Clinical picture

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 colored with a Congo Red dye, the shapeless material is shown to turn red in color 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 (of which three are acquired and one is hereditary) are AA-, AL- and two ATTR types:

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. AL-amyloidosis is a type of amyloidosis where 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. Acquired or wild-type ATTR amyloidosis occurs in older people (mainly men over 60). 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. 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 (the membranes that envelop the central nervous system).

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

In addition to the hereditary ATTR amyloidosis there are other, rarer types of systemic hereditary amyloidosis. Below is a brief overview (not comprehensive).

Localised amyloidosis
In local forms of amyloidosis, production and deposition is limited to one place or organ in the body. Well-known forms are Alzheimer’s disease (amyloid in the brain) and diabetes mellitus type II (amyloid in the islets of Langerhans in the pancreas). But in clinical practice we are mainly referring to localised deposits in the larynx, in the eyelids or conjunctiva, in the urinary tract, in the skin or in other places seen in localalised AL amyloidosis.
Subcutaneous administration of medicines sometimes leads to localised aggregation of the drug resulting in amyloid formation. The most striking example is seen in insulin-dependent diabetes mellitus. Painful swellings then occur at administration sites, such as the abdomen and upper legs. Other drugs are enfurvitide (HIV), interleukin-1 receptor antagonist (inflammatory diseases) and glucagon-like peptide 1 analogues (diabetes mellitus type 2 and obesity).