The term amyloidosis refers to a collection of diseases in which a protein deposits abnormally in one or more organs in the body. If the protein is both created in and deposits in a single organ, we call it localized amyloidosis. More commonly, the protein is created in one part in the body, circulates in the bloodstream, and deposits in other parts of the body. This form is called systemic amyloidosis.
Image: Amyloid fibrils make the heart's walls appear thicker when they accumulate in the heart. Notice how much thicker the wall is in the patient with amyloidosis (right) compared with a normal heart (left) in these ultrasound (echocardiogram) images.
Types of amyloidosis are defined by what the type of protein that is depositing. Names always start with the letter "A" for "amyloid." The next letter (or letters) refers to the type of protein that is depositing. For example, "Light chain amyloidosis" is called "AL amyloidosis" (A for "amyloid," L for a protein called a "light chain"), and "Transthyretin amyloidosis" is called "ATTR" amyloidosis (A for "amyloid," "TTR" for a protein called "transthyretin").
There are dozens of different kinds of amyloidosis, although AL or ATTR amyloidosis are the most common.
Image: Using high-powered electron microscopy of a patient's heart biopsy sample, you can see the individual amyloid fibrils composed of proteins.
Nobody knows how common amyloidosis really is. Once considered a very rare disease, it has become clear in recent years that it is much more common than previously believed. Unfortunately, many patients with amyloidosis are not diagnosed, meaning that they do not have the opportunity to receive treatment for their disease. Whereas treatment options were very limited in the past, effective therapies are now available for most forms of amyloidosis.
The bone marrow is where the blood cells in the body are made. This includes the red blood cells which carry oxygen, and the white blood cells which fight infections. One type of white blood cell is called a plasma cell, whose purpose is to make proteins called immunoglobulins or antibodies that help fight infections. One part of these proteins is called a “light chain.”
Normally, our body produces millions of different kinds of light chain proteins. In AL amyloidosis, a plasma cell begins to make exact copies of itself, with each copy making the exact same light chain protein. This process – a cell in the body making exact copies of itself in an unregulated fashion – is often considered to be a change into a form of cancer.
Depending on the structure of the specific light chain protein being produced, it can be prone to deposit in one or more organs in the body. Because it is circulating in the bloodstream, it can potentially deposit in any organ, though in each individual with the disease it is usually more prone to deposit in some organs than others.
The symptoms of the disease depend on what organs the light chain proteins deposit in. The most common vital organs for light chains to deposit in are the heart and kidneys, and the degree of heart deposition is one of the most important factors in determining prognosis.
There can be many clinical clues to the diagnosis of AL amyloidosis, including the discovery of abnormal light chains circulating in the blood or evidence of organ deposition by light chains. Ultimately, the diagnosis is made by biopsy of an organ, yielding characteristic findings of amyloid deposits made up of light chains. Regardless of which organ is biopsied to make the diagnosis, most patients also need to have a bone marrow biopsy performed, to characterize the abnormal cells making the abnormal light chain, in order to best guide treatment.
Abdominal fat pad biopsies are sometimes performed as a relatively less invasive way to make the diagnosis, but many patients with AL amyloidosis will have normal results on a fat pad biopsy. Therefore, most of the time, the diagnosis is made from a biopsy of another organ, such as the heart or kidney. Your Stanford Amyloid Center physicians will discuss with you the best options for diagnosis if the diagnosis has not already been made.
AL amyloidosis can occur at any age, although people are mostly diagnosed in their 40s, 50s, 60s, 70s, and 80s. The disease affects men and women equally.
Because heart involvement is very common in patients with AL amyloidosis and can have a big impact on prognosis, all patients with AL amyloidosis should have cardiac screening. At the least, this involves an electrocardiogram (EKG), an ultrasound of the heart (echocardiogram), blood tests, and a consultation with a cardiologist. We recommend this for all new patients seen at the Stanford Amyloid Center.
Using this staining method from a heart biopsy sample, amyloid fibrils composed of proteins, are stained light pink. Notice how the amyloid deposits are seen everywhere and encircle each heart cell.
Advanced imaging called electron microscopy shows how amyloid deposits (labeled A) infiltrate normal heart muscle (labeled H).
The treatment of AL amyloidosis follows two parallel paths:
a) Medications, interventions, and lifestyle advice to help manage the consequences of the organ dysfunction caused by light chain deposition.
b) Medication to kill the cancerous plasma cells, thereby lowering the number of abnormal light chains in the blood.
Treatments for the consequences of organ dysfunction vary depending on the organ involved. For example, treatment for heart dysfunction commonly involves treatment to remove excess fluid (diuretics), and/or treatment or prevention of abnormal electrical rhythms in the heart. Sometimes, placement of a pacemaker or defibrillator device will be recommended. Your Stanford Amyloid Center Cardiologist will advise you on the treatment options that are best for you.
