Amyloidosis: What It Is, What Causes It, and How Rare This Condition Is

The first thing to understand about amyloidosis is that it’s not a single disease, but several diseases. Just as the word “cancer” refers to a group of diseases, amyloidosis is the name for a group of diseases, too. In amyloidosis, each type is caused by the abnormal production of protein. (1) But all types of amyloidosis are very rare.

Protein molecules are the human body’s building blocks. Every cell in your body contains protein molecules. They make up the walls and other support structures of your body’s cells. Depending on the way these protein molecules assemble, they can form muscle, bone, ligaments, tendons, or tissue. They can also act as transporter proteins that carry different nutrients or chemicals around your body via your blood. (1)

In some instances, the body produces an abnormal protein called amyloid, which can accumulate over time. And when enough of this amyloid builds up — either in one part of the body or in several places at once — the resulting symptoms and medical issues are known collectively as amyloidosis. (2)

“To understand amyloid, you have to understand that everything your body produces is normally biodegradable and recyclable,” says Morie Gertz, MD, an amyloidosis expert and professor of medicine at the Mayo Clinic. “Amyloid is what happens when protein loses the ability to be degraded.”

That happens because the protein molecules “misfold” and form a chemical structure that the body can’t break apart, Dr. Gertz says.

Like that big island of floating plastic in the Pacific Ocean that keeps getting bigger and bigger, the amyloid your body can’t break apart continues to accumulate, and eventually this causes health issues.

Collectively, the different types of amyloidosis affect about 200,000 Americans, according to current estimates from the National Institutes of Health. (2) While some experts who study the disease believe those government estimates may be way too low, they agree that amyloidosis is a rare disease.

There are roughly 30 varieties of protein that experts have linked with the production of amyloid and that can therefore cause amyloidosis, says Raymond Comenzo, MD, a professor at the Tufts University School of Medicine in Boston and the director of the school’s John C. Davis Myeloma and Amyloid Program.

But some types of protein are more likely than others to develop abnormalities. These protein types are involved in the most common types of amyloidosis.

AL amyloidosis is one of the most common types of the disease. It’s diagnosed in 4,500 people each year — most of whom are between ages 50 and 80. (3)

ALamyloidosis starts in the blood cells produced in bone marrow, which is a fatty substance tucked inside the hollow chambers of bones. These blood cells are responsible for making protein “antibodies,” which are part of your immune system’s defenses against foreign invaders,Gertz explains.

In people with AL amyloidosis, some of these protein molecules — specifically, a kind called “light chain” proteins — don’t form properly. This improper assembly results in the buildup of amyloid. It’s not clear exactly why these protein molecules begin misassembling in the first place. (4)

The problem with amyloidosis starting in bone marrow is that the resulting amyloid can accumulate in many different parts of the body — including the heart, kidneys, and gut. As a result, AL amyloidosis can cause a number of different symptoms. These include shortness of breath or an irregular heartbeat, swelling of the legs, tingling or loss of feeling in the arms or legs, and carpal tunnel syndrome. (5)

Technically, AL amyloidosis is considered a type of cancer, and some drugs developed to treat other cancers closely related to it (like multiple myeloma) can help people with AL amyloidosis, too. (4) Depending on how quickly someone with AL amyloidosis receives a correct diagnosis, drugs can be very effective, Gertz says. So can some types of bone marrow transplants, chemotherapy, and other symptom-specific treatments, he says.

RELATED: What Are the Treatment Options for Multiple Myeloma?

But just as AL amyloidosis symptoms vary a lot from one person with the condition to another, the prognosis also differs greatly from person to person.

Learn More About AL Amyloidosis Causes, Symptoms, and Treatment

Unlike most other forms of amyloidosis, the AA type tends to show up in people who have another disease — a “comorbidity.” In the case of AA amyloidosis, the comorbidities tend to be inflammatory diseases like rheumatoid arthritis, and inflammatory bowel diseases, like ulcerative colitis and Crohn’s disease. (6)

These inflammatory diseases are in fact partly to blame for the development of AA amyloidosis. In response to inflammation, the liver produces high levels of a protein called serum amyloid A, or SAA. These SAA proteins help carry immune cells to inflamed parts of the body. But in patients who develop AA amyloidosis, the production of these SAA proteins becomes abnormal, and the body is unable to break apart the abnormal proteins from the healthy normal ones that carry immune cells throughout the body. (7)

The problem tends to lead to the buildup of amyloid in a person’s kidneys. This buildup often causes a cluster of symptoms known as “nephrotic syndrome,” which includes high blood pressure, fatigue, unexplained weight gain, and other symptoms that also turn up in a range of unrelated health conditions.

