Amyloidosis is a rare disease caused by abnormal deposition and accumulation of proteins in the tissues of the body. Amyloid deposits are primarily made up of protein fibres known as amyloid fibrils. These amyloid fibrils are formed when normally soluble body proteins aggregate (clump together) and then remain in the tissues instead of safely going away. Amyloid deposits cause disease by accumulating within organs and eventually disrupting the structure and damaging the function of the affected tissues.
About 30 different proteins are known to form amyloid deposits in humans, each one causing a different type of amyloidosis. The different types of amyloidosis are named according to the protein which forms the amyloid fibrils. Each name comprises the letter ‘‘A’’, denoting amyloidosis, and one or more letters identifying the specific amyloid fibril protein.
Amyloid deposits can form in many tissues and organs throughout the body, and in the blood vessels so-called connective tissues that lie within and between all parts of the body. This widespread condition is called systemic amyloidosis, although the clinical effects vary greatly depending on which part of the body is more severely affected.
Amyloid deposits are sometimes confined to just a single place in the body, or a single organ or tissues type. These localised deposits cause local amyloidosis, very different condition than systemic amyloidosis.
The most common type of systemic amyloidosis, AL amyloidosis, is caused by proteins, called monoclonal free light (L) chains, derived from abnormal production of antibody molecules. It is a very different disease from ATTR amyloidosis, requiring very different treatment. Indeed each different form of amyloidosis requires different treatment, directed at the particular amyloid fibril protein in each case.
In ATTR amyloidosis, the amyloid fibrils are formed by the blood protein called transthyretin (TTR). TTR is always present in the blood, where it transports thyroid hormone and vitamin A (retinol), hence the name: ‘trans-thy-retin’. All the TTR in the blood is produced by the liver. TTR in the brain and the eye is made separately by a structure called the choroid plexus, which is located within the brain and produces the cerebrospinal fluid that bathes the brain and spinal cord.
Types of ATTR amyloidosis
ATTR amyloidosis is a form of systemic amyloidosis can be either hereditary or acquired (non-hereditary).
Hereditary ATTR amyloidosis is caused by a mutation in the gene for a protein called TTR, inherited from one or other parent. The disease therefore runs in families, though the timing, development and severity of the disease can vary greatly.
In acquired ATTR amyloidosis, the amyloid is formed by the normal, so‑called ‘wild-type’ protein. This disease is not hereditary. It is known as wild-type ATTR (ATTRwt) amyloidosis (formerly called senile systemic amyloidosis (SSA)).
The clinical presentation and effects of ATTR amyloidosis vary widely depending on which organs are mostly affected.
Hereditary ATTR amyloidosis
People with mutations in the TTR gene produce abnormal, amyloidogenic, ‘variant’ TTR throughout their lives. Amyloid deposits start to form and then build up until they cause clinical disease, mainly affecting the nerves and/or heart, and sometimes the kidneys and eyes. Symptoms may appear at any time from early adult life onwards. This condition runs in families.
About 150 different amyloidogenic (amyloid forming) mutations have been recognised in people from all around the world. TTR mutations are relatively common in some parts of the world and extremely rare in others, and different mutations may cause different disease manifestations.
Hereditary ATTR amyloidosis has traditionally been described according to whether disease manifestations mainly affect the nerves (familial amyloid polyneuropathy (FAP)) or the heart (familial amyloid cardiomyopathy (FAC)). However it is now understood that in clinical practice there is significant overlap in disease manifestations not only between patients with different mutations but also among those with the same mutations. Most TTR mutations can cause amyloid deposits in both the nerves and the heart. The International Society of Amyloidosis has therefore recommended the use of the term hereditary ATTR amyloidosis for all patients with TTR gene mutations and ATTR amyloid deposits.
Hereditary ATTR amyloidosis is a very rare disease. The commonest type, associated with the Val30Met mutation, is thought to affect about 10,000 people in the whole world. It has hitherto clearly been by far the most commonly recognised form of hereditary systemic amyloidosis.
The Val122Ile mutation, in which ATTR amyloid deposits mainly affect the heart and often also cause carpal tunnel syndrome, is most common in men of African American ancestry over age 60. This condition was only recognised 20 years ago, is apparently not rare in this population and is widely underdiagnosed.
Wild-type ATTR amyloidosis
Wild-type ATTR amyloidosis (wtATTR, formerly known as senile systemic amyloidosis) affects elderly people, mostly men. There is no mutation in the TTR gene so the condition is not hereditary (it does not run in families). The normal, ‘wild-type’ TTR protein forms the amyloid deposits, with the only obvious major clinical effect in the heart although there may also be carpal tunnel syndrome in some people.
It has long been known that wild-type TTR commonly forms microscopic amyloid deposits in elderly people but clinical disease caused by this amyloid was very rarely diagnosed. However, discovery of new imaging techniques, now used extensively at the NAC, has shown that ‘wild-type’ ATTR amyloidosis is much more common than previously recognised. Until 2014 this disease was called senile systemic amyloidosis, or cardiac TTR amyloidosis. It was decided at the XIV International Symposium on Amyloidosis in 2014 that this condition should be referred to as wild-type transthyretin amyloidosis or wild-type ATTR amyloidosis.