About Amyloidosis

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 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.