Organ deposits can occur elsewhere in the body. Some of the most common areas of deposition include:
Your Stanford Amyloid Center team will arrange for appropriate consultation to specialists and treatment depending on which of your organs are involved by the disease.
Treatment of the cancerous plasma cells involves administration of either chemotherapy or immunotherapy (a newer kind of cancer treatment). There have been great advances in chemotherapy/immunotherapy treatments in recent years, resulting in a much better prognosis for many patients with AL amyloidosis than used to be the case. Sometimes, stem cell transplantation (bone marrow transplant) can be used with chemotherapy, though with the advances in standard chemotherapy/immunotherapy in recent years, most of the time stem cell transplantation is not the preferred treatment option.
You may be eligible for clinical trials; please discuss with your Stanford Amyloid Center physicians to learn if there are clinical trial options open to you.
This patient has amyloid deposits in the lip and tongue. Note the scalloped appearance of the tongue in which indentations are present on both sides (arrows). The indentations occur because the enlarged tongue constantly presses against the upper teeth.
These amyloid deposits are in the esophagus of a patient with amyloidosis.
These amyloid deposits are in the kidneys. The entire filtering apparatus (glomerulus) pictured here is flooded with amyloid deposits, which results in leakage of protein from the blood in to the urine.
Transthyretin is a protein which is made by the liver and is present in all people. It normally functions to help the body transport other proteins, including thyroid hormone and vitamin A.
Most of the time, the protein circulates in the body as four transthyretin proteins bound together (called a "tetramer"). However, a small amount is always circulating as a single transthyretin protein (called a "monomer"). The monomer form of the protein is prone to gradually depositing over time as amyloid deposits. The rate of deposition is slow, occurring over decades. Because a lot of deposition must typically occur before organ dysfunction and symptoms develop, most patients at diagnosis will already have a large amount of ATTR amyloid deposits. Therefore, even though the disease progresses more slowly than AL amyloidosis for most patients, it is also very important to make the diagnosis of ATTR amyloidosis and start treatment as soon as possible.
There are two main forms of ATTR amyloidosis –wild-type (also known as "senile") and hereditary (also known as "familial").
In wild-type ATTR amyloidosis (wt-ATTR), it is the normal transthyretin protein which deposits. This form is the most common form of ATTR amyloidosis (see below). Because it deposits very slowly, most patients first develop symptoms from this form of amyloidosis in their 60s, 70s, or 80s, although occasionally people will be diagnosed in their 50s or 90s. This form of amyloidosis mainly involves the heart; carpal tunnel syndrome is also common. It is unusual for this form of amyloidosis to involve vital organs besides the heart.
In hereditary ATTR amyloidosis (h-ATTR), it is an abnormal version of the transthyretin protein which deposits. This protein abnormality occurs when a person inherits an abnormal gene for transthyretin (called a "mutation") from their mother or father. Dozens of different genetic mutations have been discovered, and the specific mutation a person has plays a large role in determining the course and severity of the disease.
In the United States, by far the most common mutation encountered is called the "V122I" mutation (see below). This mutation causes a pattern of deposition similar to wt-ATTR amyloidosis, mainly involving the heart. Other mutations cause other patterns of organ involvement, including nerve and gastrointestinal tract (e.g. stomach, esophagus, colon) involvement. An example of one of the more common mutations that causes nerve involvement is the "V30M" mutation. The most common organ to be involved besides the heart is the nerves; patients with nerve involvement develop "neuropathy" – a syndrome which can be characterized by numbness, tingling, pain, weakness, and/or dizziness. In some cases, patients will have both heart and nerve involvement.
While the exact prevalence of ATTR amyloidosis is unknown, it is clearly far more common than previously believed, and most patients who have the disease have not yet been diagnosed.
Wild-type ATTR amyloidosis is extremely common in the older population. Clinically significant ATTR amyloid deposits in the heart may be present in >20% of individuals in their 80s and 90s. It is likely that many older patients with heart failure – particularly if their hearts have noted to be “thick” on ultrasound – have undiagnosed wt-ATTR amyloidosis.
Hereditary ATTR amyloidosis is also extremely underdiagnosed, though it is not as common as wt-ATTR amyloidosis. In the United States, the most common form of inherited ATTR amyloidosis is that associated with the V122I mutation. This mutation is present in approximately 3-3.5% (1 out of every 30) African-Americans. Not everyone who has inherited the mutation will develop the disease, but it is clear that those individuals who have the mutation are at much higher risk than those who don’t. The average age at diagnosis of h-ATTR amyloidosis in the United States is the 50s-60s.
