Amyloidosis is a rare and serious condition where abnormal proteins, called amyloid, build up in the body’s tissues and organs, disrupting their normal function and potentially leading to life-threatening complications if left untreated.
Understanding Amyloidosis
Amyloidosis happens when proteins in your body don’t fold correctly and instead form sticky, misshapen clumps. These abnormal protein clusters, known as fibrils, gather on organs like the heart, kidneys, liver, and nerves, causing damage over time. Think of it like rust accumulating on metal parts of a machine—the buildup gradually interferes with how things work. Without treatment, these deposits can cause serious organ damage and affect quality of life.[1][2]
The term “amyloidosis” comes from “amyloid,” which is the name for the abnormal protein, and “osis,” which means an abnormal or increased supply. Different proteins can form amyloid deposits, and the specific protein involved determines what type of amyloidosis a person has. The disease can be either localized, affecting just one area or organ, or systemic, spreading throughout multiple organs in the body.[4]
Healthcare providers categorize amyloidosis based on which protein is affected. Each type is named with an “A” for amyloid, followed by letters representing the specific protein responsible. For instance, AL amyloidosis involves light chain proteins, while ATTR amyloidosis involves a protein called transthyretin. Understanding which type you have is extremely important because treatment approaches differ significantly between types.[2]
Types of Amyloidosis
The most common type is AL amyloidosis, also known as immunoglobulin light chain amyloidosis. In this form, your bone marrow makes too many abnormal light chain proteins, which are normally part of antibodies. These faulty proteins cannot be broken down properly and accumulate primarily in the heart and kidneys, though they can also affect nerves, skin, and digestive organs. AL amyloidosis is the most frequently diagnosed form and used to be called primary amyloidosis.[2][3]
AA amyloidosis, previously known as secondary amyloidosis, occurs when fragments of serum A protein accumulate in organs. This type develops as a result of another chronic condition that causes long-term inflammation in the body, such as rheumatoid arthritis, inflammatory bowel disease like Crohn’s disease or ulcerative colitis, or chronic infections. The persistent inflammation triggers the production of too much serum A protein, which then forms amyloid deposits. AA amyloidosis most commonly affects the kidneys, spleen, and liver, but can also impact the digestive tract and heart.[2][3]
ATTR amyloidosis involves the transthyretin protein, which is made in the liver. This type comes in two forms. Hereditary or familial ATTR amyloidosis is passed down through families due to genetic mutations that cause the liver to produce abnormal transthyretin protein. Wild-type ATTR amyloidosis, formerly called senile systemic amyloidosis, occurs when normal transthyretin protein forms amyloid deposits in older adults, most commonly in older men. Both forms typically affect the heart and potentially the nerves.[2][3]
Dialysis-related amyloidosis is more common in older adults and people who have been on dialysis for more than five years. This form results from beta-2 microglobulin deposits that build up in the blood. The deposits most commonly affect bones, joints, and tendons.[3]
There is also organ-specific or localized amyloidosis, which causes deposits in a single organ rather than spreading throughout the body. This can affect the skin (cutaneous amyloidosis), lungs, throat, bladder, or other individual areas. This form is generally less severe than systemic types.[3]
Epidemiology: How Common Is Amyloidosis?
Amyloidosis is classified as a rare disease by the U.S. Office of Rare Diseases, which is part of the National Institutes of Health. This classification means that all types of amyloidosis combined affect fewer than 200,000 people in the United States population. The disease is also referred to as an “orphan” disease due to its rarity.[4]
Specifically for AL amyloidosis, healthcare providers estimate that there are only between 1,275 and 3,200 new cases diagnosed each year in the United States. This translates to an incidence of approximately one case per 100,000 people per year in Western countries. Among all diagnosed cases of systemic amyloidosis, about 78 percent annually are AL amyloidosis.[2][5]
The incidence of familial transthyretin-associated amyloidosis (ATTR) is unknown, but approximately 10 to 20 percent of diagnosed cases in specialized medical centers are due to ATTR amyloidosis. Of these cases, about seven percent are hereditary forms.[5]
Causes of Amyloidosis
Amyloidosis develops through what healthcare providers call a “protein misfolding disorder.” Normally, proteins in your body exist as neat, long chains that can be broken down when needed. In amyloidosis, something goes wrong during protein formation, causing them to become misshapen and sticky. Instead of being processed normally, these faulty proteins clump together into fibrils that get stuck in organs and tissues, where they accumulate over time.[2]
The underlying causes vary depending on the type of amyloidosis. AL amyloidosis is acquired, meaning it develops during a person’s lifetime rather than being inherited. It’s caused by a small clone of plasma cells in the bone marrow that produces misfolded amyloidogenic light chain proteins. These abnormal cells make faulty antibody fragments that deposit in different organs and tissues. There’s no known specific trigger for why this happens, though AL amyloidosis is linked to a blood cancer called multiple myeloma.[3][5]
