Tuesday, April 5, 2011

Polyclonal Gammopathies

Excess of any thing is bad, and the same is true for elevated levels of immunoglobulins. The elevated levels of immunoglobulins, i.e. hypergammaglobulinemia could be due to monoclonal gammopathies or polyclonal gammopathies. In fact the polyclonal gammopathy signifies potent immunoglobulin response rather than actually being a disorder. Chronic infections and several chronic diseases affecting the liver and collagen are the cause of polyclonal gammopathies. Once a polyclonal gammopathy is detected, it becomes first and the foremost task to identify the underlying organic disease. Tuberculosis, Osteomyelitis, Syphilis, Chronic Bronchitis, Chronic Fungal infections, Primary Billiary Cirrhosis (PBC), Chronic Active Hepatitis (CAH), infectious hepatitis, Chronic Malaria, Leishmaniasis (Kala Azar), Filariasis, Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), Polymyositis, Scleroderma, Metastatic carcinoma, slow healing trauma and Cystic fibrosis have been found to be associated with polyclonal gammopathies.

Serum protein electrophoresis (SPE) will show a broad diffuse increase in the gamma globulin region, indicative of a polyclonal gammopathy. The primary cause of the polyclonal gammopathy may be known or should be determined through conventional investigations to decide the line of treatment. The immunoglobulin excess may be resolved through the adequate treatment of underlying disease responsible for polyclonal gammopathy.

Monday, April 4, 2011

Immunoglobulin Deficiency Disorders

Immunoglobulins are serum proteins having antibody activity. These proteins migrate to gamma globulin region when we do the electrophoresis of serum. These proteins are termed as gamma globulins. The gamma globulin fraction of human serum/plasma contains a variety of immunoglobulins or antibodies. Every molecule of an immunoglobulin carries antibody specificity for a single antigen. Immunoglobulins are produced by the plasma cells, primarily in the bone marrow. Plasma cells present in the germinal centers of lymph-nodes and spleen also produce immunoglobulins. A plasma cell needs activation by a specific antigen to produce immunoglobulins capable of reacting/interacting with thestimulatory antigen. Plasma cells are capable of proliferating into an expanded population or clone of identical cells. A clone of plasma cells produces immunoglobulins/antibodies with identical physical and chemical properties, also known as homogeneous or monoclonal antibodies/immunoglobulins. If more than one antigen is involved, the plasma cells will proliferate to form multiple clones and produce heterogeneous or polyclonal immunoglobulins. Plasma cells release the immunoglobulins in the surrounding tissue and thus immunoglobulins accumulate in our blood and provide immunity against infectious organisms. There are a variety of actions and reactions performed by immunoglobulins.

There are three major classes of immunoglobulins/antibodies: Immunoglobulin-G (IgG), immunoglobulin-A (IgA) and immunoglobulin-M (IgM). The IgG is the major Immunoglobulin class and account for 80% of all antibodies. Impaired production of immunoglobulins by the plasma cells is termed as immunoglobulins' deficiency or hypogammaglobulinemia. Thehypogammaglobulinemia may be either primary (congenital) or secondary (acquired) probably due to some other disorder or immunosuppressive therapy or radiation. Primary immunodeficiency (PID) disorders are most commonly detected in children and secondary immunodeficiency (SID) among adults. Frequent and/or unusual infections are an indicator of impaired immune defenses. The clinician would get to know form the history of the patient, especially a child that he/she has impaired immune defense. Frequent Streptococcal, Pseudomonas, pneumococcal or influenza infections alerts the physician to work up to rule out the immunodeficiency in a child or adult patient. An infection history representative of generalized immunodeficiency differs from selective immunodeficiency such as IgA deficiency. Selective IgA deficiency occurs in 0.1 to 0.2% children having history of sinusitis and pneumonia.

Laboratory Investigations

In addition to detailed clinical history, it is essential to get the following investigations done:
  • Serum Electrophoresis: Serum protein electrophoresis (SPE) test
    should be done to rule out generalized deficiency or hypogammaglobulinemia.

