During the synthesis of immunoglobulins, light chains (LC) are produced the same time as heavy chains (HC), thus enabling the constitution of a functional immunoglobulin. Physiologically, there is a slight excess of free light chains (FLC), which is eliminated by the kidneys. In a disease situation, due to the proliferation of plasma sites, there will be an excess production of FLC.
- If the proliferation is POLYCLONAL (autoimmune diseases, infections, cancers, etc.), the FLCs produced will be polyclonal.
- If the proliferation is MONOCLONAL (myeloma, amyloidosis), a single type of LC will be producing excess and the FLCs will be monoclonal.
The FLCs can be assayed by nephelometry or turbidimetry. This assay allows better support for the diagnosis, follow-up and prognosis of certain plasma cell disorders. In AL amyloidosis, the essay will be useful for diagnosis, follow-up, and as a criterion of treatment response. In the context of myeloma (light-chain, non-secreting, poorly secreting), plasma site owners and light-chain to position diseases, it will be useful in monitoring the disease. The assay is intended as an early factor treatment response or relapse; the progress of FLC levels is associated with a five-year survival of 88% for patients with an FLC level reduced by more than 50% and of 39% for those with an FLC level reduced by less than 50%. The indications in the monitoring of whole-Ig plasma-cell disorders (myeloma, Waldenström’s macroglobulinemia, MGUS) are less clear.
NB: the assay measures total FLC, monoclonal AND polyclonal. It is therefore necessary to interpret the results in their overall context: electrophoresis, immunofixation of serum proteins (confirmation of monoclonal character), so as to best adapt the diagnostic process and to identify any analytical interferences:
- Risk of underestimation by a zone effect linked to an excess of antigen
- Risk of overestimation in case of polymerisation of the monoclonal FLCs or fixation of the proteins (alpha1-antitrypsin).
The recommendations indicate the parallel assay of both FLCs (? AND ?) so as to establish an FLC?/FLC? ratio that would be an indicator of monoclonality. In the case of an inflammatory syndrome or kidney disease associated with plasma-cell disorder, the level of FLCs would increase (monoclonal FLCs and also polyclonal FLCs) and so the ratio and the difference between the assays of the two FLCs would be informative for monitoring.
NB: On the other hand, it is NOT RECOMMENDED to carry out the assay of URINARY FLCs, which is never a good reflection of the tumour mass. Renal monitoring should be carried out by assay of 24h-urine albumin and protein levels, electrophoresis and immunofixation of urinary proteins.
How is it used?
Serum free light chain (SFLC) testing is ordered to help detect, diagnose, and monitor plasma cell disorders (dyscrasias), including multiple myeloma and primary amyloidosis, and to monitor the effectiveness of treatment.
Light chains are proteins produced by plasma cells. They are used to assemble immunoglobulins (Ig), antibodies that target and neutralize specific threats to the body such as bacteria and viruses. Two light chains and two heavy chains combine to form an immunoglobulin (IgG, IgM, or IgA).
With a group of conditions called plasma cell disorders or monoclonal gammopathies, a plasma cell becomes malignant, divides uncontrollably, and produces large amounts of an abnormal monoclonal immunoglobulin (M-protein). This protein may take the form of an intact immunoglobulin or of one of its component parts - a kappa or lambda light chain, or rarely, a heavy chain.
Traditionally, plasma cell disorders have been diagnosed using serum and urine protein electrophoresis tests (SPEP/UPEP), followed by immunofixation electrophoresis (IFE) tests to determine which immunoglobulin is present in excess. Blood tests may also be ordered to measure levels of intact immunoglobulins (IgG, IgM, IgA).
Serum free light chain testing provides complementary information. It can detect the low levels of free light chains that are sometimes all that is produced by a plasma cell disorder and can detect changes in the ratio of kappa and lambda production, which indicate an excess of one clone of plasma cells.
