(Note: Amyloid can be studied in the context of cell injury or immunological diseases.
For this reason, we have included the same material in both Cell Injury and
Amyloidosis is not a single disease entity but rather a diverse
group of disease processes characterized by extracellular tissue deposits, in one or many
organs, of protein materials which are generically termed amyloid. Amyloid is
distinguished grossly by a starch-like staining reaction with iodine (thus the term
amyloid), microscopically by its extracellular distribution and tinctorial and optical
properties when stained with Congo red, and by its protein fibril structure as shown by
electron microscopy and x-ray crystallography (see Table-1).
Amyloid deposition may be either a primary (idiopathic) process without known
antecedent or secondary to some other condition and may be localized to one specific site
or generalized throughout the body (systemic), usually with fatal consequences. Although
considerable overlap is seen in the organ distribution of various forms of amyloid,
primary amyloidosis tends to involve mesodermal tissues, most frequently affecting
peripheral nerves, skin, tongue, joints, heart, and liver while secondary amyloidosis
mainly affects parenchymatous organs, such as spleen, kidneys, liver, and adrenals.
Amyloid deposits typically contain three components. Amyloid protein fibrils account
for about 90% of the amyloid material and comprise one of several different types of
proteins with the capacity to fold into what are called "beta-pleated" sheet
fibrils, a unique protein configuration with binding sites for Congo red. In addition,
amyloid deposits are intimately associated with the amyloid P (pentagonal) component (AP),
a glycoprotein related to normal serum amyloid P (SAP), and are closely associated with
sulfated glycosaminoglycans (GAG), complex carbohydrates of connective tissue.
Systemic forms of amyloid are derived from circulating protein precursors by conversion
from soluble into insoluble (fibrillar) form. By convention, amyloid fibril types are
designated by two letters: A for amyloid followed by a letter for the chemical type. There
are two, chemically distinct, major types of amyloid protein fibrils designated AL and AA,
respectively, and several minor types unrelated to AL or AA. AL (amyloid light chain)
fibrils associated mainly with multiple myeloma are related to monoclonal immunoglobulin
light chains synthesized by abnormal plasma cells. AA fibrils associated mainly with
chronic inflammatory diseases are related to the nonimmunoglobulin amyloid associated (AA)
protein and its serum precursor (SAA), an acute phase reactant synthesized by liver cells.
The classification of amyloidosis is based upon the tissue
distribution of amyloid deposits (local or systemic amyloidosis), the absence or presence
of preexisting disease (primary or secondary amyloidosis), and the chemical type of
amyloid protein fibril (see Table-2).
Classifications of Amyloidosis
Amyloidosis Related to Monoclonal Ig Light Chains. AL amyloid is derived from
monoclonal Ig light chains, usually of lambda type, produced by abnormal clones of
Ig-secreting plasma cells (B cells) AL type of amyloidosis may be primary or may occur
secondary to multiple myeloma or some other monoclonal gammopathy (immunocyte dyscrasia).
It is the most common type of amyloidosis seen in the U.S. today.
AL type of amyloidosis occurs in about 5-10% of patients who have preexisting or
coexisting multiple myeloma. Multiple myeloma is seen mainly in patients over 40 years of
age (median age of 60 years) and, next to metastatic carcinoma, is the most common
malignant tumor of bone. It is a malignant tumor of plasma cells which arises in the bone
marrow, permeates the medullary cavity, erodes the bone cortex, and is characterized by
multiple osteolytic ("punched out") lesions of vertebrae, skull, ribs, pelvis,
and other bones and by narrow-banded electrophoretic peaks of monoclonal IgG (less
commonly IgA , rarely IgD or IgE) in the serum and free light chains of the same kappa or
lambda type in the urine (Bence-Jones proteinuria). An identical, patient-specific, free
monoclonal light chain protein is also usually present in myeloma serum but, being smaller
than albumin molecules, readily passes into the urine. Overall, about 70% of myeloma
patients have both serum monoclonal Ig and urinary light chains, and the remaining
patients have urinary light chains alone without serum monoclonal Ig.
The AL fibrils are derived from circulating light chains by proteolytic cleavage and
conversion to an insoluble form. The organ distribution of AL deposits is usually
generalized (systemic) and conforms to either the primary or secondary patterns previously
AL type of amyloidosis is also associated with some other rare monoclonal gammopathies
(plasma cell/B immunocyte dyscrasias), such as solitary myeloma (of bone or soft tissue),
Waldenstrom's macroglobulinemia, or heavy chain disease in which there are also sometimes
an increased production of free light chains that become deposited as amyloid.