For most forms of ATTR amyloidosis, including both wt-ATTR amyloidosis and h-ATTR amyloidosis associated with the V122I mutation, men are much more likely to develop the disease than women. The cause of this gender association is unknown.
The diagnosis of ATTR amyloidosis can be made in two ways: biopsy or nuclear medicine scanning.
Biopsy has historically been the most common way for ATTR amyloidosis to be diagnosed. Just like for AL amyloidosis, a biopsy of the clinically involved organ (such as the heart) has a very high chance of making the diagnosis. Sometimes biopsy of another organ (such as the abdominal fat pad) can make the diagnosis, but this test can often miss the diagnosis. Because ATTR amyloidosis is not a disorder of the bone marrow, a bone marrow biopsy is not needed.
In some cases, another option for diagnosis of ATTR amyloidosis exists. This test is an imaging scan in Nuclear Medicine called a "technetium pyrophosphate" or "PYP" scan. PYP scans have the advantage of being noninvasive, though in some cases are not as definitive for diagnosis as a biopsy. Your Stanford Amyloid Center physicians will help you determine the best modality for diagnosis for you.
All patients who have been diagnosed with ATTR amyloidosis should consider having genetic testing performed. This test is typically done from a blood sample and is very accurate. A genetic test will determine whether someone has wt-ATTR amyloidosis or h-ATTR amyloidosis; if the diagnosis is h-ATTR amyloidosis, it will determine which specific mutation (e.g., V122I, V30M, etc.) the patient has. All patients with h-ATTR amyloidosis should be offered genetic counseling. We can arrange consultation with a genetic counselor for you at the Stanford Amyloid Center.
Using this staining method from a heart biopsy sample, amyloid fibrils are stained blue. Notice how the amyloid deposits are seen everywhere and encircle each heart cell.
The treatment of ATTR amyloidosis follows two parallel paths:
a) Medications, interventions, and lifestyle advice to treat the consequences of the organ dysfunction caused by transthyretin deposition.
b) Medication to reduce the deposition of transthyretin.
Just as for AL amyloidosis, treatment of the organ dysfunction in ATTR amyloidosis depends on which organs are involved. Most commonly in ATTR amyloidosis, organ dysfunction is seen in the heart and/or the nerves. For the heart, treatment is primarily aimed at treatment of fluid retention and/or abnormal heart electrical rhythms. For the nerves, treatment is primarily aimed at relief of symptoms of pain and/or dizziness.
For many years, there were no medication treatment options to reduce the deposition of transthyretin. Fortunately, recent years have seen an enormous growth in development of new medications to slow new deposition. Two main strategies have been proven successful in clinical trials: “stabilizer” medications and “knockdown” medications.
Stabilizer medications aim to prevent new transthyretin amyloid deposits by stabilizing the form of the protein in which it is bound together as four protein units. As noted above, it is single protein units, not the form bound together as four units, which deposits as amyloid deposits. Two stabilizer medications have been proven in clinical trials to slow amyloid deposition, and more are being investigated in clinical trials.
Knockdown medications aim to decrease the amount of transthyretin which circulates in the bloodstream. Two knockdown medications have been proven in clinical trials to slow amyloid deposition, and more are being investigated in clinical trials.
Your Stanford Amyloid Center physician will discuss what treatment options exist for you, including approved medications and medications being studied in clinical trials.
A localized form of AL amyloidosis can occur in which the light chains are created not in the bone marrow, but within the organ itself that the light chains deposit in. This form of AL amyloidosis typically does not need chemotherapy or immunotherapy.
AA amyloidosis occurs when a protein made by the liver in response to inflammation (called “serum amyloid A protein” circulates and deposits in organs, most commonly the kidneys. This form of amyloidosis is uncommon in the United States. Treatment involves decreasing inflammation with medications.
Other forms of amyloidosis exist as well, but most are very uncommon. The Stanford Amyloid Center will help arrange for you to see the right specialists for the form of amyloidosis that you have.
Special staining reveals the amyloid deposits in the kidneys are from AA (secondary) amyloidosis. AA (secondary) amyloidosis occurs as a result of chronic infections or chronic inflammatory disorders.
If organ damage is severe enough from amyloidosis, organ transplantation can be considered. Most commonly, this occurs when a person receives a heart transplant because their heart has been severely damaged by amyloid deposits. Kidney transplantation might also be an option for patients with severe kidney involvement, while bone marrow transplantation is occasionally used in the treatment of AL amyloidosis.
Stanford is one of the leading centers in the world for heart transplantation in general, and specifically for heart transplantation in amyloidosis. However, heart transplantation is only an option for a limited number of patients, depending on the severity of disease, other health factors, and the degree of other organ involvement by amyloidosis. Your Stanford Amyloid Center physicians can speak with you about whether or not organ transplantation may be a good option for you.