Initially, serum free light chain testing is ordered along with a serum protein electrophoresis test to detect abnormal monoclonal protein (M-protein) production and to calculate a kappa/lambda free light chain ratio. If the protein electrophoresis test is abnormal, then an immunofixation electrophoresis test is performed to determine which immunoglobulin is present in excess. If a plasma disorder is detected, then the free light chain test may be ordered periodically to monitor the condition and to evaluate the effectiveness of treatment.
When is it ordered?
Serum free light chain testing and a kappa/lambda ratio is ordered along with a protein electrophoresis test when someone has signs and symptoms that a health practitioner suspects are related to a plasma cell disorder. These symptoms will vary from person to person and tend to worsen over time. They involve various parts of the body and may include:
- Bones–bone pain, soft spots, and fractures due to proliferation of plasma cells in the bone marrow
- Blood–anemia and frequent infections due to low levels of red and white blood cells; plasma cells crowd out the other types of cells in the bone marrow, leading to a decrease of RBCs and WBCs.
- Kidneys–production of abnormal amounts of light chains can lead to increased light chains in the urine (Bence-Jones protein); these proteins can lodge or deposit in the kidneys, causing damage.
A health practitioner may also order this test when someone has signs and symptoms associated with primary amyloidosis. Amyloidosis develops when abnormal proteins build up in organs or tissue, particularly the heart, liver, kidneys, spleen, gastrointestinal tract, and nervous system. In primary amyloidosis, the proteins are free light chains. Depending on the organs affected, the person may have a variety of symptoms such as:
- Swelling of ankles and legs
- Weakness, fatigue
- Numbness, weakness or tingling of the arms and legs
- Shortness of breath, difficulty breathing
- An irregular heartbeat
- Easy bruising
- Purple patches around the eyes (so-called raccoon's eyes)
- Tongue swelling
When a light chain disorder is diagnosed, the test may be ordered periodically to monitor the condition and to evaluate the effectiveness of treatment.
What does the test result mean?
Results of a serum free light chain test will often be evaluated in conjunction with the results of a protein electrophoresis test.
Free light chains will normally be present in the blood at low levels, with a kappa/lambda ratio of approximately 0.26 to 1.65.
Increased kappa free light chains and an increased kappa/lambda ratio may be seen with plasma cell disorders that produce excess monoclonal kappa light chains.
Increased lambda free light chains and a decreased kappa/lambda ratio may be seen with plasma cell disorders that produce excess monoclonal lambda light chains. In general, significantly increased free light chain production and an abnormal kappa/lambda ratio indicate a poorer prognosis and an increased risk of disease progression.
When the test is used to monitor a known plasma cell disorder, a decrease in the quantity of excess light chain and a more normal kappa/lambda ratio indicates a response to treatment.
Increased free light chains with a normal serum free kappa/lambda ratio may be seen with people who have some degree of kidney dysfunction that is unrelated to a plasma cell disorder. Decreased free light chains with a normal kappa/lambda ratio may be seen with a disorder that suppresses bone marrow cell production.
With suspected primary amyloidosis, an increase in serum free light chains with an abnormal kappa/lambda ratio may suggest that amyloidosis is the cause of symptoms. However, a biopsy of affected tissue is the primary means of establishing the diagnosis.
Is there anything else I should know?
Monoclonal gammopathy of undetermined significance (MGUS) is the most common plasma cell disorder and it usually does not cause symptoms. A percentage of people with MGUS will later develop multiple myeloma. This risk is increased in those with increased free light chain production and an abnormal kappa/lambda ratio.
Serum free light chains can also be increased, usually with a normal kappa/lambda ratio, with some connective tissue disorders, inflammatory conditions, neurological conditions, and some cancers but are not typically monitored in people with these conditions.
Serum free light chain analysis accelerates the detection of treatment response because the free light chains have a much shorter half-life (3-5 hours) than intact immunoglobulins (about 21 days). Although it is traditionally used for light chain-only plasma cell disorders, the test has increasingly been used for treatment monitoring of myelomas that produce intact immunoglobulins (e.g., IgG, IgA) as well.