GAMMOPATHIES:

Disturbance in synthesis of immunoglobulins; proteins having antibody activity increase greatly in the
blood.
A) Polyclonal Gammopathies
Heterogeneous increase in immunoglobulins involving more than one cell line, maybe cause by any
of variety of inflammatory, infectious or neoplastic disorder.
A "swell-like" elevation in the gamma zone indicates a polyclonal gammopathy, which
typically indicates a non-neoplastic condition (although is not exclusive to non-neoplastic
conditions). The most common causes of polyclonal hypergammaglobulinaemia detected by
electrophoresis are severe infection, chronic liver disease, rheumatoid arthritis, systemic
lupus erythematosus and other connective tissue diseases.
B) Monoclonal Gammopathies
A narrow spike indicates a monoclonal gammopathy, also known as an "M-spike". Typically, a
monoclonal gammopathy is malignant or clonal in origin, Myeloma being the most common
cause of IgA and IgG spikes. chronic lymphatic leukaemia and lymphosarcoma are not
uncommon and usually give rise to IgM paraproteins. Note that up to 8% of healthy geriatric
patients may have a monoclonal spike. Waldenstrom's macroglobulinaemia (IgM),
monoclonal gammopathy of undetermined significance (MGUS), amyloidosis, plasma cell
leukemia and solitary plasmacytomas also produce an M-spike.
The monoclonal gammopathies, also called paraproteinemias or dysproteinemias, are a group of
disorders characterized by the proliferation of one or more clones of differentiated B lymphocytes that
each produce an immunologically homogeneous immunoglobulin commonly referred to as a
paraprotein or monoclonal (M) protein. The circulating M-protein may consist of an intact
immunoglobulin, the light chain only, or (rarely) the heavy chain only. The heavy chain is from one of
the five immunoglobulin classes G, A, M, D or E, while the light chain is either kappa or lambda in
type. The monoclonal gammopathies encompass a number of diseases including:
a) Multiple myeloma: 60% Malignancy of IgG-secreting plasm cell
Multiple myeloma (also known as myeloma or plasma cell myeloma) is a progressive
hematologic (blood) disease. It is a cancer of the plasma cell, an important part of the immune
system that produces immunoglobulins (antibodies) to help fight infection and disease. Multiple
myeloma is characterized by excessive numbers of abnormal plasma cells in the bone marrow
and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or BenceJones protein (free monoclonal and light chains). Hypercalcemia, anemia, renal damage,
increased susceptibility to bacterial infection, and impaired production of normal
immunoglobulin are common clinical manifestations of multiple myeloma. It is often also
characterized by diffuse osteoporosis, usually in the pelvis, spine, ribs, and skull.
b) Waldenstrms macroglobulinemia (WM): 10% hypersecretion of IgM
Discovered In 1944, by Jan Gosta Waldenstrom (1906-1996), a Swedish physician

The Waldenstrom's macroglobulinemia is a rare, chronic cancer that is classified as a plasma

cell neoplasm. It affects plasma cells, which develop from white blood cells called Blymphocytes, or B cells.
B cells form in the lymph nodes and the bone marrow, the soft, spongy tissue inside bones.
They are an important part of the body's immune (defense) system. Some B cells become
plasma cells, which make, store, and release antibodies. Antibodies help the body fight
viruses, bacteria, and other foreign substances.
Abnormal plasma cells multiply out of control. They invade the bone marrow, lymph nodes, and
spleen and produce excessive amounts of an antibody called IgM. Excess IgM in the blood
causes hyperviscosity (thickening) of the blood.
Waldenstrom's macroglobulinemia usually occurs in people over age 65, but can occur in
younger people. A review of cancer registries in the United States found that the disease is
more common among men than women and among whites than blacks.
Some patients do not experience symptoms. Others may have enlarged lymph nodes or
spleen, and may experience fatigue, headaches, weight loss, a tendency to bleed easily, visual
problems, confusion, dizziness, and loss of co-ordination. These symptoms are often due to
the thickening of the blood. In extreme cases, the increased concentration of IgM in the blood
can lead to heart failure.
c) Lymphomas, Leukemias: 10%
d) Monoclonal gammopathy of undetermined significance (MGUS): 10%
Monoclonal gammopathy of undetermined significance is an asymptomatic disorder associated
with serum monoclonal immunoglobulin spike. Its incidence is about 1% in patients of 50 years
of age, and rapidly increases in elderly patients.
Within the 20 years following diagnosis, about 25% of patients will evolve towards either
multiple myeloma (for patients with IgG or IgA) or malignant lymphoproliferative disorder (for
patients with IgM). Definition, circumstances associated with a transient monoclonal spike, and
currently available parameters used for differential diagnosis with either multiple myeloma or
malignant lymphoproliferative disorder are successively discussed. One part of the most usual
biological parameters is of prognostic value, and is reviewed in more detail. Recent data
concerning immunophenotype, cytogenetics and molecular biology of plasma cells reinforce
the link between the asymptomatic condition and multiple myeloma. In monoclonal
gammopathy of undetermined significance, some plasma cells resemble normal or reactive
plasma cells, whereas others mimic those found in multiple myeloma.
e) Rare cause: systemic amyloid light-chain (AL) amyloidosis, solitary plasmacytoma,
heavy chain disease

