Amyloidosis

Amyloidosis is a rare disease that occurs when abnormal proteins called amyloid build up in your body’s organs and tissues, affecting how they work. While the disease can be serious, new treatments and better understanding mean that many people can manage their condition and live fulfilling lives.

Table of contents

• What is amyloidosis?
• Types of amyloidosis
• How common is amyloidosis?
• Organs and parts of the body affected
• Symptoms
• What causes amyloidosis?
• How is amyloidosis diagnosed?
• Treatment
• Living with amyloidosis

What is amyloidosis?

Amyloidosis is a disease that happens when a protein called amyloid builds up in your organs and tissues^[1]. These proteins exist normally in your body, but in amyloidosis they become misshapen and stick together, forming clumps or deposits^[2]. Healthcare providers call amyloidosis a “protein misfolding disorder” because instead of being neat, long chains that your body can break down, the proteins get stuck in organs and cause problems^[2].

When amyloid deposits (also called fibrils) build up, they affect the shape of your organs and how they work^[3]. Without treatment, these abnormal proteins can cause serious organ damage^[2]. The disease can be localized, meaning the abnormal proteins gather in a small area on a single organ, or systemic, where fibrils build up on an entire organ or on different organs throughout your body^[2][4].

Amyloidosis can be acquired during a person’s lifetime or hereditary, passed down through families^[5]. The good news is that healthcare providers can stop the production of abnormal proteins that cause amyloidosis, and your body’s own immune system can help remove these proteins in some types of the disease^[2].

Types of amyloidosis

Healthcare providers categorize amyloidosis by the type of protein that becomes abnormal^[2]. The type of protein and where it collects determines which kind of amyloidosis you have^[3]. Each type is named with an “A” for amyloid, followed by letters that stand for the specific protein involved^[4].

The most common types include:

• AL amyloidosis (also called immunoglobulin light chain amyloidosis): This is the most common type and used to be called primary amyloidosis^[3]. In this type, your body makes too many abnormal light chain proteins, which are a key component of antibodies^[2]. The fibrils usually gather in your heart and kidneys, but may also affect your nerves, skin and organs in your digestive system^[1][2]. There’s no known cause, but it happens when your bone marrow makes abnormal antibodies that can’t be broken down^[3].
• AA amyloidosis: Previously known as secondary amyloidosis, this condition results from another chronic infectious or inflammatory disease^[3]. Fragments of serum A protein gather in your organs^[2]. This can happen if you have a condition that causes long-term inflammation, like rheumatoid arthritis, inflammatory bowel disease such as Crohn’s disease or ulcerative colitis, or chronic infection^[1][3]. It mostly affects your kidneys, spleen, liver, digestive organs or heart^[1][3].
• ATTR amyloidosis: In this type, your liver makes abnormal transthyretin protein^[2]. The faulty transthyretin proteins build up in your heart and potentially your nerves^[2]. Some forms are inherited (called familial or hereditary amyloidosis), while others happen in a person’s lifetime as they age (called wild-type ATTR, formerly known as senile systemic amyloidosis)^[2][3]. Wild-type amyloidosis is caused by deposits of normal transthyretin protein in the heart and other tissues, and happens most commonly in older men^[3].
• Dialysis-related amyloidosis (DRA): This is more common in older adults and people who have been on dialysis for more than 5 years^[3]. This form is caused by beta-2 microglobulin deposits that build up in the blood^[3]. Deposits can build up in many different tissues, but they most commonly affect bones, joints and tendons^[3].
• Organ-specific (localized) amyloidosis: This causes deposits of amyloid protein in single organs, including the skin (called cutaneous amyloidosis), lungs, throat or bladder^[3]. Localized amyloidosis usually affects your skin, or small areas of your bladder or airways^[2].

How common is amyloidosis?

Amyloidosis is a rare disease^[2]. It has been labeled as a rare disease by the U.S. Office of Rare Diseases, which is part of the National Institutes of Health^[4]. This classification means that all types of amyloidosis combined are estimated to affect less than 200,000 people in the U.S. population^[4].

Healthcare providers estimate that in the United States, there are only 1,275 to 3,200 new cases of AL amyloidosis diagnosed each year^[2][5]. Many experts suspect that some of the amyloidosis diseases are not actually that rare, just rarely diagnosed^[4]. A major challenge is the current lack of early diagnosis for patients with amyloidosis^[4].

Organs and parts of the body affected

Amyloidosis may affect many different parts of the body. Amyloid can build up in the heart, kidneys, liver, spleen, nervous system, soft tissue, muscle and digestive tract^[1][5]. The disease can also affect blood vessels and nerves^[5].

• Heart
• Kidneys
• Liver
• Spleen
• Nervous system
• Digestive tract
• Soft tissue
• Muscles
• Blood vessels
• Skin
• Bladder
• Airways
• Bones
• Joints
• Tendons

Some types of amyloidosis affect specific organs, while other types spread throughout your body^[2]. Which organs are affected depends on the type of amyloidosis you have. AL amyloidosis most commonly involves the heart and kidneys, followed by other organs such as the liver, gastrointestinal tract and nerves^[9].

