Light chain disease is caused by the overproduction of abnormal protein fragments, specifically components of antibodies known as light chains. These fragments are produced by a specific type of white blood cell and circulate through the bloodstream. The disease develops when these abnormal light chains deposit in various organs and tissues throughout the body. This accumulation of misfolded proteins progressively disrupts normal organ function, leading to serious health complications over time.
The Role of Plasma Cells and Immunoglobulin Structure
Light chain disease originates with plasma cells, specialized white blood cells found primarily in the bone marrow. The normal function of plasma cells is to produce large quantities of antibodies, or immunoglobulins, which are the body’s primary defense against infection. Each normal antibody molecule is structured like a “Y,” composed of two heavy chains and two light chains (kappa or lambda type).
In light chain disease, a single clone of plasma cells becomes abnormal and multiplies uncontrollably. This clone produces an excessive amount of only one type of light chain, which is structurally identical, or monoclonal. These excess light chains, referred to as monoclonal protein or M-protein, are secreted into the blood without being properly assembled. The abnormal free light chains then circulate throughout the body, where they can misfold and aggregate.
Clinical Manifestations of Light Chain Deposition
The umbrella term “light chain disease” covers distinct disorders characterized by how the abnormal light chains deposit in tissue. The two most common deposition syndromes are AL amyloidosis and Light Chain Deposition Disease (LCDD). These conditions differ significantly based on the structure of the resulting protein deposit, which dictates the pattern of organ damage.
In AL amyloidosis, the light chains misfold and aggregate into insoluble, rigid protein structures called amyloid fibrils. These fibrils accumulate outside of the cells, gradually replacing normal tissue architecture in vital organs like the heart and kidneys. The presence of these specific amyloid deposits is confirmed by a Congo red stain during a biopsy, which causes the material to glow green under polarized light.
LCDD involves a different mechanism, where the light chains deposit in a non-fibrillar, granular form. In LCDD, the light chains deposit within the basement membranes and mesangium of organs, causing thickening and nodular changes. Unlike AL amyloidosis, these deposits do not stain with Congo red, and the disease is often characterized by the predominance of kappa light chains.
Common Symptoms and Diagnostic Testing
The symptoms of light chain disease can be vague and depend entirely on which organs are affected by the protein deposition. Kidney involvement is particularly frequent, often presenting as nephrotic syndrome, which includes high levels of protein in the urine (proteinuria) and swelling (edema), particularly in the legs and around the eyes. The rapid decline in kidney function seen in these conditions can lead to kidney failure.
When the heart is involved, patients may experience shortness of breath, profound fatigue, and irregular heart rhythms due to the thickening and stiffening of the heart muscle. Deposits in the nervous system can cause peripheral neuropathy, leading to numbness, tingling, or pain in the hands and feet. Diagnosis begins with laboratory tests to detect the abnormal protein in the blood and urine.
A serum free light chain (sFLC) assay is a sensitive test that measures the levels of kappa and lambda light chains circulating freely. The test calculates a kappa-to-lambda ratio, which normally falls within a specific reference range. A highly skewed ratio, meaning a significant overabundance of one type of light chain, strongly suggests the presence of a monoclonal plasma cell disorder. This is often followed by serum protein electrophoresis (SPEP) and immunofixation to identify the abnormal monoclonal protein.
The definitive diagnosis requires a biopsy of an affected organ, such as the kidney, heart, or a fat pad. Tissue removed during the biopsy is examined under a microscope to confirm the presence and specific nature of the light chain deposits. This microscopic analysis differentiates between the fibrillar deposits of AL amyloidosis and the granular deposits of LCDD, which is necessary to guide treatment decisions.
Treatment Strategies and Organ Management
Treatment for light chain disease focuses on two primary goals: eliminating the source of the abnormal light chains and managing the damage already inflicted on the organs. The underlying abnormal plasma cell clone must be targeted to stop the continuous production of the toxic protein fragments. Treatment regimens are often similar to those used for multiple myeloma, aiming for a rapid and deep hematologic response, which means a significant reduction in the levels of the circulating free light chains.
Chemotherapy regimens typically combine a steroid, an alkylating agent, and a novel agent. For example, modern treatments frequently utilize a proteasome inhibitor, such as bortezomib, which interferes with protein breakdown within the abnormal plasma cells, leading to their death. Newer monoclonal antibodies, such as daratumumab, which targets the CD38 protein on plasma cells, are also used to further reduce the plasma cell population.
For eligible patients, autologous stem cell transplantation (ASCT) may be considered, involving high-dose chemotherapy followed by the reinfusion of the patient’s own healthy stem cells. Simultaneously, managing organ damage is essential to support quality of life. This may involve dialysis for patients with severe kidney failure or specialized medications to manage congestive heart failure and irregular heart rhythms resulting from cardiac deposition.