AA amyloidosis is associated with various chronic inflammatory conditions that persist over long periods. Conditions like rheumatoid arthritis, chronic infections, or inflammatory bowel diseases cause the body to continuously produce inflammatory proteins. Over time, fragments of serum amyloid A protein accumulate and form deposits. The ongoing inflammation essentially creates too much of this protein for the body to handle properly.[5]
Hereditary forms of amyloidosis occur when someone inherits a gene mutation from a parent that causes blood proteins to be made abnormally. These genetic defects are linked to a higher chance of developing amyloid disease. For example, mutations in the gene that produces transthyretin protein can lead to hereditary ATTR amyloidosis. However, not everyone who carries these gene mutations will develop the disease, and among those who do, it can progress very slowly.[3][6]
In wild-type ATTR amyloidosis, normal transthyretin protein produced in normal quantities somehow converts into amyloid in the bodies of some older people. Researchers aren’t entirely sure why this happens, but it appears to be related to aging processes.[6]
Risk Factors
Several factors can increase the likelihood of developing amyloidosis. Age is a significant risk factor, as most people diagnosed with AL amyloidosis are in their 60s or 70s, although it can occur in younger people. Wild-type ATTR amyloidosis typically affects older adults and is most common in older men.[2][3]
Having certain chronic diseases substantially increases risk, particularly for AA amyloidosis. Conditions that cause long-term inflammation, such as rheumatoid arthritis, inflammatory bowel disease, chronic infections like tuberculosis or osteomyelitis, and rarely certain cancers, can trigger the development of AA amyloidosis. The longer these inflammatory conditions persist, the higher the risk becomes.[2][5]
Family history plays a crucial role in hereditary forms of amyloidosis. If someone in your family has been diagnosed with hereditary ATTR amyloidosis or other inherited forms, you have an increased risk of developing the condition. DNA testing can help identify whether you carry the gene mutations associated with familial amyloidosis.[6]
Long-term dialysis increases the risk of dialysis-related amyloidosis. People who have been on dialysis for more than five years are more likely to develop this type, as beta-2 microglobulin builds up in the blood over time when kidneys aren’t functioning properly.[3]
Being diagnosed with multiple myeloma or having related blood disorders increases the risk of developing AL amyloidosis, as both conditions involve abnormal plasma cells that can produce misfolded light chain proteins.[3]
Symptoms of Amyloidosis
One of the challenges with amyloidosis is that you may not experience symptoms until later in the course of the disease, after significant amyloid deposits have already formed. The symptoms can also be quite vague and easily mistaken for other, more common conditions or simply attributed to aging. This often leads to delayed diagnosis, with many people visiting multiple physicians before receiving the correct diagnosis.[1][11]
The symptoms vary considerably depending on which organs are affected by amyloid deposits. Common general symptoms include severe fatigue and weakness that doesn’t improve with rest. People often experience unexplained weight loss without trying to lose weight. Shortness of breath can occur, especially when the heart is affected. Many people develop numbness, tingling, or pain in the hands or feet, similar to a pins-and-needles sensation. Swelling of the ankles and legs is also common.[1][2]
Additional symptoms may include dizziness and low blood pressure, particularly when standing up. Some people experience digestive problems like diarrhea (possibly with blood), constipation, nausea, and loss of appetite. These symptoms occur when amyloid deposits affect the digestive tract.[1]
Visible skin changes are sometimes present. These include easy bruising and a distinctive condition called purpura, where small blood vessels leak blood into the skin, creating purple patches. This most commonly occurs around the eyes but can affect other body parts. Skin may also become thickened in some cases.[1][2]
An enlarged tongue, called macroglossia, can develop in some people with amyloidosis. The tongue may appear larger than normal and sometimes shows a rippled edge. This occurs when amyloid proteins deposit in tongue tissue.[1]
When cardiac amyloidosis specifically affects the heart, symptoms include weakness, shortness of breath during activities or while lying flat, fainting episodes (which can indicate abnormal heart rhythms), and leg swelling associated with heart failure. When kidneys are primarily affected (renal amyloidosis), symptoms may include swollen feet and legs and bubbles or foam in urine, indicating protein leakage.[2]
Nerve damage can cause numbness or weakness in hands and feet, increased sensitivity to temperature changes, and difficulty gripping objects. Some people experience unexplained back pain or pain, tingling, or numbness in their arms.[9]
Prevention
Because the exact causes of many types of amyloidosis aren’t fully understood, there are limited specific prevention strategies. However, certain approaches can reduce risk or help detect the disease earlier when treatment may be more effective.