Symptoms

You may not experience symptoms of amyloidosis until later in the course of the disease^[1]. Symptoms may vary, depending on which organs are affected^[1]. Amyloidosis symptoms vary based on the specific protein type and where the fibrils land^[2].

Common symptoms of amyloidosis may include^[1][2]:

• Serious fatigue and weakness
• Excessive fatigue
• Shortness of breath
• Numbness, tingling or pain in the hands or feet
• Swelling of the ankles and legs
• Unexplained weight loss
• General weakness or weak grip
• Skin changes, including easy bruising and purple circles around your eyes (called purpura)

Additional symptoms may include^[1]:

• Dizziness
• Low blood pressure
• Diarrhea, possibly with blood
• Constipation
• Nausea and loss of appetite
• An enlarged tongue (called macroglossia)

For cardiac amyloidosis (when the disease affects the heart), symptoms include weakness or shortness of breath, fainting (a sign of abnormal heart rhythms) or leg swelling with heart failure^[2]. For renal or kidney amyloidosis, symptoms may include swollen feet and legs or bubbles in your urine^[2].

Nerve damage could be the reason you experience some symptoms, like a tingling or prickling sensation similar to pins and needles, increased sensitivity to temperature, numbness or weakness in the hands and feet^[15].

What causes amyloidosis?

Amyloidosis happens when proteins in your body become misshapen and sticky^[2]. They make clumps, or fibrils, that land on organs and tissues^[2]. Instead of being neat, long chains that your body can break down, the fibrils get stuck in organs and cause problems^[2].

Many different proteins can lead to amyloid deposits, but only a few have been linked to major health problems^[3]. In most cases, amyloids form when too many of these proteins are produced or when they are produced in abnormal forms^[6]. Amyloidosis can happen without any known cause, or it can be caused by another disease, such as cancer^[3]. It can also be inherited genetically^[3].

Causes of amyloidosis include^[2]:

• Gene changes (mutations): You may inherit a change (mutation) in the gene that makes abnormal amyloid proteins^[2]. Hereditary types of amyloids occur when a gene is inherited from a parent that causes a blood protein to be made slightly abnormally^[6]. These mutations can also happen during a person’s lifetime for unknown reasons^[2]. Many people with potential amyloid-causing genes never develop the disease, and among those who do, it can progress very slowly^[6].
• Underlying conditions: Amyloidosis may happen because of a separate condition^[2]. This is the case with AA amyloidosis, which is more common in people with conditions that cause long-term inflammation, like long-term infections, rheumatoid arthritis or chronic inflammatory conditions^[2][5].

In AL amyloidosis, the abnormal light chain protein is produced by an abnormal growth of plasma cells in the bone marrow, which do not usually cause symptoms themselves^[6]. In wild-type ATTR amyloidosis, a normal form of transthyretin protein is converted into amyloid in the bodies of some older people, though we are not sure why^[6].

How is amyloidosis diagnosed?

Amyloidosis is often overlooked because the symptoms can mimic those of more common diseases^[7]. Early diagnosis can help prevent further organ damage^[7]. Precise diagnosis of the type of amyloidosis you have is important because treatment varies greatly depending on your specific condition^[7].

Part of the problem in receiving the correct diagnosis is that the symptoms of amyloidosis can be similar to the symptoms of many other, often more common diseases, and the first signs can be mistaken as aging^[15]. Research shows that almost one-third of people with the condition will visit over five physicians before getting diagnosed, and around 70% of patients will not receive a diagnosis for over a year after symptoms first begin^[15]. A delayed diagnosis may also be due to limited awareness of amyloidosis amongst doctors, although this is continuously improving over time^[15].

Evaluation of amyloidosis begins with a set of basic laboratory tests:

• Laboratory tests: Blood and urine may be analyzed for proteins that can indicate amyloidosis^[7]. Assessment for abnormal protein includes serum and urine protein testing^[9]. Screening through 24-hour urine collection is essential, along with serum free light chain ratio analysis^[9]. People with certain symptoms also may need thyroid and kidney function tests^[7].
• Biopsy: A tissue sample can be checked for signs of amyloidosis^[7]. The biopsy may be taken from the fat under the skin on the belly or from bone marrow^[7]. Some people may need a biopsy of an affected organ, such as the liver or kidney^[7]. The tissue can be tested to see what type of amyloid is involved^[7].
• Imaging tests: Images of the organs affected by amyloidosis help your doctor understand the extent of the disease^[7]. These may include:
  • Echocardiogram: This technology uses sound waves to create moving images that can show how well the heart is working and can show heart damage that can be specific to amyloidosis^[7].
  • MRI (Magnetic Resonance Imaging): MRI uses radio waves and a strong magnetic field to create detailed images of organs and tissues^[7]. These images can be used to check the structure and function of the heart and can be useful in diagnosing whether amyloidosis is affecting the heart^[7].
  • Nuclear imaging: In this test, tiny amounts of radioactive material, called tracers, are injected into a vein^[7]. This can reveal early heart damage caused by certain types of amyloidosis and can help distinguish between different types of amyloidosis, which guides treatment decisions^[7].

