Clinical picture

Amyloid

The human body is made up of over 30,000 different proteins. Each protein has a specific three-dimensional shape (spatial folding) to be able to perform a specific function. If the shape of a protein changes, it can be dangerous. For example, that altered protein can attach to a copy of itself. This process of aggregation can continue to be repeated, resulting in long fibers, called amyloid fibrils.

These amyloid fibrils can deposit as amyloid in various places in the body. When viewed in a biopsy under an ordinary microscope, this amyloid appears to be a shapeless material, but at higher magnification under the electron microscope (10,000 x), the amyloid fibrils are easily recognizable. When the biopsy is stained with Congo Red, the amyloid turns red under the usual microscope. A distinctive feature of amyloid is the specific birefringence – this red material glows green when viewed in polarized light.

Different types of amyloid can be distinguished depending on the protein from which the amyloid fibrils are made.

Amyloidosis

Amyloidosis is the name of a group of diseases all characterized by deposition of amyloid fibrils. In the systemic forms of amyloidosis, deposition of amyloid fibrils between the cells in the tissues leads to swelling and impaired organ function.

Types of amyloidosis with clinical presentations

As already mentioned, different proteins can accumulate in tissues as amyloid. The amyloid is locally produced and deposited there (such as in the pancreas, brains or the larynx) or distributed and deposited throughout the body. The former we call local amyloidosis, and the latter is known as systemic amyloidosis. Localized forms of amyloid are common (such as in the brain in Alzheimer’s disease and in the pancreas in age-related diabetes) and – despite all being called amyloid – they are therefore different from each other and also from the systemic forms of amyloidosis.

In addition, a distinction can be made between hereditary and non-hereditary, acquired forms.

Systemic amyloidosis
Different types of amyloidosis can be distinguished depending on the protein from which the amyloid fibrils are made. The four main systemic types of amyloid that are identified (three acquired and one hereditary) are, respectively, AA, AL and two ATTR types:

1. AA amyloidosis can occur as a result of chronic inflammation, for example in chronic infections or not (sufficiently) treated chronic inflammatory diseases such as rheumatoid arthritis. The inflammatory protein serum amyloid A (SAA) is the precursor protein from which amyloid fibrils arise. Clinically, this form of amyloidosis mainly manifests itself in kidney problems such as proteinuria and renal impairment, but can sometimes also be due to an enlarged spleen and/or liver, an enlarged thyroid gland, cardiomyopathy, autonomic neuropathy or problems of the gastrointestinal system.
2. AL amyloidosis is a type of amyloidosis in which the amyloid fibrils are formed from a kappa or lambda free light chain. These immunoglobulin free light chains are produced by plasma cell dyscrasia, which are clonal plasma cells usually located in the bone marrow. In this type of amyloidosis, amyloid can accumulate in almost any organ and tissue. It can be associated with cardiomyopathy, enlarged organs, proteinuria and renal dysfunction, severe diarrhea and neuropathy.
3. Hereditary amyloidosis is an ATTR-type amyloidosis in which amyloid fibrils are formed from the protein transthyretin. Transthyretin is a protein produced in the liver that normally plays a role in transporting thyroid hormone and vitamin A throughout the body. A mutation in the gene for this protein can cause the protein to fold incorrectly and form amyloid fibrils. The hereditary form of ATTR amyloidosis manifests itself mainly through neuropathy and cardiomyopathy, but amyloid deposits can also occur in the eyes, kidneys and meninges.
4. Acquired or wild-type ATTR amyloidosis occurs in the elderly, especially in men over 60 years of age. This type of ATTR amyloidosis is not hereditary and is clinically characterized by slowly progressive cardiomyopathy and often also has carpal tunnel syndrome or spinal stenosis.

The following 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).