Systemic amyloidosis is a rare condition characterized by the accumulation of abnormal proteins, known as amyloid, within various organs and tissues throughout the body. These protein deposits can disrupt the normal functioning of affected organs, potentially leading to serious health complications. The term “systemic” indicates that the disease is widespread, impacting multiple body systems rather than being confined to a single location.
The Underlying Cause of Amyloidosis
Amyloidosis develops when certain proteins, normally soluble and functional, misfold into an abnormal configuration. This misfolding allows them to clump together, forming insoluble aggregates called amyloid fibrils.
These fibrils possess a distinct cross-beta sheet structure, making them highly stable and resistant to the body’s natural breakdown processes. The body struggles to clear these misfolded protein deposits, leading to their gradual accumulation. The amyloid fibrils then deposit in the extracellular space between cells in various tissues, disrupting normal organ architecture and interfering with their ability to perform their intended functions.
Major Types of Systemic Amyloidosis
Systemic amyloidosis is categorized based on the specific precursor protein that misfolds and forms the amyloid deposits. The most common type is AL amyloidosis, which originates from abnormal plasma cells in the bone marrow. These plasma cells produce an excess of misfolded immunoglobulin light chain proteins, which then aggregate to form AL amyloid fibrils. AL amyloidosis is the most frequently diagnosed form in the United States.
Another type is ATTR amyloidosis, involving the transthyretin (TTR) protein. This type has two main variants: hereditary ATTR (hATTR) and wild-type ATTR (wtATTR). Hereditary ATTR amyloidosis is caused by a genetic mutation in the TTR gene, leading to an unstable, misfolding TTR protein. Wild-type ATTR amyloidosis is associated with aging and occurs when a normally structured TTR protein misfolds without a known genetic mutation.
AA amyloidosis stems from chronic inflammatory diseases or infections. The liver produces an excess of serum amyloid A (SAA) protein. This elevated SAA can then misfold and deposit as amyloid fibrils, often affecting organs like the kidneys and spleen.
Organ Involvement and Associated Symptoms
The heart is a frequently affected organ, particularly in AL and ATTR amyloidosis. Cardiac involvement can lead to symptoms such as shortness of breath, even during light activity, and swelling in the legs, ankles, and abdomen due to fluid buildup. Irregular heartbeats or palpitations may also occur.
The kidneys are another common site for amyloid accumulation, especially in AL and AA amyloidosis. Amyloid deposits can impair the kidneys’ filtering system, leading to high levels of protein in the urine, which may cause it to appear foamy. This can progress to nephrotic syndrome, characterized by significant swelling and may result in kidney failure.
Neurological symptoms are observed, particularly in ATTR and some AL cases. Carpal tunnel syndrome, caused by amyloid pressing on nerves in the wrist, can be an early indicator. Peripheral neuropathy may manifest as numbness, tingling, or pain in the hands and feet. Autonomic nerve damage can lead to a drop in blood pressure upon standing, causing dizziness or fainting, and can also affect bowel or bladder function.
Gastrointestinal involvement can present with various symptoms, including unintended weight loss, a feeling of being full quickly after eating, and changes in bowel habits, such as alternating diarrhea and constipation. In some cases, the tongue may become noticeably enlarged and firm, a condition known as macroglossia. Skin changes, like easy bruising or purplish patches around the eyes, may also be present.
The Diagnostic Process
Diagnosing systemic amyloidosis can be challenging because its symptoms often resemble those of more common conditions. Diagnosis typically begins with a doctor’s suspicion based on a patient’s symptoms and initial laboratory tests. Blood and urine analyses are often performed to detect abnormal proteins that might suggest the presence of amyloidosis.
Imaging techniques assess organ involvement and damage. An echocardiogram, which uses sound waves, can provide moving images of the heart’s function and identify changes characteristic of amyloid deposition. Magnetic resonance imaging (MRI) offers detailed views of organs and tissues, helping to evaluate their structure and function. Nuclear imaging, involving the injection of small amounts of radioactive tracers, can reveal early heart damage and help distinguish between certain types of amyloidosis.
The definitive diagnosis requires a tissue biopsy to confirm the presence of amyloid deposits. A small sample of tissue, often from the abdominal fat pad or bone marrow, is taken and examined under a microscope. If amyloid is found, further specialized tests are performed on the biopsy sample to identify the specific type of protein forming the amyloid. This precise typing guides the subsequent treatment strategy.
Approaches to Treatment and Management
Treatment for systemic amyloidosis aims to halt or reduce the production of the misfolding precursor protein and to manage the symptoms and damage to affected organs. Therapies focus on limiting further amyloid deposition and supporting overall health. The specific treatment approach is highly individualized, depending on the type of amyloidosis and the organs involved.
For AL amyloidosis, treatments often involve chemotherapy regimens, similar to those used for certain blood cancers. These medications work to suppress the abnormal plasma cells that produce misfolded light chain proteins. Targeted therapies, such as monoclonal antibodies, may also be used to interfere with the production or aggregation of the amyloid-forming proteins. Reducing the supply of the precursor protein can prevent new amyloid formation.
Managing organ damage includes medications to control heart rate, reduce fluid buildup, or improve kidney function. If organ damage is severe, procedures like dialysis or organ transplants may be considered. The goal is to stabilize organ function, improve symptoms, and enhance the patient’s quality of life.