Noteworthy, the majority of patients who develop AL type of amyloidosis apparently do
so in the absence of clinically overt myeloma or other predisposing disease, and such
cases are commonly referred to as primary or idiopathic amyloidosis. Nevertheless, in long
term follow up, a substantial proportion of these patients do manifest overt, monoclonal
Ig-producing plasma cell or lymphoid cell dyscrasias, such as myeloma, macroglobulinemia,
Amyloidosis Associated with Inflammatory or Infectious Diseases. The amyloid deposits
in this form of amyloidosis have a systemic distribution and contain AA
(amyloid-associated) fibrils which are related to the nonimmunoglobulin AA protein and its
serum protein precursor (SAA), an acute phase reactant synthesized by hepatic cells. Also
called reactive or secondary amyloidosis, this form of amyloidosis occurs mainly as a
complication of long standing inflammatory diseases, most frequently rheumatoid arthritis
(Å 5-10% of rheumatoid patients) and also dermatomyositis, scleroderma, regional
enteritis, and ulcerative colitis.
Prior to the antibiotic era, chronic tissue-destructive infectious diseases, such as
tuberculosis, chronic osteomyelitis, and bronchiectasis, were the most common antecedants
of secondary amyloidosis. Now, amyloidosis often develops as a complication of skin and
lung abscesses occurring in subcutaneous heroin abusers.
Reactive-type amyloidosis may also occur in association with cancer, such as Hodgkin's
disease and renal cell carcinoma.
Other Amyloids and Disease Associations.
- Amyloid associated with hemodialysis (AH). The systemic amyloid deposition of
beta2-microglobulin (beta2-m), a normal serum protein, occurs as a complication of
long-term dialysis in patients with chronic renal failure because this protein does not
pass through conventional dialysis membranes.
- Amyloid associated with familial Mediterranean fever. The systemic deposition of AA
fibrils occurs in familial Mediterranean fever, an autosomal recessive disorder seen in
individuals of Sephardic Jewish, Armenian, and Arabic descent.
- Amyloid associated with familial amyloid neuropathies (AF). Amyloid deposition of a
mutant form of transthyretin, a normal serum protein that transports thyroxin and retinol
(vitamin A), occurs in peripheral nerves in familial amyloid polyneuropathy, an autosomal
dominant disorder occurring in different parts of the world (Sweden, Portugal, Japan, and
- Localized deposits of amyloid.
Endocrine-related. Localized amyloid deposits are associated with hormones produced by
certain endocrine tumors and endocrine glands, such as medullary carcinoma of the thyroid
gland (procalcitonin), islet cell tumors of the pancreas, and the islets of Langerhans
(islet associated polypeptide, IAPP) in patients with type II diabetes mellitus.
Age-related. Amyloid deposits of transthyretin occur in the heart of elderly patients
with senile cardiac amyloidosis. Beta amyloid protein is deposited in the cerebral blood
vessels and plaques of patients with senile cerebral amyloidosis and Alzheimer's disease.
Pathogenesis of Amyloidosis
Amyloidosis is not one disease but a diverse group of diseases
of acquired or hereditary origin and characterized by the extracellular deposition of one
of several different types of protein fibrils with similar properties and called amyloid.
Despite their biochemical diversity, amyloid proteins share unique features: fibril
ultrastructure, cross beta x-ray diffraction pattern, and staining characteristics (with
The mechanisms of amyloid formation, although not well understood, can be summarized as
Figure 3 - Formation and deposition of AL and AA amyloid.
Systemic amyloidosis (AA) related to chronic inflammation tends
to involve parenchymatous organs, such as kidneys, spleen, liver, and adrenals, while
amyloidosis (AL) related to myeloma tends to affect mesodermal or other tissues, such as
heart, gastrointestinal tract, peripheral nerves, skin, and tongue. Nevertheless, the
overlap in organ involvement is such that the different forms of systemic amyloidosis are
not distinguishable on that basis alone.
Grossly, organs extensively infiltrated by amyloid are usually enlarged and have a
pale, waxy ("lardaceous") or varnished appearance and tough consistency. The
iodine test for amyloid is done by applying iodine solution to the washed cut surface of
the organ: amyloid typically stains mahogany-brown, and this color reaction changes to
blue ( a "starch-like" reaction) after the application of dilute sulfuric acid.
Amyloidosis of the left atrial
Cross section of amyloid
myocardium stained with Lugol's iodine solution.
The staining reactions of amyloid reflect its complex composition. Amyloid deposits in
tissues typically stain as follows: homogeneously pink (as do other eosinophilic hyaline
materials) with H&E; metachromatically (as do sulfated glycosaminoglycans) with
crystal violet and similar dyes; and positively (as do glycoproteins) with periodic
acid-Schiff. A diagnostic criterion, amyloid stains pink or orange with Congo red and,
further, with Congo red staining shows green birefringence by polarizing microscopy,
specific and unique properties shared by all amyloids due to their beta-pleated fibrillar
Amyloid deposition (green
birefringence) in tongue. Congo red. Polarizing microscopy.
