disease profile

Amyloid

The human body consists of over 30,000 different proteins. Each protein has a specific form (a three-dimensional, folded chain) which enables it to carry out a certain function. But if the form of a protein changes then it can become dangerous. If this happens, a protein can stick to a copy of itself, and then this process can repeat. In this way, long protein fibers, known as amyloid fibrils, are created.

These amyloid fibrils can deposit themselves in various parts of the body, and these accumulations are known as amyloid. When one of these accumulations in a tissue sample (known as a biopsy) is examined under a microscope it appears to be a shapeless material, but when examined under greater magnification using an electron microscope (10,000x) the amyloid fibrils are clearly recognisable. When the biopsy (tissue sample) is coloured with a Congo Red dye, the shapeless material is shown to turn red in colour under a normal microscope. A characteristic feature of amyloids is that this red material appears green when it is lit with polarised light.

Depending on the protein that the amyloid fibrils are composed of, different types of amyloid can be distinguished.

Amyloidosis

Amyloidosis is the name of a group of diseases which are all characterised by the depositing of amyloid fibrils. In systemic forms of amyloidosis, the deposition of amyloid fibrils between cells within organs and tissues leads to impaired functioning and eventually failure of these organs.


Types of amyloidosis with clinical presentations

As already described, various proteins can accumulate in tissues as amyloid. The amyloid can remain localised (such as in the pancreas, brain, or in the larynx) or can spread throughout the whole body. We call the former type ‘localised amyloidosis’ and the latter is known as ‘systemic amyloidosis’. A further distinction can be made between hereditary forms and non-hereditary (acquired) forms.
Daarnaast kan onderscheid gemaakt worden in erfelijke vormen en niet-erfelijke (zogeheten verworven) vormen.

Systemic amyloidosis
Depending on the protein that the amyloid fibrils are composed of, different types of amyloid can be distinguished. The four most common systemic types of amyloidosis are (three acquired and one hereditary) are AA-, AL- and two ATTR types:

  1. 1. AA amyloidosis can develop as a result of chronic inflammation, for example through chronic infection or through failure to (adequately) treat inflammatory conditions such as rheumatism. The inflammatory protein, called serum amyloid A (SAA), is the precursor protein from which amyloid fibrils are formed. Clinically, this form of amyloidosis is mainly characterized by protein loss in urine (proteinuria) and renal impairment, but sometimes also by enlargement of the spleen and/or liver, an enlarged thyroid, heart problems (cardiomyopathy), problems with the autonomic nervous system (autonomic neuropathy), or problems with the gastrointestinal tract.
  2. 2. AL-amyloidosis is a type of amyloidosis whereby the amyloid fibrils are formed from a kappa or lambda free light chain. These are segments of a defence protein. These free light chains are produced by malignant plasma cells. In this form of amyloidosis, amyloid accumulation can occur in almost any organ and tissue. It can manifest with cardiomyopathy, enlarged organs, proteinuria and renal impairment, severe diarrhea and neuropathy.
  3. 3. Acquired or wild-type ATTR amyloidosis occurs in older people (mainly men over 60 years). This type of ATTR amyloidosis is not hereditary and is characterised by slowly progressive cardiomyopathy, and often there is also carpal tunnel syndrome or spinal stenosis.
  4. 4. Hereditary ATTR amyloidosis is a type of amyloidosis whereby the amyloid fibrils are formed from the transthyretin protein. Transthyretin is a protein which is created in the liver and normally plays a role in transporting the thyroid hormone and vitamin A throughout the body. A mutation (error) in the gene (blueprint) for this protein can cause it to become incorrectly folded and form amyloid fibrils. The hereditary form of ATTR amyloidosis manifests itself mainly by neuropathy and cardiomyopathy, but amyloid deposits can also occur in the eyes, kidneys and meninges.

Below is an overview of the four most common types of systemic amyloidosis:

Amyloidosis type Protein Underlying disease/process Affected orgaans
AA Serum amyloid A Chronic inflammation Kidneys, autonomic nervous system, gastrointestinal tract
AL Kappa or Lambda free light chains Plasma cell cancer Heart, kidneys, liver, spleen, nervous system, gastrointestinal tract, joints, tongue, blood vessels
Acquired/wild type ATTR Transthyretin Age Heart, carpal tunnel syndrome, spinal stenosis, tendon ruptures
Hereditary ATTR Transthyretin Mutation Nervous system, heart, eyes, meninges

Besides the hereditary ATTR amyloidosis there are other, rarer types of systemic hereditary amyloidosis. Below is a short overview (not comprehensive).

Mutated protein Affected organs
Apolipoprotein A-I Nerves, kidneys, heart, liver, larynx, skin
Apolipoprotein A-II Kidneys, heart
Apolipoprotein C-II Kidneys
Apolipoprotein C-III Kidneys
Beta-2 microglobulin Gastrointestinal tract, autonomic nervous system, salivary gland, lacrimal glands (tear ducts)
Cystatin Brain
Fibrinogen A α-chain Kidneys
Gelsolin Nervous system, skin and eyes
Interleukin-31 receptor A Skin
Lysozyme Kidneys, liver, heart, spleen, gastrointestinal tract and salivary gland
Oncostatin M receptor Skin


Localised amyloidosis
In localised forms of amyloidosis, the deposition is limited to one place or organ in the body. Well-known forms include Alzheimer’s disease (amyloids in the brain) and type 2 diabetes (amyloids in the islets of Langerhans in the pancreas). But in clinical practice, we mainly mean localised deposits in the larynx, in the eyelids or conjunctiva, in the urinary tract and so on.

 

In short

There are various types of amyloidosis: with AA amyloidosis there is a build-up of an inflammatory protein, mostly in the kidneys. With AL amyloidosis there is a build-up of proteins made by malignant plasma cells. This protein can accumulate almost anywhere in the body. With ATTR amyloidosis the protein mostly accumulates in the nervous system and/or heart, and sometimes in the eyes or the brain. With the age-related form of ATTR amyloidosis the protein mostly builds up in the heart, but also in the carpal tunnel. Besides the hereditary form of ATTR amyloidosis there are also other, rare types of hereditary amyloidosis. Local forms of amyloidosis also exist. With these, the accumulation of proteins are restricted to one place or organ in the body.