Amyloidosis is a group of diseases defined by the abnormal buildup of misfolded proteins, called amyloid fibrils, in various organs and tissues. This accumulation causes organs to become stiff and eventually fail, leading to serious health complications. AL Amyloidosis, or light chain amyloidosis, is the most common systemic form, meaning it affects multiple body systems.
The “AL” refers to the protein forming the deposits, which are derived from immunoglobulin light chains. This condition is caused by an underlying bone marrow abnormality that results in the overproduction of these specific proteins. Managing this complex condition requires understanding the mechanism by which these proteins are created.
The Underlying Mechanism of AL Amyloidosis
AL amyloidosis begins in the bone marrow, the soft tissue inside bones responsible for producing blood cells. A specific type of white blood cell, called a plasma cell, becomes abnormal and multiplies uncontrollably. Normal plasma cells produce antibodies (immunoglobulins) to fight infection, which are made up of heavy and light protein chains.
In AL amyloidosis, this abnormal plasma cell clone overproduces a single type of immunoglobulin light chain (kappa or lambda). These excess light chains are released into the bloodstream as “free” light chains. Unlike normal proteins, these free light chains are structurally unstable and misfold.
The misfolded light chains then aggregate to form insoluble strands known as amyloid fibrils. These fibrils circulate in the blood before gradually depositing in tissues and organs, disrupting their normal structure and function.
This process is progressive, meaning extended production of the misfolded protein leads to more extensive organ damage. The light chains themselves are thought to be directly toxic to cells, adding to the damage caused by the physical deposits. Treatment must target the source of protein production in the bone marrow to halt organ damage.
Common Signs and Affected Body Systems
The clinical presentation of AL amyloidosis is highly variable because amyloid deposits can accumulate in almost any organ or tissue outside the central nervous system. Symptoms depend on which organs are most affected and the extent of the damage. Since the disease often affects multiple body systems simultaneously, symptoms are frequently non-specific.
The heart is often the most severely affected organ. Amyloid deposits cause the heart muscle walls to become stiff and thickened, a condition known as restrictive cardiomyopathy. This stiffening prevents the heart from relaxing properly to fill with blood, leading to heart failure symptoms like shortness of breath and swelling (edema) in the legs and abdomen. Heart involvement is the most significant factor determining a patient’s prognosis.
The kidneys are also a frequent target, where amyloid deposits damage the filtering units. This damage causes proteins that should be retained in the blood to leak into the urine, a condition called proteinuria. Significant protein loss can lead to nephrotic syndrome, which often presents as swelling in the lower extremities and sometimes progresses to kidney failure requiring dialysis.
Amyloid can also deposit in the nervous system, leading to peripheral neuropathy (numbness, tingling, or pain, typically in the hands and feet). Deposits in the autonomic nervous system affect nerves controlling involuntary functions. This results in symptoms like dizziness upon standing (orthostatic hypotension) or gastrointestinal issues such as alternating diarrhea and constipation.
Certain physical signs are suggestive of AL amyloidosis and prompt investigation. The tongue can become enlarged and firm (macroglossia) due to amyloid deposits within the muscle tissue. Another distinctive sign is periorbital purpura, which manifests as purplish bruising around the eyelids, often called “raccoon eyes,” caused by deposits in the small blood vessels.
Diagnostic Procedures
Confirming AL amyloidosis requires laboratory tests and tissue analysis to identify the abnormal protein and resulting organ deposits. Initial suspicion often arises from blood and urine tests screening for the abnormal light chains.
The Serum Free Light Chain Assay is a specific blood test used to measure the levels and ratio of kappa and lambda light chains. An abnormal ratio strongly indicates the overproduction of a single type of light chain by a plasma cell clone. Further blood tests, such as cardiac biomarkers like NT-proBNP, assess the severity of heart involvement.
The definitive diagnosis relies on demonstrating amyloid fibrils in a tissue sample. The gold standard is a biopsy, where tissue is removed and stained with Congo red dye. When viewed under polarized light, the amyloid deposits exhibit a characteristic apple-green color, confirming the abnormal material.
Biopsies are often taken from easily accessible sites, such as the abdominal fat pad or the bone marrow (the source of the abnormal plasma cells). A fat pad aspirate is a common, minimally invasive procedure with high diagnostic sensitivity. Imaging tests, such as an echocardiogram or cardiac MRI, are used to assess which organs are involved and the extent of the damage.
Treatment Approaches
The management of AL amyloidosis follows a two-pronged approach: stopping the production of toxic light chains and providing supportive care for damaged organs. The goal of therapy is to quickly reduce circulating free light chains to prevent further amyloid deposition and allow for potential organ recovery.
Treatment aimed at the underlying disease focuses on eliminating or suppressing the abnormal plasma cells in the bone marrow, similar to treatments for multiple myeloma. These systemic treatments often involve combination chemotherapy regimens, including drugs like proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. These drugs destroy the disease-causing plasma cells, shutting down the source of the misfolded light chains.
For selected patients, high-dose chemotherapy followed by an autologous stem cell transplant (ASCT) may be an option. In this procedure, the patient’s own stem cells are collected, high-dose chemotherapy destroys the plasma cells, and stored stem cells are returned to restore blood cell production. ASCT can lead to deep and sustained remissions. However, only a subset of patients with limited organ damage are eligible due to the procedure’s intensity.
Supportive care is an important component of treatment, focused on managing symptoms and preserving the function of damaged organs. This includes medications like diuretics to manage fluid retention and swelling caused by heart or kidney involvement, alongside strict attention to fluid and salt intake. For patients with severe kidney failure, dialysis may be required. In rare cases of advanced heart damage, a heart transplant may be considered.