Treatment

Some types of amyloidosis occur with other diseases and improve with treatment^[1]. Other types may lead to life-threatening organ failure^[1]. Treatment is now available for most types of amyloidosis, but accurate diagnosis and aggressive intervention are essential^[6].

The goal of treatment is to stop the production of abnormal proteins that cause amyloidosis^[2]. This can improve your symptoms and the health of the involved organs^[2]. Therapy for amyloidosis is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils^[12].

Treatment options may include^[1][2][10]:

• Chemotherapy medicines used to treat cancer: These medicines may help reduce the production of abnormal proteins^[1]. Chemotherapy regimens similar to those used for myeloma are employed^[12].
• Targeted therapies: The current standard treatment regimen for AL amyloidosis is daratumumab plus hyaluronidase, in combination with cyclophosphamide, bortezomib and dexamethasone^[12]. This is the first and only specific treatment for newly diagnosed AL amyloidosis approved by the U.S. Food and Drug Administration^[12].
• Autologous stem cell transplantation (ASCT): This is performed in eligible patients, especially those with an incomplete response to drug therapy^[12]. Some people may benefit from blood stem cell transplants^[1].
• Organ transplants: Some people may benefit from organ transplants^[1][2].
• Medicines to manage symptoms: Other medicines can reduce amyloid production and manage symptoms^[1].

The goal of treatment is to achieve a complete response, with the difference between involved and uninvolved free light chains less than 10 mg/L or involved free light chain less than 20 mg/L^[12]. All patients with amyloidosis should be considered for enrollment in a clinical trial, as several novel treatment approaches are being studied for this disorder^[12].

Living with amyloidosis

Although life with amyloidosis can present a variety of challenges, people diagnosed with the condition can experience productive and fulfilling lives by proactively managing their disease^[20]. To enjoy your best life with amyloidosis, it’s important to take care of your body, manage stress and communicate effectively about your condition^[20].

Finding out that you or someone you care about has amyloidosis can be worrying^[17]. Being diagnosed with amyloidosis can be overwhelming, particularly if you’ve never heard of it before^[11]. You’re not alone, and many people feel scared and uncertain at first^[11].

As amyloidosis may affect several organs in your body, there might be changes in your life that are necessary and unavoidable^[14]. If you are receiving treatment, these changes may be complemented by additional adjustments and constraints that arise from the treatment or its side effects^[14]. Discomfort is common with amyloidosis, and so are inexplicable bouts of fatigue, cramps and fluid retention^[14].

You may choose to continue working after receiving your diagnosis, however, you should keep in mind that it may be necessary to take time off work for tests and treatments, possibly involving extended hospital stays^[14]. It will also depend on the type of employment you are in^[14]. Many employers may be open to adopting a more flexible approach to working conditions and reducing the level of responsibility should that be required^[14].

Lifestyle factors can play into how you will feel after being diagnosed with amyloidosis^[20]. These factors include eating a healthy diet, getting enough exercise, managing stress and not smoking^[20]. Your healthcare team may recommend some small considerations and changes as a complementary approach to primary treatment^[15]:

• Eat healthily and lower your salt intake^[15]
• Try to drink 2–3 litres of water a day to stay hydrated (unless your doctor has advised otherwise)^[15]
• Be sensible about moving around, taking your ableness into account^[15]
• Record any symptoms or side effects you are experiencing and be sure to tell your doctor about them^[15]
• Keep a record of your medical history, treatments and test results^[15]
• Stop smoking, as nicotine and other chemicals in cigarettes can damage blood vessels, making it harder to manage your symptoms^[15]

To help relieve symptoms related to nerve damage, you can^[15]:

• Keep your hands and feet warm
• Use light bed covers to reduce pressure on your legs
• Be careful when using sharp objects such as knives or scissors
• Wear appropriate shoes to avoid pain and check your feet for redness or blisters every day
• Check the temperature of your bath or shower water before you get in to avoid scalding yourself
• Do light physical activity such as walking, to improve blood circulation
• Think about using mobility aids, such as a walking stick or frame, to help with your everyday tasks

Research shows that stress changes the way amyloid proteins act and are deposited^[20]. Try to focus on lowering your stress levels after a diagnosis of amyloidosis^[20]. Many people diagnosed with amyloidosis report struggling with depression or anxiety, both of which can be made worse by stress^[20].

Because amyloidosis can affect many parts of the body, you may see several specialists^[17]. If you have issues with your muscles, bones, joints or other musculoskeletal problems (for example, unexplained back pain, or pain, tingling or numbness in your arms or hands) or stomach issues (diarrhea, nausea, weight loss), be sure to tell your care team^[17]. They can refer you to and coordinate with other specialists if needed^[17].

If you have an inherited form of amyloidosis, ask your care team about who in your family should be screened to diagnose, monitor and start treatment as early as possible and help lessen the damage^[17].