Other AA amyloidosis symptoms include: (7)

• Frothy urine, which is caused by high levels of protein in a patient’s pee
• High cholesterol
• Swelling of the lower legs
• Diarrhea
• Irregular heartbeat

It’s not certain how many people develop AA amyloidosis each year, but the majority of cases turn up in developing countries where serious cases of inflammation-causing infections (such as tuberculosis) are more common. (8)

AA amyloidosis can be deadly. But the average individual who develops the disease lives for another 13 years. There are a range of effective treatments for the disease, including inflammation-blocking drugs and those that slow or stop the accumulation of amyloid. Some dietary changes — including low-salt diets — can also help relieve some of the disease’s symptoms.

Learn More About Why Some People Get AA Amyloidosis

Typically, amyloidosis does not run in families. But there are two types (and more than 100 subtypes) of the disease that stem from hereditary genetic mutations — meaning DNA abnormalities that can be passed on from parents to children. These two types are known as ATTR and non-TTR amyloidosis. (9)

Both ATTR and non-TTR amyloidosis get the “TTR” part of their name from a blood protein called transthyretin. Transthyretin is a protein that helps carry some vitamins and hormones to different parts of the body.

ATTR Amyloidosis

ATTR amyloidosis usually turns up in adults between ages 20 and 70. While it’s thought to be rare, there’s some evidence that up to 4 percent of African-Americans carry the genetic mutation that causes ATTR amyloidosis. (9) The symptoms of the disease depend on where in the body the amyloid builds up. Most cases of ATTR amyloidosis, however, can be grouped into three categories: (10)

1. Neuropathic form of ATTR This subtype affects the nervous system and tends to cause symptoms like nerve pain, tingling or numbness in the hands and feet, GI issues (like diarrhea and constipation), vision problems, and issues controlling bodily functions.
2. Leptomeningeal form of ATTR This subtype strikes the leptomeninges, which are layers of tissue that surround the brain and spinal cord. Stroke and bleeding of the brain are two possible complications, and symptoms include problems with coordination and balance, muscle stiffness and weakness, seizures, and dementia.
3. Cardiac form of ATTR This subtype strikes the heart, and causes symptoms and side-effects like an abnormal heartbeat, hypertension, and — in advanced stages — heart disease and heart failure.

Non-TTR Amyloidosis

Meanwhile, non-TTR amyloidosis (as its name implies) is a hereditary disease that does not have to do with transthyretin. Instead, its associated genetic mutations tend to show up in genes that play a role in kidney function. This can lead to kidney damage or disease, as well as heart problems, liver problems, nerve and/or muscle pain, and other symptoms and side effects common to a wide range of health conditions. (11)

The specific treatments for the different types of ATTR and non-TTR amyloidosis depend a lot on an individual’s symptoms. Also, it’s important to note that the genetic mutations that cause each of these diseases can be passed down from parent to child, but they can also form spontaneously, meaning they just show up. A person who has the gene mutation, whether inherited or spontaneous, can pass it on to his or her children. (9)

Learn More About the Types of Hereditary Amyloidosis

There’s a reason why the name for wild-type ATTR amyloidosis looks familiar. Like ATTR amyloidosis, wild-type ATTR has to do with the transthyretin protein molecules that are affected by some heredity forms of amyloidosis. But unlike those hereditary forms, wild-type ATTR is not caused by a heritable genetic mutation (one that gets passed down from parent to child). (12)

In fact, it’s not clear exactly why the TTR proteins become abnormal in people with this type of amyloidosis. Age and sex seem to be big factors: more than 90 percent of individuals with wild-type ATTR are men, and it’s much more common among seniors than among younger adults. (13) By some estimates, up to 1 percent of all adults age 80 and older have some amyloid buildup associated with wild-type ATTR. (14)

And in up to 50 percent of these individuals, the amyloid buildup happens in the person’s heart. This amyloid buildup can lead to symptoms like dizziness, fatigue, leg swelling, shortness of breath, and an unusual heartbeat. It can also contribute to hypertension. (12)

While no one is certain why, Dr. Comenzo says one theory is that wild-type ATTR is much more common than formal estimates suggest because it may in many cases never be diagnosed. And in many cases it may be an underlying cause of heart failure because standard tests to monitor cardiovascular conditions may not be able to identify amyloidosis. (12,15)

