Primary Amyloidosis

Primary amyloidosis, also known as AL amyloidosis, is a rare disorder where abnormal proteins build up in organs and tissues throughout the body, potentially affecting the heart, kidneys, nerves, and other vital systems.

Table of contents

• What Is Primary Amyloidosis?
• Other Names for This Disease
• What Causes Primary Amyloidosis?
• Signs and Symptoms
• Organs Affected by Primary Amyloidosis
• How Is Primary Amyloidosis Diagnosed?
• Treatment Options
• What to Expect
• Living with Primary Amyloidosis

What Is Primary Amyloidosis?

Primary amyloidosis is a rare disease that occurs when abnormal proteins build up in organs and tissues^[1][2]. These abnormal proteins are called amyloid, which refers to clumps of proteins that stick together in ways they should not. When amyloid builds up, it can make it harder for organs to work correctly^[1].

The disease is also called AL amyloidosis or light chain amyloidosis. The “A” stands for amyloid, and the “L” stands for light chain, which is the specific type of protein involved^[3][5]. This is the most common form of systemic amyloidosis, meaning it can affect multiple organs throughout the body^[5][7].

In the United States, between 1,275 and 3,200 new cases are diagnosed each year, with an incidence of approximately 9 to 14 cases per million people yearly^[7]. Most people are diagnosed after age 50, though some adults have been diagnosed as early as their 20s^[4]. The disease affects slightly more men than women^[4].

AL amyloidosis, light chain amyloidosis, primary systemic amyloidosis, immunoglobulin light chain amyloidosis

What Causes Primary Amyloidosis?

Primary amyloidosis is caused by problems with special cells in your bone marrow called plasma cells^[3]. Normally, plasma cells are part of your immune system and produce antibodies, which are proteins that help fight infections^[4].

Antibodies are made up of two types of protein chains: heavy chains and light chains. In primary amyloidosis, some plasma cells become abnormal and produce too many light chain proteins^[3][4]. Instead of forming normal antibodies, these extra light chains become misfolded and stick together, forming amyloid deposits in various organs^[4].

The exact cause of why plasma cells become abnormal is not well understood, and genes may play a role^[2]. However, primary amyloidosis is not considered to be hereditary^[5].

Primary amyloidosis is closely related to a bone marrow cancer called multiple myeloma, which also involves abnormal plasma cells^[3]. In multiple myeloma, the main problem is the rapid growth of abnormal cells in the bone marrow, while in primary amyloidosis, the main problem is the buildup of light chains produced by those cells^[3]. About 10 to 15 percent of people with primary amyloidosis also have multiple myeloma and receive care for both conditions^[4][5].

Signs and Symptoms

You may not experience symptoms of primary amyloidosis until later in the course of the disease^[1]. Symptoms vary depending on which organs are affected and how much damage the amyloid deposits have caused^[2][4].

The most common symptoms include^[1][4]:

• Severe fatigue and weakness
• Shortness of breath
• Numbness, tingling, or pain in the hands or feet
• Swelling of the ankles and legs
• Unintentional, significant weight loss

Additional symptoms may include^[1][4]:

• Dizziness or feeling lightheaded when standing up
• Low blood pressure
• Diarrhea, possibly with blood, or constipation
• Nausea and loss of appetite
• An enlarged tongue
• Skin changes, such as thickening or easy bruising, and purplish patches around the eyes
• An irregular heartbeat
• Difficulty swallowing
• Hoarseness or voice changes

One characteristic sign of primary amyloidosis is purplish discoloration around the eyes, which occurs because of bleeding under the skin when small blood vessels are damaged by amyloid deposits^[1]. This can happen with minor trauma and is sometimes called “pinch purpura” or “raccoon eyes sign”^[6].

Another characteristic finding is an enlarged tongue, called macroglossia, which can sometimes appear rippled along its edge^[1][5].

Organs Affected by Primary Amyloidosis

Primary amyloidosis can affect many different organs and tissues. Any organ apart from the brain can be affected^[4]. The disease can affect the tongue, intestines, muscles, nerves, skin, ligaments, heart, liver, spleen, kidneys, and bladder^[2].

• Heart
• Kidneys
• Liver
• Spleen
• Nervous system
• Gastrointestinal tract
• Soft tissue and muscles
• Skin
• Tongue

Heart

Between 70 and 80 percent of people with primary amyloidosis have heart involvement, and heart complications are the leading cause of death^[5]. Amyloid deposits in the heart affect the heart muscle’s ability to relax and squeeze properly^[3]. They can also disrupt the heart’s electrical system, causing the heart to beat too fast or too slow^[2].

