Light Chain (AL) Amyloidosis is a serious, progressive disorder resulting from the misfolding of specific proteins in the body. The condition is characterized by the accumulation of these abnormal proteins, known as amyloid fibrils, in various organs and tissues. This buildup physically disrupts the normal function of affected organs, leading to a decline in health. AL amyloidosis is currently the most common type of systemic amyloidosis in the United States.
The Underlying Cause: Plasma Cell Dysfunction
Light Chain (AL) amyloidosis originates with a dysfunction in plasma cells, specialized white blood cells located primarily within the bone marrow. These plasma cells normally produce antibodies, or immunoglobulins, which are essential for fighting infections. A standard antibody molecule is composed of two heavy chains and two smaller light chains.
In AL amyloidosis, a small number of plasma cells become abnormal and multiply uncontrollably, forming a clone. This clone produces an excessive amount of a single, structurally unstable light chain protein, either kappa or lambda. Unlike normal light chains, which are harmlessly excreted by the kidneys, these abnormal light chains misfold into a rigid, insoluble beta-pleated sheet structure.
These misfolded light chains aggregate to form waxy, non-branching amyloid fibrils. The “A” in AL stands for amyloid, and the “L” stands for light chain, indicating the specific protein causing the disease. These fibrils are deposited into the spaces between cells within organs throughout the body. This deposition causes mechanical stress and physical disruption, ultimately leading to organ damage and functional failure.
The abnormal plasma cell population is often referred to as a plasma cell dyscrasia. Although AL amyloidosis is not technically a cancer, the underlying process is similar to that seen in multiple myeloma. Treatments for AL amyloidosis target the abnormal plasma cell clone in the bone marrow to stop the production of the toxic light chains.
How Light Chain Amyloidosis Manifests
The symptoms of AL amyloidosis are diverse and often non-specific, frequently complicating and delaying diagnosis. Presentation depends on which organs are infiltrated by the amyloid fibrils and the extent of the deposition. Organs most frequently affected include the heart, kidneys, nervous system, and gastrointestinal tract.
Cardiac involvement, known as amyloid cardiomyopathy, is the leading cause of death in AL amyloidosis patients. Amyloid deposition stiffens the heart ventricles, preventing them from relaxing properly to fill with blood. This causes restrictive cardiomyopathy, leading to heart failure symptoms such as shortness of breath, fatigue, and fluid retention.
The kidneys are also a common target, as amyloid deposits interfere with their ability to filter waste and retain necessary proteins. This damage often results in nephrotic syndrome, characterized by significant protein loss in the urine. This leads to low blood protein levels and widespread swelling (edema). Progressive damage can result in kidney failure, requiring dialysis.
Amyloid deposits can affect the nervous system, leading to both peripheral and autonomic neuropathies. Peripheral neuropathy typically manifests as numbness, tingling, or pain in the hands and feet, sometimes presenting as carpal tunnel syndrome. Autonomic neuropathy affects involuntary body functions, causing symptoms like light-headedness upon standing due to low blood pressure, or issues with bowel and bladder function.
Other unique manifestations of AL amyloidosis can provide strong diagnostic clues. The tongue may become noticeably enlarged and firm, a condition called macroglossia, which can interfere with speech and swallowing. Bruising around the eyes, known as periorbital purpura or “raccoon eyes,” can occur due to amyloid affecting small blood vessels in the skin.
Confirming the Diagnosis
Diagnosing Light Chain (AL) amyloidosis requires multiple complementary tests to confirm both the presence of amyloid deposits and the underlying plasma cell disorder. The primary step is obtaining a tissue sample for analysis, typically through a biopsy. A sample is often taken from an accessible site like the abdominal fat pad or bone marrow, though a biopsy of an affected organ, such as the kidney or heart, may be necessary.
The tissue sample is stained with Congo Red dye, which causes the amyloid deposits to appear apple-green when viewed under polarized light. Once amyloid presence is confirmed, the specific protein that formed the fibrils must be identified to confirm the AL type. This is often accomplished using mass spectrometry or immunohistochemical staining techniques on the biopsy sample.
Blood and urine tests are used to detect the abnormal light chains produced by the plasma cell clone. The serum free light chain assay is highly sensitive and measures the amount of kappa and lambda light chains circulating in the blood. An abnormal ratio between these two types of chains strongly suggests a plasma cell dyscrasia. Immunofixation electrophoresis of the serum and urine is also performed to identify the specific monoclonal protein, often referred to as an M-spike.
Imaging studies are essential for assessing the extent of organ damage caused by the amyloid. An echocardiogram or cardiac magnetic resonance imaging (MRI) is used to evaluate the heart’s structure and function, looking for the thickening of the walls and poor relaxation characteristic of amyloidosis. For the kidneys, specific renal function tests, such as measuring protein in the urine, monitor the degree of damage.
Modern Treatment Strategies
Treatment for Light Chain (AL) amyloidosis focuses on two simultaneous goals: eradicating the abnormal plasma cell clone and providing supportive care to manage organ damage. The primary therapeutic approach is clonal therapy, which aims to eliminate the source of the toxic light chains. Chemotherapy protocols are often adapted from treatments for multiple myeloma, but doses are adjusted due to the patient’s existing organ damage.
Combination chemotherapy regimens kill the disease-causing plasma cells in the bone marrow. Specific drug combinations often include a proteasome inhibitor (e.g., bortezomib), an immunomodulatory drug, and a corticosteroid (e.g., dexamethasone). These drugs work together to disrupt the plasma cell’s survival mechanisms and induce cell death.
For select patients who are younger and in good health, high-dose chemotherapy followed by an autologous stem cell transplantation (ASCT) may be an option. This intensive procedure involves collecting the patient’s own healthy stem cells. High-dose chemotherapy is administered to destroy the abnormal plasma cells, and the stored stem cells are then reinfused to rescue the bone marrow. This approach can lead to deep and durable remissions.
Supportive care is an equally important part of treatment to preserve organ function and manage symptoms. Patients with cardiac involvement may be prescribed diuretics to control fluid retention and manage heart failure symptoms. For those with advanced kidney disease, medications reduce protein loss in the urine, and dialysis may be required if the kidneys fail completely.
Newer therapies, including monoclonal antibodies, are being investigated to directly target and clear the amyloid fibrils already deposited in the organs. These emerging treatments represent a promising strategy to not only stop the production of new amyloid but also actively remove existing deposits, potentially leading to improved organ function.