Legend Structure of an amyloid fibril, depicting the beta-pleated sheet
structure and binding sites for the Congo red dye, which is used for diagnosis of
The distribution of amyloid deposits is extracellular, closely related to the
connective tissue framework of involved organs, and often interposed between parenchymal
cells and their blood supply.
Kidneys. Grossly, amyloid kidneys are usually enlarged, pale, and smooth surfaced and
have a tough consistency. On cortical transection, the glomeruli (barely visible as pink
dots in the normal kidney) may be seen as enlarged, waxy, gray dots.
Primary amyloidosis of
Histologically, the mesangium and capillary basement membrane of glomeruli are the most
frequent renal sites of amyloid deposition, followed by involvement of arteriolar and
arterial walls and peritubular interstitial tissues. As the extent of the amyloid
deposition increases, the glomerular capillary tufts become obliterated and replaced by
functionless spherical masses of amyloid material
Amyloidosis of kidney. Most of
this glomerulus is the site of homogeneous pink "soft fluffy" deposits of
amyloid located focally in the widened mesangial regions and in the thickened capillary
basement membranes. H&E.
Amyloidosis of kidney. This
photomicrograph taken with plane polarized light shows diffuse amyloid deposition ( green
birefringence) in the glomerular tufts throughout the mesangial regions. Congo red.
Amyloidosis of kidney. Congo
red - polarizing microscopy.
Amyloidosis of kidney. In this
photomicrograph, the glomerulus shows diffuse amyloid deposition in the widened mesangial,
or intercapillary, regions and in the thickened capillary basement membranes. Glomerular
capillary lumens are narrowed by concentric and eccentric deposits of amyloid material.
Amyloidosis of kidney. As the
amyloid deposition continues, the glomerular tufts become obliterated and replaced by
spherical masses of amyloid material. H&E.
By electron microscopy, the first deposition of amyloid fibrils in the kidney is seen
on the endothelial side of the glomerular capillary basement membrane (subendothelial
Liver. The amyloid liver is usually grossly enlarged, pale, smooth surfaced, and firm
and, when sectioned, has sharp rigid edges.
Microscopically, amyloid is initially deposited in the spaces (of Disse) between the
hepatocytes and vascular sinusoids. As more amyloid accumulates, it compresses the hepatic
cords and sinusoids. The hepatic cords undergo nutritional and pressure atrophy and become
displaced or replaced by bands and nodules of amyloid.
Amyloidosis of liver. The
hepatic cords are diminished in size and are compressed, fragmented, and replaced by
amyloid deposition (pink). H&E.
Amyloidosis of liver. The
hepatic parenchyma is infiltrated and replaced by nodular accumulations of amyloid (pink)
in which remnants of hepatic cords are seen. H&E.
Spleen. Amyloidosis of the spleen has two different anatomical patterns. Most commonly,
the amyloid deposition is limited to the splenic follicles, resulting in the gross
appearance of a moderately enlarged spleen dotted with gray nodules (so called
"sago" spleen). Alternatively, the amyloid deposits may spare the follicles and
mainly infiltrate the red pulp sinuses, producing a large, firm spleen mottled with waxy
discolorations ("lardaceous" spleen).
Amyloidosis of the spleen
Heart. Amyloidosis of the heart may accompany systemic amyloid deposition or localized
organ involvement (amyloidosis of aging). Histologically, the deposits are located between
the myocardial fibers or in the walls of the coronary arteries
Amyloidosis of heart. Amyloid
infiltrates the muscular wall of a coronary artery. Congo red.
Other Organs. Amyloid deposition may involve the adrenals, thyroid, skin, tongue, and
other portions of the alimentary tract. In the adrenals, extracellular amyloid deposits
encompass, compress, and replace the cortical cells. A comparable pattern of amyloid
deposition is seen in the thyroid. The alimentary tract may be involved at any level, from
the tongue to the rectum (submucosa).
Amyloidosis of adrenal gland.
Amyloid deposits surround, compress, and replace some cortical cells and infiltrate the
wall of a small blood vessel (at one corner of the photomicrograph). Congo red.
Amyloidosis of tongue
(interstitial tissue). Amyloid infiltrates the capillary walls and narrows the lumens of
some of them. H&E.
The clinical manifestations of amyloidosis vary from minimal to life threatening,
depending upon the organs involved (see Table-3).
The clinical standard for the diagnosis of amyloidosis is a tissue
biopsy. Common biopsy sites include: gingiva, rectum (submucosa), subcutaneous fat-pad
tissue, skin, and specific organs, such as kidney and liver.