Amyloidosis is a condition in
which there is a deposition, in many tissues, of an abnormal extracellular
fibrillar protein, termed amyloid.
Amyloid is derived from many different precursor peptides, with the precursors
themselves often being fragments derived from larger proteins; it is deposited
as a meshwork of rigid, straight fibrils that are 10-15 nm in diameter, being
composed of the precursor peptides lined up in an antiparallel b-pleated sheet
It is therefore the physical arrangement of the constituent peptides that makes
a protein an amyloid, rather than any specific peptide sequence.
Amyloid is detected
histologically as a bright-pink hyaline material.
It also takes up certain special stains, with the most widely known being Congo
red, with electron microscopy showing it to have a fibrillar ultrastructure.
Despite uncertainty about why
amyloid is formed, there are well characterized associations between particular
diseases and the deposition of amyloid.
In each case, there is an accumulation of a precursor peptide which is processed
into an amyloid protein.
In some of these diseases
there is an identifiable reason for the accumulation of the precursor peptide,
and the amyloid is termed secondary amyloid.
In other cases, the cause of the accumulation of a precursor peptide is not
known, and the amyloid is termed primary amyloid.
In addition, there are several inherited disorders, the heredofamilial
Amyloid is composed of
filaments of protein deposited extracellularly.
Amyloid is deposited outside
cells, and can be classified into localized or systemic patterns
Amyloid is deposited in the
extracellular compartment of tissues, and in H&E preparation it is seen as a
uniformly eosinophilic (pink-staining) material.
It can be highlighted in histological sections by the use of special stains such
as Sirius red and Congo red.
Congo red staining is commonly used for diagnostic purposes, with amyloid
staining orange, and exhibiting a green coloration when viewed with polarized
Amyloidosis may involve many
tissues in the body as it is particularly deposited in the blood vessel walls
and basement membranes.
The progressive accumulation of amyloid leads to cellular dysfunction, either by
preventing the normal processes of diffusion through extracellular tissues, or
by the physical compression of functioning parenchymal cells.
In some diseases, amyloidosis is a systemic process affecting many organs
simultaneously (systemic amyloid); there is also a group of conditions in which
amyloid only affects one organ or tissue (localized amyloid).
Amino-acid sequencing of
amyloid proteins in different disease states has enabled a classification of
amyloid to be made on biochemical grounds.
The commonest example of
amyloid deposition is in the nervous system, in both Alzheimer's disease and
The amyloid is derived from a normal, neuronal membrane protein termed Alzheimer
precursor protein (APP), being formed from a peptide fragment termed b-protein
or A4 protein.
Amyloid that is associated
with an abnormal proliferation of plasma cells is made up of immunoglobulin
light chains, with such amyloid deposition occurring in diseases such as myeloma
Reactive amyloid may be associated with long-standing chronic inflammatory
As in any inflammatory disorder, the associated systemic acute-phase response
causes excessive production of serum amyloid A protein (a normal, acute phase
protein) by the liver. With time, and for uncertain reasons, some of this
protein is deposited as amyloid.
Diseases that lead to this type of secondary amyloid include tuberculosis,
rheumatoid arthritis, bronchiectasis and chronic osteomyelitis.
Tumours of peptide-secreting
endocrine cells may form amyloid from the hormone peptide, e.g. in the
calcitonin-derived amyloid in medullary carcinoma of the thyroid.
In Type II diabetes, the excessive secretion of amylin by the b-cells of the
pancreas is associated with its deposition as islet amyloid.
Uncommon familial types of amyloid are believed to be caused by gene
polymorphisms in normal proteins.
The amino-acid substitutions are believed to make the proteins, or their peptide
fragments, susceptible to amyloid formation.
Amyloid is mainly deposited in
the kidney, heart, liver, spleen and nerves
The kidneys are the organs
most commonly functionally impaired by systemic amyloidosis, usually presenting
with proteinuria or the nephrotic syndrome.
Deposition of amyloid in the
spleen can occur in either a diffuse pattern or a nodular pattern.
In the liver, amyloid is
deposited in the space between the sinusoidal lining cells and the hepatocytes.
Clinically, hepatic amyloidosis may be a cause of hepatomegaly.
However, there is rarely significant clinical evidence of impaired liver
Amyloid involvement of the
heart may be a manifestation of senile cardiac amyloid, which is derived from
The most severe form of cardiac amyloid is seen in systemic amyloidosis, causing
Extensive deposition of
pink-staining amyloid in glomeruli and blood vessels leads to failing renal