Common signs of heart involvement include shortness of breath, fatigue, swelling in the legs and ankles, dizziness, low blood pressure, and irregular heartbeat^[3][5]. As amyloid deposits increase, a person may progress to heart failure^[5].

Kidneys

The kidneys are commonly affected in primary amyloidosis, with 60 to 70 percent of people having kidney involvement^[5]. Amyloid deposits can lead to protein loss in the urine, low levels of protein in the blood, high cholesterol, high triglycerides, and swelling throughout the body—a group of signs called nephrotic syndrome^[2]. Kidney damage may progress to kidney failure requiring dialysis^[5].

Nervous System

Amyloid deposits in the nerves can cause numbness, tingling, pain, or weakness in the hands and feet, a condition called peripheral neuropathy^[2][5]. It can also cause pain in the wrist from carpal tunnel syndrome^[2]. When amyloid affects nerves that control automatic body functions, it can cause problems with blood pressure regulation, digestion, and bladder control^[5].

Gastrointestinal Tract and Liver

Amyloid deposits in the digestive system can cause nausea, loss of appetite, diarrhea (possibly with blood), constipation, weight loss, and difficulty swallowing^[1][5]. The liver may become swollen and stop working properly^[2].

How Is Primary Amyloidosis Diagnosed?

Primary amyloidosis is often overlooked because the symptoms can mimic those of more common diseases^[8]. Early diagnosis can help prevent further organ damage^[8]. The journey to receiving a diagnosis can be long and frustrating—almost one-third of people will visit over five physicians before getting diagnosed, and around 70 percent will not receive a diagnosis for over a year after symptoms first begin^[15].

Diagnosis of primary amyloidosis requires identifying amyloid deposits within a tissue sample and confirming the presence of a plasma cell disorder^[5].

Blood and Urine Tests

Blood and urine may be analyzed for abnormal light chain proteins that can indicate amyloidosis^[8]. The first step in diagnosing amyloidosis should be blood and urine tests to look for abnormal proteins^[2]. A 24-hour urine collection may be done to measure protein loss^[2]. Tests also measure the levels of light chains in the blood and the ratio between different types of light chains^[4].

Tissue Biopsy

A biopsy is required to confirm the diagnosis. A tissue sample is checked for signs of amyloid^[8]. The biopsy may be taken from the fat under the skin on the belly (abdominal fat pad), from bone marrow, or from an affected organ such as the liver or kidney^[2][8]. The tissue is tested to see what type of amyloid is involved^[8].

Bone Marrow Biopsy

A bone marrow biopsy is usually performed to confirm the presence of abnormal plasma cells^[4].

Imaging Tests

Images of organs affected by amyloidosis help determine the extent of damage^[8]:

• Echocardiogram: This test uses sound waves to create moving images that show how well the heart is working and can show heart damage specific to amyloidosis^[8].
• MRI (Magnetic Resonance Imaging): MRI uses radio waves and a strong magnetic field to create detailed images of organs and can check the structure and function of the heart^[8].
• Nuclear imaging: This test uses tiny amounts of radioactive material injected into a vein to reveal early heart damage and help distinguish between different types of amyloidosis^[8].
• Electrocardiogram (ECG): This test measures the heart’s electrical activity^[4].

Other tests may include kidney function tests, thyroid tests, and abdominal ultrasound to check the liver and spleen^[2].

Treatment Options

Treatment for primary amyloidosis has two main goals: to improve the function of affected organs and to decrease the production of abnormal light chains^[3][4]. While there is no cure for primary amyloidosis, many patients can go into remission with treatment^[14].

Standard Treatment Regimen

The current standard treatment for newly diagnosed primary amyloidosis is a combination of daratumumab (a monoclonal antibody), cyclophosphamide (a chemotherapy drug), bortezomib (a proteasome inhibitor), and dexamethasone (a steroid)^[13]. This combination is the first and only specific treatment approved for newly diagnosed primary amyloidosis^[13]. The goal is to achieve a very good partial response after 4 to 6 cycles of treatment^[13].