  • Complete Immunoglobulin evaluation: Levels of IgG, IgA and IgM in serum should be determined by single radial immunodiffusion (SRID) method. To rule out selective IgA deficiency, salivary IgA level should also be detected in patient's saliva by SRID assay. While determining immunoglobulin deficiency in infants, it should be kept in mind that their immunoglobulin levels may drop temporarily at third to fifth month of age. Since birth the infant is protected by the maternal immunoglobulins transferred from the mother's blood circulation through placental barrier. The infant's own plasma cells (immune system) get mature around sixth month of age and start producing immunoglobulins. The transient hypogammaglobulinemia during third to fifth month of age should not be confused as PID.

  • Ancillary Tests: Following ancillary tests should be done to assess the antibody producing capacity of the patient: i) Titer value of ABO hemagglutinins, ii) Titer value of antistreptolysin-O, and iii) Assay for diphtheria antibodies (Schick test).
Treatment of Immunodeficiency

In most instances, immunoglobulin deficiency disorders (IDD) cannot be prevented. However, if diagnosed early enough, these can be treated successfully. Three means of treatment are available to the physician to manage immunoglobulin deficiency disorders (IDD):

  • Prophylaxis from infectious agents: Proper immunization of the infants is must as per W.H.O. protocol for immunization

  • Antibiotic therapy: Appropriate antibiotic therapy should be administered through appropriate route depending on the condition of patient.

  • Gamma globulin replacement therapy: If a patient has severe infection which is unresponsive to antibiotics, the IgG level should be determined. If this level is <200 mg/dl, as determined by SRID, or if the total gamma globulin is <300 mg/dl as determined by densitometry of SPE, then gamma globulin replacement therapy would be appropriate line of treatment. Gamma globulin replacement therapy may have serious side effects like anaphylaxis, so it should be administered at hospital or nursing home, under strict medical supervision. A variety of commercial gamma globulin preparations are available for intramuscular injections. The dosage must be adjusted to ensure minimum of 0.1 g/kg of IgG per month or 0.025 g/kg per week. The dosages are determined as milliliter per kilogram dose as per instructions on the vial. A variety of side effects are anticipated in about 20% of patients getting regular gamma globulin replacement therapy. There may be anxiety, facial swelling, flushing faintness, hypotension and dyspnea. In cases of secondary hypogammaglobulinemia, at first the underlying disease responsible for causing hypogammaglobulinemia needs to be treated. Gamma globulin replacement therapy is administered in very severe cases of secondary hypogammaglobulinemia. IgG levels in the sera are determined at regular intervals to monitor the clinical course and therapeutic response of patients with immunoglobulin deficiency disorders.

Clinical Manifestations of Multiple Myeloma

Multiple myeloma can be defined as symptomatic monoclonal gammopathy. Elevated levels of immunoglobulin-G (IgG), immunoglobulin-A (IgA), immunoglobulin-M (IgM), immunoglobulin-D (IgD) or immunoglobulin-E (IgE) could be detected by immunoelectrophoresis. (IEP) of patient's serum. The frequency of occurrence for each immunoglobulin class is in the order mentioned above. The basis for all monoclonal gammopathies is an unrestricted proliferation of a single plasma cell clone probably due to failure of its immuno-regulatory switch or gene. The resulting homogeneous immunoglobulin accumulates in the plasma/serum and plasma cells crowd out the bone marrow. There would be suppressed/decreased production of the functional antibodies with the consequences of higher tendency towards infections.

Clinical Manifestations:

The patients with multiple myeloma present with bone pain, fatigue, pallor, anemia and weight loss. Upon examination, the bones may show osteoporosis pathologic fractures and there may also be sternal tenderness. Some patients may also show neurologic symptoms. Neurologic symptoms are caused by collapsed vertebrae compressing the spinal cord. When a patient presents with clinical symptoms of multiple myeloma, following tests should be requested immediately:

  • X-Rays of the skull, ribs and vertebrae

  • Blood count

  • Bone marrow aspiration

  • Serum protein electrophoresis (SPE)

  • Urine examination for Bence Jones Protein
If the x-rays show osteolytic lesions, blood count is indicative of anemia, bone marrow aspiration examination shows sheets of plasma cells and SPE shows myeloma band (M-band) in gamma globulin region, the diagnosis would be multiple myeloma. Chemical examination of urine may or may not show presence of Bence Jones protein. There would be need to determine the type/class of M-band by immunoelectrophoresis (IEP) of patient's serum.