The science of amyloidosis

There are four main types of systemic amyloidosis – AL, ATTR, AA and non-ATTR hereditary. 

• Systemic AL amyloidosis occurs in a small proportion of patients who have either multiple myeloma (a bone marrow cancer) or, much more commonly, a non‑malignant disorder of the bone marrow. This is currently the most common type in the UK, accounting for about 55% of the patients we see at the National Amyloidosis Centre.
• Systemic AA amyloidosis occurs in up to 5% of patients with chronic inflammatory diseases, most commonly rheumatoid arthritis. 
• ATTR amyloidosis may be hereditary or non‑hereditary. In recent years there have been improvements in the understanding of the non‑hereditary type, known as wild‑type ATTR amyloidosis, which have led to a big increase in the frequency of diagnosis of this condition.

Amyloids

Amyloid deposits are composed of abnormal protein fibres (amyloid fibrils) that accumulate more quickly than they are cleared away, and which progressively interfere with the structure and function of affected organs. Normal healthy proteins are cleared away at about the same rate that they are produced, but amyloid proteins are broken down very slowly.

About 30 different proteins have been found to form amyloid in man, but only a few are associated with clinically significant disease. Amyloidosis is classified according to the protein that forms the amyloid fibrils. The clinical picture and symptoms can differ greatly between one amyloid type and another.

The proteins that cause two types of systemic amyloidosis are produced in the presence of other disorders. Patients with systemic AL amyloidosis (formerly primary amyloidosis) have an underlying bone marrow disorder, and patients with systemic AA amyloidosis (formerly secondary amyloidosis) have some form of long‑standing inflammatory disorder.

Some types of systemic amyloidosis have a genetic basis, most of which can be identified by DNA tests. One relatively common type, known as wild‑type ATTR amyloidosis, is not related to an underlying disease and does not have a genetic basis.

Amyloid deposits can accumulate virtually anywhere in the body or can remain localised to one organ or tissue. Symptoms occur due of progressive damage to affected organs and tissues, such as the kidneys or heart, and may vary greatly from patient to patient.

Although various specific anti‑amyloid drugs are under development, none yet have been introduced into clinical practice. However, treatments for the conditions that underlie AL and AA amyloidosis and new gene silencing therapies to prevent hereditary ATTR amyloidosis can stabilise or improve organ function and may greatly improve the outlook. We have shown that amyloid deposits often gradually diminish when the formation of new amyloid is prevented.

Localised forms of amyloidosis can cause significant disease, for example in the airways, skin, bladder, genitals, or eye. In the past, almost all patients with end‑stage kidney failure who received dialysis for over five years developed dialysis-related amyloidosis from a protein called β2‑microglobulin. This has become less common due to modern dialysis which has improved the clearance of β2‑microglobulin.

Localised amyloid deposits composed of a protein called Aβ occur in the brains of patients with Alzheimer’s disease, but it is not known whether they are the cause of the disease. The brain is almost never directly involved in systemic amyloidosis.

Diagnostic imaging of amyloidosis: The SAP scan

In 1987, we devised a completely new diagnostic test for systemic amyloidosis comprising a whole-body scanning procedure called SAP scintigraphy. This can show the distribution and amount of amyloid within the body’s organs without the need for biopsies. 

SAP scans take about 45 minutes and are performed 6-24 hours after an intravenous injection of a small dose of radioactive tracer. The radiation dose is like a routine X‑ray. The scan is specific and is used routinely as part of our clinical assessment. The procedure is safe and painless and can be repeated every 6-12 months to monitor the course of amyloid deposits and guide the need for ongoing treatment. 

We have performed over 35,000 scans and used the information to improve our understanding of amyloidosis and our approach to treatment. We have shown that amyloid deposits often disperse when the underlying disease is controlled, which is usually accompanied by an improvement in general health.

Effectiveness of treatment

Although not so many formal clinical trials have been conducted due to the rarity and diversity of amyloidosis, the principles and objectives of treatment are now clear. Until drugs become available that can specifically disperse amyloid deposits, therapy is aimed at suppressing production of the relevant amyloid forming protein, whilst supporting the function of damaged organs. This involves treating the underlying condition, such as bone marrow abnormality (AL amyloidosis) or rheumatoid arthritis (AA amyloidosis), or otherwise suppressing the production of amyloid forming proteins (e.g. hereditary ATTR amyloidosis) as rapidly and completely as possible. 

Treatment varies depending on the type of amyloid, but this typically requires chemotherapy in AL amyloidosis, gene silencing therapies in hereditary ATTR amyloidosis and anti‑inflammatory drugs in AA amyloidosis; most patients do derive significant benefit. Dialysis‑related amyloidosis can be reversed following renal transplantation. The prognosis depends very much on the degree by which production of new amyloid can be suppressed and on which organs are affected, and how severely.

Clinical services provided by the National Amyloidosis Centre

The National Amyloidosis Centre offers a clinical service for patients with all types of amyloidosis except Alzheimer’s disease (although that is included in its research programme). Altogether, about 1000 new cases of amyloidosis are diagnosed each year.

Unfortunately, all types of amyloidosis cause rather non‑specific symptoms, and diagnosis is often delayed until many investigations, often culminating in a tissue biopsy, have been performed.