C) Hypogammaglobulinemia
It is characterized by the absence or deficiency of one or more of the five classes of immunoglobulins
(IgG, IgM, IgA, IgD, and IgE) from defective B-cell function.
This is easily identifiable as a "slump" or decrease in the gamma zone. It is normal in infants.
It is found in patients with X-linked agammaglobulinemia. IgA deficiency occurs in 1:500 of
the population, as is suggested by pallor in the gamma zone.
a) Due to inherited immune deficiency:
a.1. X-linked IgA deficiency: common 1/750birth
a.2. Agammaglobulinemia: rare
b) acquired
malnutrition.

causes:

malignancies,

immunosuppressive

drugs,

HIV,

measles,

Therapeutic Measures
Treatment is aimed at minimizing infections while increasing immune system function through
injections of immunoglobulin. These injections mainly contain IgG, so fresh frozen plasma is given to
replace IgM. IgA cannot be replaced, increasing the risk for frequent pulmonary infections.
Nursing Management
The infant is monitored for infections. Any breaks in the skin must be cleansed immediately and
monitored for infection development. Genetic counseling may be recommended for parents.
Education
The family is educated about signs and symptoms of a variety of infections and the importance
in seeking medical help immediately. They are taught that the infant should not be in the crowds and
that good nutrition, hydration, and hygiene are important in preventing infections.

LABORATORY DIAGNOSIS, SCREENING AND MONITORING

Protein electrophoresis

Protein electrophoresis should be undertaken whenever multiple myeloma, Waldenstrm's

macroglobulinemia, or MGUS is suspected.
The immunoglobulins (IgA, IgM, IgG, IgE and IgD) are the only proteins present in the normal gamma
region, but note that immunoglobulins may be found in the alpha and beta zones. If the gamma zone
shows an increase (or spike), the first step in interpretation is to establish if the region is narrow or
wide. If it is elevated in a single narrow "spike-like" manner it could indicate monoclonal production of
a single immunoglobulin (monoclonal gammopathy), while a broad "swell-like" manner (wide)
indicates polyclonal immunoglobulin production. Immunofixation (gel electrophoresis) or

immunosubtraction (capillary electrophoresis) are performed to detect and confirm monoclonal

immunoglobulins.

Immmunotyping

Immunotyping is used to identify the clonality (type) of M-proteins observed on electrophoresis and to
probe further for the presence of monoclonal proteins when suspicion persists despite a normal
protein electrophoretogram. In addition, screening for systemic AL amyloidosis requires the use of
serum and urine immunotyping since the quantity of M proteins in the vast majority of cases is too
small to be detected by electrophoresis.

Quantitation of immunoglobulin

Quantitation of IgG, IgA and IgM, is routinely carried out by nephelometric and turbidimetric
procedures that measure the light scattered by the macromolecular lattices formed from the reaction
of immunoglobulin heavy chains with polyvalent class-specific heavy chain antisera. These
procedures are currently fully automated which makes them convenient to use both in serial
monitoring of disease progression in monoclonal gammopathy and in monitoring for hyperviscosity
syndrome. In addition, quantitation is clinically useful in detecting and monitoring the polyclonal
hypogammaglobulinemia that results from functional impairment of the normal immunoglobulin
producing cells of the bone marrow by excessive expansion of the malignant clone(s).

Serum viscosity

Determination of serum viscosity is clinically indicated in any patient with a monoclonal gammopathy
and symptoms of oronasal bleeding, blurred vision, dilatation of retinal veins, flame-shaped retinal
hemorrhages, unexplained congestive heart failure, or neurologic symptoms such as headaches,
vertigo, nystagmus, deafness, tinnitus, ataxia, diplopia, paresthesias, disorientation, stupor, or
somnolence.

Cryoglobulins

Cryoglobulins are immunoglobulins and complement components that precipitate upon refrigeration
of serum. The major clinical manifestations of mixed cryoglobulinemia include palpable purpura,
arthralgias,
lymphadenopathy,
hepatosplenomegaly,
peripheral
neuropathy,
and
hypocomplementemia (with the fall in C4 levels often being most prominent). For patients for whom
cryoglobulinemia is a significant clinical problem, plasma exchange and newer therapies such as
Rituximab can be considered. After phlebotomy, blood must be maintained at 37oC during delivery
to the laboratory and prior to clotting and centrifugation in order to avoid premature loss of the
cryoglobulins among the separated cells. The serum is then placed in a refrigerator or ice bath and
examined at 24 hours for the presence of cryoprecipitate. If no precipitate is observed, the specimen
is kept at 4oC for an additional six days, at which time it is examined once again for precipitate. Any
precipitate is washed at 4oC, re-dissolved in warmed buffer and subjected to immunoelectrophoresis
with monospecific antisera to determine the type of immunoglobulin in the precipitate.