Other Treatment Options

Many treatment options have been adapted from treatments used for multiple myeloma^[4][14]. Possible treatments include:

• Chemotherapy drugs, such as cyclophosphamide or melphalan
• Steroids, such as dexamethasone or prednisone
• Proteasome inhibitors, such as bortezomib or ixazomib
• Immunomodulatory drugs, such as lenalidomide or pomalidomide
• Monoclonal antibodies, such as daratumumab

Stem Cell Transplant

Autologous stem cell transplant can be considered in selected patients, especially those with an incomplete response to drug therapy^[13]. In this procedure, your own blood stem cells are collected, you receive high-dose chemotherapy to destroy abnormal plasma cells, and then your stem cells are returned to help rebuild your bone marrow^[3][4]. However, there is no strong evidence that stem cell transplant is better than chemotherapy alone^[12].

Organ Transplant

Some people may benefit from organ transplants if organs have been severely damaged^[1].

Supportive Care

Supportive treatments are aimed at improving organ function, maintaining quality of life, and prolonging survival while the anti-plasma cell therapy has time to take effect^[4]. These may include treatments for heart failure, kidney failure, and other complications^[2].

Treatment Team

Your treatment team typically includes^[3]:

• A hematologist, who manages the specific treatment aimed at reducing light chain production
• Specialists who help manage associated organ problems, such as a cardiologist for heart involvement
• A bone marrow transplant physician, if this is a treatment option for you

What to Expect

How well you do depends on which organs are affected and how much they have been damaged^[2]. The degree of heart involvement is the most important factor in determining life expectancy^[3][7].

Heart and kidney involvement may lead to organ failure and death^[2]. Without treatment, widespread amyloidosis can lead to death within 2 years^[2]. However, in many centers’ experience, the majority of patients surviving the first six months can often start recovering and can typically live normal or near-normal lives for years to come^[14]. When remissions occur, they can last a decade or longer^[14].

Early diagnosis and treatment are essential to prevent or slow disease progression^[4]. Major therapeutic advances have been discovered over the last decade that can put primary amyloidosis into prolonged remission and extend life^[4]. If diagnosed and treated early, primary amyloidosis may become a chronic disease that can be managed^[9].

Living with Primary Amyloidosis

Living with primary amyloidosis can significantly impact your life both physically and emotionally^[15]. It is important to take a holistic approach to care that considers both your physical and mental wellness^[15].

Working with Your Healthcare Team

It is vital to develop good communication with your doctor and healthcare team^[21]. Many people find it helpful to prepare questions before appointments and to bring a partner or friend to help remember the doctor’s suggestions^[21]. Because amyloidosis can affect many parts of the body, you may see several specialists^[20].

Managing Symptoms

There are some changes your healthcare team may recommend to help manage symptoms^[15]:

• Eat healthily and lower your salt intake
• Try to drink 2 to 3 liters of water a day to stay hydrated (unless your doctor has advised otherwise)
• Be sensible about physical activity, taking your abilities into account
• Record any symptoms or side effects you are experiencing and tell your doctor about them
• Keep a record of your medical history, treatments, and test results

For nerve-related symptoms like tingling, numbness, or pain in the hands and feet^[15]:

• Keep your hands and feet warm
• Use light bed covers to reduce pressure on your legs
• Be careful when using sharp objects, as numbness can affect your grip
• Check your feet for redness or blisters every day
• Check bath or shower water temperature before getting in
• Do light physical activity such as walking to improve blood circulation
• Stop smoking, as it can damage blood vessels and make symptoms worse
• Consider using mobility aids if needed

Diet and Exercise

Your doctor may give you specific recommendations about what to eat and drink. It is important to follow a healthy diet, especially regarding how much you may drink per day and the salt and protein content^[21]. It is advised to consult a dietician^[21].

Exercise and physical activity may reduce fatigue, feelings of anxiety and depression, and build muscle strength^[21]. Some form of exercise may benefit you, but aerobic exercises must be performed carefully, especially in patients with heart involvement^[21].

Work and Financial Matters

You may choose to continue working after receiving your diagnosis, but you should keep in mind that you may need to take time off for tests and treatments^[16]. Many employers may be open to adopting a more flexible approach to working conditions^[16]. If your illness affects your ability to work, governmental support may be available, and you might be eligible for certain benefits^[16].

Emotional Support

Finding out you have primary amyloidosis can be worrying^[20]. Making heart-healthy choices, working to lower stress, and getting quality sleep are important^[20]. Talking with other people who have the condition may help too^[20].