For hereditary forms of amyloidosis, genetic counseling and testing are important preventive tools. If you have a family member diagnosed with hereditary ATTR amyloidosis or another inherited form, ask your healthcare team about genetic screening. Early identification of gene mutations allows for monitoring and potentially starting treatment before significant organ damage occurs. Family members can be screened to diagnose, monitor, and begin treatment as early as possible to help lessen damage.[17]
Managing chronic inflammatory conditions effectively may help prevent AA amyloidosis. If you have rheumatoid arthritis, inflammatory bowel disease, or chronic infections, working closely with your healthcare provider to control inflammation and treat underlying conditions is important. Proper disease management may reduce the excessive production of serum amyloid A protein.[2]
For people on long-term dialysis, regular monitoring is essential since dialysis-related amyloidosis becomes more common after five years of treatment. While dialysis itself is necessary for kidney failure, awareness of this potential complication allows for earlier detection.[3]
Being aware of early symptoms and seeking medical attention promptly can lead to earlier diagnosis. Research shows that seeking medical help as early as possible when concerning symptoms develop can lead to an earlier, correct diagnosis. Don’t dismiss persistent fatigue, unexplained weight loss, or unusual symptoms as simply part of aging.[11]
Maintaining overall heart-healthy lifestyle choices—eating a balanced diet, staying physically active within your capabilities, managing stress, not smoking, and getting quality sleep—supports general health and may help your body better cope with disease processes. While these measures don’t prevent amyloidosis specifically, they support organ function and overall well-being.[17]
Pathophysiology: How Amyloidosis Affects the Body
Understanding what happens in the body during amyloidosis helps explain why the disease causes the symptoms it does. The process begins at the molecular level with protein production. In healthy circumstances, proteins are made with specific shapes that allow them to perform their jobs correctly, and when they’re no longer needed, the body breaks them down efficiently.[2]
In amyloidosis, something disrupts this normal process. The proteins don’t fold into their proper shapes. Instead, they form what’s called a beta-sheet structure, creating rigid, insoluble fibers. These misfolded proteins are abnormally stable and resistant to the body’s normal breakdown mechanisms. They begin to stick together, forming larger and larger clumps or aggregates.[5]
Most amyloid-forming proteins circulate in the blood, with some originating in the bone marrow (as in AL amyloidosis) and others produced in the liver (as in ATTR and AA amyloidosis). In most cases, amyloids form when too many of these proteins are produced or when they’re produced in abnormal forms. Once amyloid formation begins, the protein accumulates faster than the body can break it down, creating a progressive cycle of deposition.[6]
These amyloid fibrils travel through the bloodstream and eventually lodge in tissues and organs. The specific organs affected depend on the type of amyloid protein and individual factors. Once deposited, the amyloid disrupts the normal architecture and function of the tissue. Think of it like filling a sponge with concrete—the structure becomes rigid and can’t work properly anymore.[1]
In the heart, amyloid deposits infiltrate the heart muscle tissue, making the walls of the heart chambers thick and stiff. This stiffness prevents the heart from filling properly with blood between beats and reduces its ability to pump effectively. The heart’s electrical system can also be disrupted, leading to abnormal rhythms. Over time, this leads to heart failure, where the heart cannot pump enough blood to meet the body’s needs.[2]
When kidneys are affected, amyloid deposits accumulate in the filtering units called glomeruli. These tiny structures normally filter waste from blood while retaining important proteins. Amyloid deposits damage this delicate filtering mechanism, causing protein to leak into the urine (proteinuria) and reducing the kidney’s ability to filter waste. As deposits increase, kidney function progressively declines, potentially leading to kidney failure.[6]
In nerves, amyloid deposits can damage both the peripheral nerves (which control sensation and movement in limbs) and autonomic nerves (which control automatic body functions like blood pressure, digestion, and heart rate). This explains symptoms like numbness, tingling, weakness, dizziness upon standing, and digestive problems. The deposits physically disrupt nerve signals and can damage the protective covering around nerves.[2]
In the digestive tract, amyloid infiltration of the intestinal walls affects normal movement and absorption. This can cause diarrhea, constipation, feeling full quickly, or poor nutrient absorption leading to weight loss. When the liver is affected, amyloid deposits cause enlargement (hepatomegaly) and can interfere with the liver’s many functions.[1]
The progressive nature of amyloidosis means that without treatment to stop or slow protein production, deposits continue accumulating, and organ function continues declining. The rate of progression varies considerably between types of amyloidosis and between individuals, but understanding this process emphasizes why early diagnosis and treatment intervention are so important.[6]
