogammaglobulinemia: This has been reported in Arabian horses and dogs. They have a delayed onset of post-natal immunoglobulin synthesis and are susceptible to adenoviral and bacterial infections.
    • Acquired immunodeficiencies: These are, by far, more common than inherited immunodeficiencies.
      • Failure of passive transfer (FPT): Animals are dependent upon ingestion of colostrum for passive immunity as immunoglobulins do not cross the placenta as they do in human beings. FPT results when neonates fail to suckle or if dams leak colostrum pre-parturition. For diagnosis of FPT, determination of IgG is recommended within 24 to 48 hours of birth. Rapid ELISA assays are available, however radial immunodiffusion is more accurate (but slow - a minimum of 24 hours is required). In calves, zinc sulfate turbidity, glutaraldehyde coagulation and sodium sulfite precipitation tests can be used, but are not as accurate as direct measurement of IgG.
    • Infectious diseases
      • Viruses: Feline leukemia virus and feline immunodeficiency virus are known causes for acquired immunodeficiencies in cats. Canine distemper virus causes immunodeficiency in dogs. Bovine viral diarrhea causes immunodeficiency in cattle and Aleutian mink disease virus (a parvovirus) causes immunosuppression in ferrets.
      • Parasites: Toxoplasmosis and Theileria cause immunodeficiency. Generalized infection with Demodex canis is often found in immunodeficient dogs, however it may be a result of immunodeficiency and not its cause. Eperythrozoon wenyonii infection in cattle is associated with reduced humoral immunity.
      • Johne's disease: causes decreased T cell function.
    • Neoplasia: Lymphoma in cattle and horses is associated with immunosuppression. Very low IgM levels are often observed in horses with lymphoma and can be a valuable non-invasive tumor marker if there is a high clinical index of suspicion for lymphoma.
    • Idiopathic: Idiopathic immunodeficiency has been reported in young llamas with failure to gain weight, ill-thrift and recurrent infections. Many of these llamas have concurrent Eperythrozoon infections.
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