Nerve-related trouble is also common in people with wild-type ATTR amyloidosis. In these cases, the disease can cause pain, tingling, or loss of feeling in a person’s arms or legs. Carpal tunnel syndrome — a numbness or tingling in the hand and arm — is also common. In fact, carpal tunnel syndrome is often the earliest symptom of the disease. (12)

While none of those symptoms is desirable, the good news is that this form of amyloidosis tends to progress very slowly. It may contribute to heart trouble or other potentially life-threatening health conditions, but it’s not clear how often wild-type ATTR is the sole cause or driving force behind these issues. In fact, many people with this type of amyloidosis will never experience symptoms. (6)

It’s important to note that there’s still a lot of mystery swirling around wild-type ATTR amyloidosis. Experts are only now getting a good grip on the disease’s commonness and symptoms, and so the thinking on it may soon shift, Comenzo says.

Learn More About Wild-Type AATR Amyloidosis

Discovered a little more than a decade ago, ALECT2 amyloidosis involves a blood protein that is made in a person’s liver. It can cause amyloid accumulation in many different parts of a patient’s body, but it tends primarily to interfere with kidney function — and so leads to symptoms like lower leg swelling, as well as nephrotic syndrome (characterized by high cholesterol, high blood pressure, and swelling in the legs and arms). (16)

While ALECT2 seems to be quite rare, there’s evidence that it shows up much more commonly in people of Hispanic ancestry. (17) Not a lot is known about the disease, but the current research suggests it’s not typically fatal. One study found only 6 percent of people diagnosed with the disease died as a result, and roughly 30 percent have stable kidney function following treatment. (18)

Learn More About What Doctors Know About ALECT2 Amyloidosis

Most of the amyloidosis types mentioned above are quite rare. The following subtypes, however, are even less common.

AB2M This type of amyloidosis involves the erred folding of a protein found on the surface of white blood cells. AB2M typically appears only in people who are experiencing kidney failure following many years of dialysis treatment. Amyloid tends to build up around a patient's bones and joint-related tissues. Carpal tunnel syndrome and nerve pain or stiffness are the most common symptoms. This type is also sometimes called Abeta2m and DRA (which stands for dialysis-related amyloidosis). (19)

Apolipoprotein amyloidosis This type affects proteins that play a role in transporting or breaking down cholesterol and fat. There are at least five subtypes of apolipoprotein amyloidosis, several of which are hereditary, and each can affect different parts of the body and cause varying symptoms, from kidney problems to heart problems to nervous system problems. (20)

Hereditary fibrinogen amyloidosis Sometimes called AFib amyloidosis, this type affects a protein that plays a role in blood clotting. It's hereditary, and can be caused by any of 16 different inherited genetic mutations. It usually causes amyloid to accumulate in a patient's kidneys. (20)

Hereditary gelsolin amyloidosis Known also as AGel amyloidosis, this type affects a protein that helps give cells shape and structure. It is a hereditary type of amyloidosis, and it tends to affect a patient's cranial nerves, eyes, skin, or kidneys. (20)

Hereditary lysozyme amyloidosis Sometimes called ALys amyloidosis, this type affects a protein enzyme found in tears and mucus that helps the body break down invading bacteria. It's another hereditary type, and it can affect the function of multiple organs or systems, including the GI system. (20)

Amyloidosis is not a disease that most doctors are trained to look for. Also, it can cause a wide range of symptoms or health complications — many of which also turn up as a result of more common ailments. This can make it quite hard for a patient to receive an accurate diagnosis. “It’s very likely that many patients who have amyloidosis die without ever knowing they had it,” Gertz says.

Even for patients who are diagnosed with amyloidosis, the road to that diagnosis is usually long and difficult. Many patients see multiple doctors, and it may take a year or two to receive an accurate diagnosis, Comenzo says.

How is that diagnosis made? Urine and blood tests are two preliminary types of analysis that can point to the presence of amyloid buildup. “Protein in urine is a very powerful indicator of amyloidosis,” Gertz says. “It’s not routine to do this kind of urine analysis, but it’s a simple test.”

In addition to (and often, following) those urine and blood tests, doctors will perform tissue biopsies to look for amyloid deposits. They’ll also analyze that amyloid to determine which particular type of protein is causing the patient’s amyloidosis, Comenzo says.

If you believe you may have amyloidosis, you shouldn’t feel shy about bringing it up with your doctor, he says. It may take some time — and a lengthy process of elimination — for your doctor to determine if amyloidosis is the cause of your health issues.

Learn More About How Doctors Diagnose Amyloidosis