Amyloidosis

Author: Leandro Alegsa Creation date: November 13, 2022

Amyloidosis is a rare and serious disease that could be fatal that is caused by accumulation of proteins in the form of abnormal, insoluble fibres, known as amyloid fibrils, within the tissues of the body.

Amyloid deposits can be confined to only one part of the body or a single organ system in 'local amyloidosis' or they can be widely distributed in organs and tissues throughout the body in 'systemic amyloidosis'. The symptoms of amyloidosis are accordingly highly variable and confirmation of the presence of amyloid in the tissues can be challenging, so that diagnosis is often delayed.

There are many different types of amyloidosis, each caused by formation of amyloid fibrils from different soluble precursor proteins in different patients. About 30 different proteins are known to form amyloid fibrils in humans and amyloidosis is named and classified according to the identity of the respective fibril protein.

Though this disease being rare, many famous people have died from this disease such as: Martin McGuinness, David Lange, Robert Jordan and Robert P. Casey.

Amyloid in the connective tissue layer (lamina propria) of the duodenum. Staining with Congo red. The amyloid deposits appear as bright red, structureless material in the connective tissue and around the blood vessels.

Amyloidosis - Lymph nodes in polarized light

Cause and origin

Amyloidosis is caused by a disorder in the folding of a normally soluble protein. Several different diseases can trigger the disease through overproduction, lack of/reduced degradation or impaired excretion of certain proteins. These proteins are usually present in the blood plasma in a dissolved form. However, if their concentration increases, they also reach the surrounding tissue, where enzymes attack them. The aggregation of the resulting amino acid chains in the area of the β-sheet structures results in the formation of insoluble complexes in the form of microscopic fibres (fibrils).

Since the fibrils are resistant to the defense mechanisms (phagocytosis and proteolysis), they can no longer be removed. According to recent findings, however, amyloid deposits can at least be reduced by removing the precursor proteins.

The amyloid deposits destroy the architecture of the organs and thus lead to functional disorders. There is evidence that the deposits also exert a direct toxic effect on cells.

Diagnosis

The symptoms of amyloidosis are often non-specific, especially in the early stages of the disease. For this reason, the diagnosis is often only made in an advanced stage of the disease. Amyloidosis should be considered in the presence of otherwise unexplained proteinuria, as well as in patients with cardiomyopathy, neuropathy, liver enlargement, or multiple myeloma.

Since, if scintigraphic evidence of cardiac ATTR amyloidosis (transthyretin amyloidosis) has not been obtained when a monoclonal gammopathy has been excluded, the exact composition of the amyloid must be known for treatment, a biopsy (tissue sample) for histological amyloid detection with subtyping is usually required. This can be obtained from an affected organ (kidney, heart, stomach). A recent discovery is that generalized amyloidoses can also be classified with biopsies from subcutaneous adipose tissue, a less stressful procedure for the patient. Other less burdensome sampling sites include the minor salivary glands, gums, rectum, or skin. The histologically prepared specimens are stained with Congo red and examined by immunohistochemistry. Amyloid binds the dye Congo red and then becomes visible with a greenish glow under polarized light. The electron microscope shows that the amyloid deposits consist of fibrils, irregularly arranged, thread-like structures of different lengths with a diameter between 8 and 15 nm.

If amyloidosis has been confirmed by tissue sampling, a search for light chain disease should be performed by bone marrow aspiration, blood and urine tests. In the bone marrow, a monoclonal proliferation of plasma cells, i.e. plasma cells that produce either only kappa or only lambda chains, is indicative of AL amyloidosis. The light chains can also be detected by immunoelectrophoresis in serum or urine.

The extent of amyloid deposition can be visualized by scintigraphy with radiolabeled substances that bind to amyloid. Binding to amyloid are technetium Tc 99m-pyrophosphate, technetium-labeled aprotinin, and $^{123}$ I-labeled serum amyloid P component. The extent of cardiac involvement can be visualized by echocardiography or magnetic resonance imaging.

In many cases, the diagnosis is made only after death by autopsy. An oversized tongue and characteristic coarse subcutaneous swellings point the pathologist to the correct diagnosis. Because of the bacon-like appearance of the cut surfaces of affected organs, they are also called bacon liver, bacon spleen, or bacon kidney. Just like Virchow, he can sprinkle the cut surface of any organ (so also tongue, heart) with Lugol's solution, which, with amyloid, gives a characteristic brown colour.